Cancer Medicine - 2023 - Ma - Novel strategies to reverse chemoresistance in colorectal cancer.pdf

Cancer Medicine. 2023;12:11073–11096. | 11073
wileyonlinelibrary.com/journal/cam4
Received: 25 September 2022
| Revised: 2 December 2022
| Accepted: 21 December 2022
DOI: 10.1002/cam4.5594
R E V I E W
Novel strategies to reverse chemoresistance in colorectal
cancer
Shu-
Chang Ma1,2
| Jia-
Qi Zhang1
| Tian-
Hua Yan2
| Ming-
Xing Miao2
|
Ye-
Min Cao1
| Yong-
Bing Cao1
| Li-
Chao Zhang3
| Ling Li1
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
1
Institute of Vascular Disease, Shanghai
TCM-
Integrated Hospital, Shanghai
University of Traditional Chinese
Medicine, Shanghai, China
2
Department of Physiology and
Pharmacology, China Pharmaceutic
University, Nanjing, China
3
Department of Pharmacy, Shanghai
Municipal Hospital of Traditional
Chinese Medicine, Shanghai, China
Correspondence
Ling Li and Yong-
Bing Cao, Institute
of Vascular Disease, Shanghai
TCM- Integrated Hospital, Shanghai
University of Traditional Chinese
Medicine, Shanghai, China.
Email: lingli_z163@163.com and
ybcao@vip.sina.com
Li-
Chao Zhang, Department of
Pharmacy, Shanghai Municipal
Hospital of Traditional Chinese
Medicine, Shanghai, China.
Email: changhaiskin@163.com
Funding information
Future plan for Traditional Chinese
Medicine development of Science and
Technology of Shanghai Municipal
Hospital of Traditional Chinese
Medicine, Grant/Award Number: WL-
HBBD-
2021001K; Innovative projects
of Shanghai University of Traditional
Chinese Medicine, Grant/Award
Number: Y2021030; National Natural
Science Foundation of China, Grant/
Award Number: 81973551; Science and
Technology Commission of Shanghai
Municipality, Grant/Award Number:
21ZR1460400 and 19ZR1451800
Abstract
Colorectal cancer (CRC) is a common gastrointestinal malignancy with high
morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has ex-
erted well antitumor effect and greatly improved the survival of CRC patients.
Nevertheless, chemoresistance is one of the major problems during chemother-
apy for CRC and significantly limits the efficacy of the treatment and influences
the prognosis of patients. To overcome chemoresistance in CRC, many strategies
are being investigated. Here, we review the common and novel measures to com-
bat the resistance, including drug repurposing (nonsteroidal anti-
inflammatory
drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, me-
latonin, and S-
adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/
Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs),
protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase
inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alka-
loids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes,
and hydrogels), and combination therapy. These common or novel strategies for
the reversal of chemoresistance promise to improve the treatment of CRC.
K E Y W O R D S
chemoresistance, colorectal cancer, novel strategies, reversal of resistance

11074 | MA et al.
1 | INTRODUCTION
Colorectal cancer (CRC) is the third most prevalent cancer
around the world, with increasing morbidity and mortal-
ity every year.1
As reported by the International Agency
for Research on Cancer (IARC) in 2020, there were over
193,000 new cases of CRC and more than 953,000 deaths
worldwide, and CRC accounted for 10.0% of overall can-
cer incidence.2
Currently, the treatment of CRC mainly
consists of surgery, targeted therapy, radiotherapy, and
chemotherapy.3
Generally, chemotherapy, as the most
classical and most common-
used therapy in CRC, can be
applied at different stages of the treatment and is com-
monly provided after surgery as adjuvant therapy for
patients with advanced CRC.4
Treatment with chemo-
therapeutic agents like 5-
fluorouracil (5-
FU), oxaliplatin
(L-
OHP), vincristine (VCR), doxorubicin (DOX), cisplatin
(CDDP)and irinotecan (CPT-
11) has improved the over-
all survival of patients with advanced CRC in the past
decades.5
However, even though chemotherapy is well
demonstrated to reduce tumor burden and prolong sur-
vival, it remains a palliative treatment since most CRC pa-
tients eventually exhibit drug resistance.6
More than 90%
of patients with metastatic cancer may suffer chemother-
apy failure due to drug resistance.7
Chemotherapy resistance, according to drug respon-
siveness, can be classified into two types: intrinsic resis-
tance and acquired resistance. It can also be divided into
primary drug resistance and multidrug resistance (MDR)
in terms of the drug resistance spectrum. Multidrug re-
sistance is seem to be the major determinant of cancer
chemotherapy failure. Nowadays, drug resistance not
only undermines the therapeutic effects of anticancer
chemical drugs but also causes CRC refractory. Therefore,
drug resistance has become a thorny issue and urgently
needed to be solved. Various strategies have been applied
or investigated to the drug resistance reversal in CRC. The
most common treatment among them is the combined
use of chemical drugs and marketed medicines with al-
ready known effects such as drug repurposing (nonsteroi-
dal anti-
inflammatory drugs, metformin, dichloroacetate,
enalapril, ivermectin, bazedoxifene, melatonin, and S-
adenosylmethionine) and natural herbal compounds
(polyphenols, terpenoids, quinones, alkaloids, and ste-
rols). Gene therapy, as an emerging technology, has also
been studied in chemoresistance reversal, including
ribozymes, RNA interference, CRISPR/Cas9, epigene-
tic therapy, antisense oligonucleotides, and noncoding
RNAs, which opens the door to a new genetical world in
this field. Protein inhibitors are countermeasures at pro-
tein levels, which exserts their reversal effects directly by
reacting with specific proteins such as EGFR inhibitor,
S1PR2 inhibitor, and DNA methyltransferase inhibitor. It
has been known that conventional drug delivery systems
have many shortcomings comprising low bioavailability
and cytotoxicity, which contribute to drug resistance. New
drug delivery systems, including nanocarriers, liposomes,
exosomes, and hydrogels, can overcome the drawbacks of
traditional delivery systems and transport the therapeutic
molecules directly to the specific tumor site, which plays
an important role in reversing chemoresistance (Figure 1).
In this review, the aforementioned novel strategies to
overcome chemoresistance in CRC will be clarified, which
will provide new ideas for the treatment of drug resistance
in CRC.
2 | DRUG REPURPOSING
Recently, increased classical drugs, which were widely
used in the clinic for different diseases, have been found
to possess the ability to reverse chemoresistance in CRC,
such as some nonsteroidal anti-
inflammatory drugs (as-
pirin, ibuprofen, and NS-
398), metformin, dichloroac-
etate, enalapril, ivermectin, bazedoxifene, melatonin, and
S-
adenosylmethionine. Due to their low expenses, low
toxicity, and high safety, drug repurposing is a promising
strategy for combating chemoresistance in CRC (Table 1).
2.1 | Nonsteroidal anti-
inflammatory
drugs
Nonsteroidal anti-
inflammatory drugs (NSAIDs), as a
kind of widely used medicine worldwide, have potent
anti-
inflammatory, analgesic, and antipyretic activity. The
main mechanism of the action is the inhibition of cyclo-
oxygenase(COX),whichisresponsibleforthebiosynthesis
of prostaglandins and thromboxane.8
Aspirin, ibuprofen,
and NS-
398 are found to own the potential for overcom-
ing drug resistance in CRC. It was reported that the com-
bined use of aspirin (a nonselective COX inhibitor) and
5-
FU could reverse drug resistance and potentiate the an-
tineoplasm effect of 5-
FU by abolishing 5-
FU-
induced nu-
clear factor-
kappaB (NF-
κB) activation in 5-
FU-
resistant
SW480, SW620 (SW480/5-
FU and SW620/5-
FU) cell lines
and xenograft mice of CRC.9
Wawro et al. found that both
aspirin and ibuprofen inhibit the VCR-
dependent secre-
tion of tumor growth factor-
βs (TGF-
βs) and interleukin-
6
(IL-
6) from cancer-
associated fibroblasts (CAFs) in CAF-
like cells, suggesting that aspirin and ibuprofen may re-
verse VCR-
resistance in CRC to some extent.10
NS-
398,
a selective COX-
2 inhibitor, could significantly inhibit
the expression of multidrug resistance protein 1 (MDR1)
mRNA, P-
glycoprotein (P-
gp/ABCB1), phosphorylated-
c-
Jun levels and increase the intracellular concentration of
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VCR in VCR-
resistant HCT-
8/VCR cell line, promoting
the sensitivity to VCR in resistant cells.11
2.2 | Metformin
Metformin (MET), which suppresses hepatic glucose pro-
duction, is the first-
line therapy for type 2 diabetes mel-
litus.12
MET has been recently demonstrated to reverse
the resistance after chemotherapy and possess a potential
therapeutic effect on colorectal cancer.13
MET enhanced
the chemosensitivity of SW480 and SW620 cell lines to
CDDP, inhibited cell proliferation, induced cell apoptosis,
and increased the production of reactive oxygen species
(ROS) through ROS-
mediated phosphatidylinositol 3 kinase
(PI3K)/protein kinase B (AKT) signaling pathway.14
MET
was also found to sensitize HCT1116 and SW480 cell lines to
CPT-
11-
induced cytotoxicity and block the cell cycle in G1
and S phases, which indicates an innovative strategy in the
treatment of CPT-
11-
resistant CRC.15
Moreover, MET could
inhibit cell proliferation, migration, and cancer stem cell
(CSC) population in 5-
FU-
resistant SNU-
C5 CRC cell line,
which was mediated by the activation of AMP-
activated
protein kinase (AMPK) and suppression of DNA replica-
tion, and NF-
κB pathway.16
MET was also found to resen-
sitize HCT116 cells to 5-
FU resistance, which was realized
by attenuating stemness and epithelial–
mesenchymal trans-
formation (EMT) via inhibiting the Wnt3a/β-
catenin path-
way.17
Furthermore, it was found that the combined use of
MET and propranolol (mainly used for hypertension treat-
ment) could block 5-
FU chemoresistance in HCT116 cells to
some extent, which could be applied as a putative adjuvant
treatment for CRC and chemo-
resistant CRC.18
2.3 | Dichloroacetate
Dichloroacetate (DCA), originally utilized to treat metabolic
diseases as a metabolic regulator, was discovered to overcome
chemoresistance in CRC through p53/miR-
149-
3p/pyruvate
dehydrogenase kinase 2 (PDK2) glucose metabolic path-
way.19
Liang et al. found that dichloroacetate could increase
L-
OHP chemosensitivity in CRC by upregulating calcium-
binding protein 39 expression and then activating the AMPK-
mammalian target of the rapamycin (mTOR) pathway.20
2.4 | Enalapril
Enalapril, an antihypertensive and antiheart failure drug,
was found to inhibit cell migration and invasion and over-
come chemoresistance in the 5-
FU-
resistant CRC cells at
FIGURE 1 Novel strategies to
reverse chemoresistance in colorectal
cancer. ABCB1, ATP-
binding cassette
subfamily B member 1; ASOs, antisense
oligonucleotides; BCRP, breast cancer
resistance protein; CRC, colorectal
cancer; CRISPR/Cas9, clustered
regularly interspaced short palindromic
repeat/cas9; DOX, doxorubicin; EGFR,
epidermal growth factor receptor; 5-
FU,
5-
fluorouracil; L-
OHP, oxaliplatin; LP
SN, lactobacillus plantarum supernatant;
ncRNAs, noncoding RNAs; NSAIDs,
nonsteroidal anti-
inflammatory drugs;
PKC, protein kinase C; RNAi, RNA
interference; S1PRs, sphingosine
1-
phosphate receptors.
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11076 | MA et al.
clinically acceptable dosages without extra toxicity. And
the effect may be primarily achieved by the suppression of
cell proliferation, angiogenesis, and NF-
κB/signal trans-
ducer and activator of transcription 3 (STAT3)-
regulated
proteins, including Cyclin D1, c-
Myc, matrix metallopro-
teinase-
2 (MMP-
2), matrix metalloproteinase-
9 (MMP-
9),
vascular endothelial growth factor (VEGF), Bcl-
2, and
X-
linked inhibitor of apoptosis protein (XIAP).21
TABLE 1 Drug repurposing in the reversal of chemoresistance in CRC
Drug Common uses Chemical drugs Cell model
Aspirin Nonsteroidal anti-
inflammatory
drugs: antipyretic, analgesic, and
anti-
inflammatory
5-
FU SW480/5-
FU, SW620/5-
FU cell lines
VCR CAF-
like cells obtained by TGF-
β2
stimulation of HMEC-
1
Ibuprofen VCR CAF-
like cells obtained by TGF-
β2
stimulation of HMEC-
1
NS-
398 VCR HCT-
8/VCR cell line
Metformin The first-
line treatment for type 2
diabetes mellitus, suppresses
hepatic glucose production
CDDP SW480 and SW620 cell lines
CPT-
11 HCT1116 and SW480 cell lines
5-
FU SNU-
C5/5-
FU cell line
5-
FU HCT116 cell line
Combined use of metformin
and propranolol
Propranolol (mainly used for
hypertension)
5-
FU HCT116/ 5-
FU cell line
Dichloroacetate Metabolic diseases 5-
FU HCT-
8/5-
FU cell line
L-
OHP HCT-
116/L-
OHP cell line
Enalapril Antihypertensive and anti-
heart failure 5-
FU SW620 and HCT116 cell line
Ivermectin Antiparasitic drug VCR HCT-
8/VCR cell line
Bazedoxifene Third-
generation selective estrogen
receptor modulator and novel IL-
6/
GP130 target inhibitor
5-
FU HT29, SW480, LOVO and HCT116 cell
lines
Melatonin Insomnia 5-
FU SW480/5-
FU and HCT116/5-
FU cell
lines
S-
Adenosylmethionine Nutritional supplement 5-
FU HCT 116p53+/+
and LoVo cell lines
Vitamin C Dietary supplements L-
OHP C2BBe1 and WiDr cell lines
Vitamin D 5-
FU CBS, Moser, Caco-
2 and HCT116 cell
lines
1α,25-
dihydroxyvitamin D3 5-
FU/CPT-
11 5-
FU/CPT-
11-
resistant MIP101 human
CRC cell line
Note: “⬆” means upregulation or activation; “⬇” means downregulation or inhibition.
Abbreviations: AKT, protein kinase B; AMPK, AMP-
activated protein kinase; AOM, azoxymethane; CAFs, cancer-
associated fibroblast; CaSR, calcium-
sensing
receptor; CDDP, cisplatin; CPT-
11, irinotecan; CPT-
11, irinotecan; DSS, dextran sodium sulfate; EGFR, epidermal growth factor receptor; EMT, epithelial
mesenchymal transformation; ERK, extracellular regulated protein kinases; 5-
FU, 5-
fluorouracil; GP130, glycoprotein 130; HMEC-
1, human microvascular
endothelial cells; IL-
6, interleukin-
6; L-
OHP, oxaliplatin; PDK2, MDR1, multidrug resistance protein 1; MMP-
2, matrix metalloproteinase-
2; MMP-
9, matrix
metalloproteinase-
9; mTOR, mammalian target of rapamycin; NF-
κB, nuclear factor-
kappa B; p-
c-
Jun, phospho-
c-
Jun; P-
gp, P-
glycoprotein; PI3K,
phosphatidylinositol 3 kinase; pyruvate dehydrogenase kinase 2; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3;
TGF-
β, tumor growth factor-
β; TS, thymidylate synthase; TYMS, thymidylate synthase; VEGF, vascular endothelial growth factor; VCR, vincristine; VDR
(vitamin D receptor); XIAP, X-
linked inhibitor of apoptosis protein.
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2.5 | Ivermectin
Ivermectin, an antiparasitic drug, could reverse the
chemoresistance in VCR-
resistant HCT-
8/VCR cells by
diminishing P-
gp expression via reducing the activation
of epidermal growth factor receptor (EGFR) and its down-
stream extracellular signal-
regulated kinases (ERK)/Akt/
NF-
κB signaling pathway.22
Animal species Animal model Resistant mechanisms Reference
BALB/c nude mice (female,
6–
8weeks)
Xenograft ⬇5-
FU-
induced NF-
κB activation 9
— — ⬇TGF-
βs and IL-
6 10
— — ⬇TGF-
βs and IL-
6 10
— — ⬇MDR1, P-
gp and p-
c-
Jun 11
— — ⬇ROS production, PI3K/Akt signaling
pathway
14
— — Block cell cycle in G1 and S phases 15
— — ⬇DNA replication and NF-
κB ⬆AMPK 16
— — ⬇stemness, EMT and Wnt3a/β‑catenin
pathway
17
BALB/c mice and athymic nude
mice (female, 8weeks)
Xenograft (HCT116 cells,
HCT116/5-
FU cells);
AOM/DSS model
⬇EMT 18
Nude mice (male, 6weeks) Xenograft (HCT-
8/5-
FU cells) ⬇p53/miR-
149-
3p/PDK2 glucose metabolic
pathway
19
BALB/c nude mice (male, 8weeks) Xenograft (HCT-
116/L-
OHP
cells, HCT-
116/miR-
107-
overexpressing cells)
⬆AMPK-
mTOR pathway 20
6–
8weeks)
Xenograft (SW620 cells) ⬇NF-
κB/STAT3-
regulated proteins (c-
Myc,
Cyclin D1, MMP-
9, MMP-
2, VEGF, Bcl-
2,
and XIAP)
21
4-
week-
old)
Xenograft (VCR-
sensitive or
resistant HCT-
8 cells)
⬇P-
gp, EGFR, ERK/Akt/NF-
κB signal 22
Athymic nude mice (female,
4–
6weeks)
Xenograft (HT29 cells) ⬇IL-
6/GP130 signaling pathway and
phosphorylation of AKT, ERK and STAT3
23
— — ⬆miR-
215-
5p and ⬇TYMS 24
— — ⬇P-
gp and activation of NF-
κB 25
— — ⬇BAX/BCL2 ratio 26
— — ⬇TS and surviving in aCaSR-
dependent
manner
27
— — ⬆vitamin D receptor (VDR) 28
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2.6 | Bazedoxifene
Bazedoxifene, the third-
generation of selective estrogen
receptor modulator, also a novel IL-
6/glycoprotein 130
(GP130) target inhibitor, improved the anticancer effect of
5-
FU in CRC via impeding the IL-
6/GP130 signaling path-
way and the phosphorylation of the downstream effectors
such as AKT, ERK, and STAT3, suggesting that the block
of IL-
6/GP130 might reverse chemoresistance in CRC.23
2.7 | Melatonin
Melatonin, used for insomnia in usual, was found to re-
duce cell viability, promote apoptosis, and reverse 5-
FU
resistance in SW480/5-
FU and HCT116/5-
FU cells by
downregulating thymidylate synthase (TYMS) via upreg-
ulating miR-
215-
5p.24
2.8 | S-
adenosylmethionine
S-
adenosylmethionine (AdoMet), a natural chemical
and generally utilized as a dietary supplement, was
capable of conquering 5-
FU chemoresistance in CRC
cells through reverting the P-
gp upregulation induced
by 5-
FU and suppressing the activation of the key
anti-
apoptotic factor NF-
κB implicated in P-
gp-
related
chemoresistance.25
2.9 | Vitamins
Vitamins are common dietary supplement used in daily
life and their potential effects on chemoresistance rever-
sal in CRC have been found, including vitamin C and
vitamin D. Vitamin C, also called ascorbic acid, could
sensitize the human CRC cells to L-
OHP by inducing cell
apoptosis.26
Vitamin D, which promotes calcium absorp-
tion and maintains bones healthy, could increase the sen-
sitivity of human CRC cells to 5-
FU by suppressing TYMS
and survivin expression in a calcium-
sensing receptor
(CaSR) -
dependent manner.27
Taghizadeh et al. found
that the active metabolite of vitamin D 1α,25-
dihydroxy
vitamin D3 (1,25-
D3) could restore the sensitivity to 5-
FU
and CPT-
11 in 5-
FU/CPT-
11-
resistant MIP101 human
CRC cell line. Furthermore, they also found that com-
bined 1α,25-
dihydroxy vitamin D3 with secreted protein
acidic and rich in cysteine (SPARC) which is a matricel-
lular protein could augment chemosensitivity in CRC
through upregulating the expression of vitamin D recep-
tor (VDR) with a lower dosage of chemo drugs.28
3 | GENE THERAPY
Gene therapy has become a novel strategy to conquer
chemoresistance in CRC by gene correction, immunogene
therapy, prodrug activation, oncolytic viruses, and other
technologies manipulated on genes.29
Recently, various
studies have confirmed the reversal effect of ribozymes,
antisense oligonucleotides (ASOs), RNA interference
(RNAi), clustered regularly interspaced short palindromic
repeat (CRISPR)/Cas9, epigenetic therapy, and noncoding
RNAs (ncRNAs), including micro-
RNAs (miRNAs), long
noncoding RNAs (lncRNAs), and circular RNAs (circR-
NAs) in CRC (Table 2).
3.1 | Ribozymes
Ribozymes are small RNA molecules with catalytic
functions, which can degrade specific mRNA se-
quences. Transfection of the anti-
MDR1 ribozyme,
bound to the carcino-
embryonic-
antigen (CEA)
promoter, could reverse DOX resistance by reduc-
ing P-
gp expression in SW1116R MDR CRC cells.30
Hammerhead ribozyme-
mediated-
specific suppression
of MDR1 and multidrug resistance-
associated protein
(MRP) could reverse resistance to DOX and etopo-
side (VP-
16) in CDDP-
resistant HCT-
8/CDDP cells.31
Hammerhead ribozyme against γ-
glutamylcysteine
synthetase (γ-
GCS) could reverse resistance to CDDP,
DOX, and VP-
16 in CDDP-
resistant HCT-
8 cells by
markedly downregulating the expression of the γ-
GCS
gene and MRP/MDR1.32
3.2 | Antisense oligonucleotides
Antisense oligonucleotides (ASOs) are synthesized nu-
cleic acids, containing 12–
25 nucleotides in general, which
exert their inhibitive effect by binding to the target RNA
through Watson–
Crick hybridization.33
It was reported
that combined use of miR-
21 inhibitor oligonucleotide
(miR-
21i) and 5-
FU delivered by the engineered exosomes
could overcome resistance and markedly enhance the
drug cytotoxicity in 5-
FU-
resistant HCT-
116/5-
FU cell
line by increasing apoptosis, inducing cell cycle arrest,
reducing tumor proliferation, and rescuing the decrease
of phosphatase and tensin homolog (PTEN) and hMSH2
(regulatory targets of miR-
21) due to the downregulation
of miR-
21.34
The antisense oligonucleotide of miR-
19a
(anti-
miR-
19a) has been found to reverse L-
OHP resist-
ance in L-
OHP-
resistant SW480 and HT29 cell lines via
PTEN /PI3K/AKT pathway.35
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3.3 | RNA interference
RNA interference (RNAi) regulates gene expression and
contributes to the targeted therapy through 20–
24bp RNA
including small interfering RNAs (siRNAs) and short
hairpin RNAs (shRNAs).
3.3.1 | Small interfering RNAs
Knockdown of the ubiquitin fusion-
degradation 1-
like protein (UFD1) could restore the sensitivity of hy-
droxycamptothecin (HCPT)-
resistant SW1116/HCPT
colon cancer cell line to HCPT probably via increasing
caspase-
3-
mediated apoptosis and inducing endoplasmic
reticulum (ER) stress.36
Suppression of Src homology
3-
domain GRB2-
like protein 1 (SH3GL1) could reverse
the 5-
FU resistance in a multitude of CRC cell lines in-
cluding HT29/5-
FU, HCT116/5-
FU, LoVo/5-
FU, and
HCT8/5-
FU cell lines through downregulating MDR1/
P-
gp via the EGFR/ERK/activator protein-
1 (AP-
1) path-
way.37
Silencing MDR1 could reverse the drug resistance
in SW480L/OHP cells by downregulating MDR1 gene
expression and reducing the gp level.38
Knockdown of
β-
1,3-
N-
acetyl glucosaminyltransferase 8 (β3GnT8),
which synthesizes polylactosamines on β1-
6 branched
N-
glycans and with high expression in 5-
FU-
resistant
SW620/5-
FU cell line, could reverse 5-
FU resistance via
the suppression of the polylactosamines formation.39
RNAi of kallikrein 11 (KLK11) that is correlated with
malignant behaviors of CRC can overcome L-
OHP resist-
ance by inducing apoptosis and evading cell growth by
suppressing the PI3K/AKT signaling pathway in L-
OHP-
resistant HCT-
8/L-
OHP cell line.40
3.3.2 | Short hairpin RNAs
A disintegrin and metalloproteinase 17 (ADAM17)
shRNA could inhibit cell proliferation, increase apop-
tosis, and reverse L-
OHP resistance in L-
OHP resistant
HCT-
8 cell line by suppressing the EGFR/PI3K/AKT
signaling pathway.41
Silencing PIK3CA and PIK3CB by
RNAi could repress the capability of proliferation, mi-
gration, and invasion of CRC cells and reverse MDR in
5-
FU-
resistant HCT-
8/5-
FU cell line.42
GOLPH3 shRNA
could reverse L-
OHP resistance by limiting cell prolif-
eration and inducing apoptosis through the suppres-
sion of P13K/AKT/mTOR pathway in L-
OHP resistance
HCT116/L-
OHP cell line.43
RNAi of CD147 was observed
to inhibit cell proliferation and invasion and resensitize
HT29 cells to CDDP and DOX.44
Transfected of livin (an
inhibitor of apoptosis proteins) shRNA to VCR resistant
HCT-
8/VCR cells could increase apoptosis in response
to VCR, VP-
16, and 5-
FU, which is able to reverse drug
resistance.45
RNAi of carboxylesterase-
2 can suppress
proliferation and induce apoptosis and reverse L-
OHP
resistance by suppression of PI3K signaling in L-
OHP-
resistant HCT116/L-
OHP and RKO/L-
OHP cell lines.46
Overexpression of nuclear protein FK506-
binding pro-
tein 3 (FKBP3) and histone deacetylase 2 (HDAC2)
could promote L-
OHP resistance in CRC cells, whereas
knockdown of FKBP3 could abate L-
OHP resistance by
decreasing HDAC2 expression and perhaps through reg-
ulating PTEN/AKT pathway in CRC cells.47
Knockdown
of CDK2-
associated cullin domain 1 (CAC1), an innova-
tive regulator of cell cycle, could promote the sensitiv-
ity of SW480/5-
FU and LoVo/5-
FU cell lines to 5-
FU by
inducing cell apoptosis, arresting tumor cells at the G1/S
phase, and lowering the expression of P-
gp and MRP-
1.48
Knockdown of CSC biomarker CD133 could reverse
DOX chemoresistance by downregulating MDR1/P-
gp
expression via AKT/NF-
κB/MDR1 signaling in DOX-
resistant LoVo and HCT8 cell lines.49
Knockout of
SLC25A22 increased chemosensitivity of KRAS-
mutant
DLD1 and SW1116 cell lines to 5-
FU, and it is also af-
firmed in DLD1 xenograft mice.50
3.4 | CRISPR/Cas9
CRISPR/Cas9 technology, a powerful, efficient, easy,
and specific gene editing tool, is extensively adminis-
trated in tumor pathogenesis, treatment, and drug resist-
ance by inserting or knocking out the related genes.51
Identifying and modulating resistance-
related genes by
CRISPR/Cas9 is an efficient way to reverse chemoresist-
ance and inhibit tumor recurrence. Knockout ABCB1
gene by CRISPR/Cas9 tool increased the chemosensitiv-
ity of ABCB1 overexpressed MDR HCT8/VCR cell line to
DOX by increasing intracellular accumulation of DOX.52
Similarly, Lei et al. also found that ABCB1 knockout
could reverse 3H-
paclitaxel (PTX) resistance mediated
by ABCB1 in SW620/Ad300 CRC cells by decreasing
drug efflux.53
Knockout of redox-
inducible antioxidant
protein RING-
box 2 (RBX2) by CRISPR/Cas9 technique
enhanced the sensitivity of HCT116 and SW480 cell
lines to PTX probably by deactivating mTOR/S6 kinase
1 (S6K1).54
Knockdown of T-
lymphoma invasion and
metastasis-
inducing protein-
1 (TIAM1) enhanced sensi-
tivity to 5-
FU and reduced tumor invasiveness in HCT116
xenograft mice.55
Apart from gene knockout, CRISPR/
Cas9 can screen resistance-
associated genes by whole-
genome screening. Lan et al. found that TRAF5, a criti-
cal mediator of necroptosis, confers to L-
OHP-
resistance
METTL3-
deleted HCT-
116 cells.56
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TABLE 2 Gene therapy investigated in the reversal of chemoresistance in CRC (2016~2022)
Gene therapy Chemical drugs Cell model
Ribozymes
Anti-
MDR1 Rz DOX SW1116R/MDR cell line
Anti-
MRP Rz and Anti-
MDR1 Rz DOX and VP-
16 HCT-
8/ CDDP cell line
Anti-
γ-
GCS Rz CDDP, DOX and VP-
16 HCT-
8/ CDDP cell line
RNAi
ADAM17 shRNA L-
OHP HCT-
8/L-
OHP cell line
PIK3CA shRNA and PIK3CB
shRNA
5-
FU HCT-
8/5-
FU cell line
GOLPH3 shRNA L-
OHP HCT116/L-
OHP cell line
Ufd1 siRNA HCPT SW1116/HCPT cell line
CD147 shRNA CDDP, DOX, GEM HT29 cell line
livin shRNA VCR, VP-
16, 5-
FU HCT-
8/VCR cell line
KLK11 RNAi L-
OHP HCT-
8/L-
OHP cell line
CES2 shRNA L-
OHP HCT116/L-
OHP and RKO/ L-
OHP cell lines
SH3GL1 siRNA 5-
FU LoVo/5-
FU, HT29/5-
FU, HCT8/5-
FU, and HCT116/5-
FU cell lines
MDR1 siRNA L-
OHP SW480/L-
OHP cell line
FKBP3 shRNA L-
OHP primary CRC cells
CAC1 shRNA 5-
FU SW480/5-
FU and LoVo/5-
FU cell lines
β3GnT8 siRNA 5-
FU SW620 /5-
FU cell line
CD133 knockdown plasmid DOX DOX-
resistant LoVo/ADR and HCT8/ADR cell line
CRISPR/Cas9
ABCB1 knockout DOX MDR HCT8/VCR cell line
ABCB1 knockout PTX SW620/Ad300 cell line
RBX2 knockout HCT116 and SW480 cell lines
TIAM1 knockdown 5-
FU —
ASOs
miR-
21i 5-
FU HCT-
116/5-
FU cell line
Anti-
miR-
19a L-
OHP SW480/L-
OHP and HT29/L-
OHP cell lines
MiRNAs
miR-
200b-
3p L-
OHP HT29/L-
OHP and HCT116/L-
OHP cell lines
miR-
506 L-
OHP HCT116/L-
OHP cell line
miR-
27b-
3p L-
OHP SW480/L-
OHP cell line
miR-
195-
5p 5-
FU HCT116/5-
FU and SW480/5-
FU cell line
miR-
133b 5-
FU, L-
OHP 5-
FU and L-
OHP chemoresistance in HT29 and SW620 cells
miR-
375-
3p 5-
FU HT29 and HCT116 cell lines
miR-
1914* and miR-
1915 5-
FU, L-
OHP 5-
FU and L-
OHP resistant HCT116 cells
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Animal species Animal model Reversal mechanisms Reference
BALB/c-
nu/nu nude mice
(male, 6weeks)
Xenograft (SW1116R MDR cells) ⬇p-
gp 30
— — ⬇MRP and MDR1 31
— — ⬇γ-
GCS gene and ⬇MRP/MDR1 32
— — ⬇EGFR/PI3K/AKT signaling pathway 41
6weeks)
Xenograft (HCT-
8/5-
FU cells stably
transfected with PIK3CA shRNA,
PIK3CB shRNA)
⬇PIK3CA, PIK3CB, and MDR-
1 42
BALB/cSlc-
nu/nu mice
(male, weighing 19 g
±2 g)
Xenograft (HCT116/L-
OHP cells
transfected with GOLPH3 shRNA)
⬇PI3K/AKT/mTOR pathway 43
— — ⬆caspase-
3 pathway and ⬇endoplasmic
reticulum functions
36
— — ⬇CD147 44
— — ⬇livin (antiapoptotic) 45
— — ⬆apoptosis and ⬇PI3K/AKT pathway 40
— — ⬆apoptosis and ⬇PI3K/AKT pathway 46
— — ⬇MDR1/P-
gp and EGFR/ERK/AP-
1 pathway 37
— — ⬇MDR1/P-
gp 38
— — ⬇HDAC2, p‑AKT, ⬆PTEN and cleaved
caspase‑3
47
BALB/C, Nu/Nu nude mice
(4-
6weeks)
Xenograft (SW480/5-
FU cells transfected
with CAC1 shRNA); tumor liver
metastasis nude mice model
⬆apoptosis, ⬇MDR1/P-
gp 48
— — ⬇polylactosamine formation 39
Athymic nude mice (male,
18–
22g)
Xenograft (LoVo/ADRCD133KD
cells) ⬇CD133, AKT/NF-
κB/MDR1 pathway 49
— — ⬇ABCB1 52
— — ⬇ABCB1 53
BALB/c-
nude mice
(5weeks)
Xenograft (HCT116 or SW480 cells
transfected with RBX2-
shRNA)
⬇mTOR/S6K1 54
athymic nude mice (male,
5weeks)
Xenograft (HCT116 cells with stably
knocked down TIAM1)
⬇TIAM1 55
— — ⬇miR-
21, ⬆cell cycle arrest and apoptosis 34
— — ⬇ miR-
19a 35
— — ⬆miR-
200b-
3p, apoptosis ⬇βIII-
tubulin protein 60
— — ⬆miR-
506, ⬇P-
gp, Wnt/β-
catenin pathway 61
— — ⬆miR-
27b-
3p, ⬇autophagy, ATG10 62
— — ⬆MiR-
195-
5p, ⬇GDPD5 63
— — ⬆MiR-
133b, ⬇DOT1L, stemness 64
BALB/c nude mice
(4weeks)
Xenograft (HCT116 cells) ⬆MiR-
375-
3p, ⬇apoptosis and cell cycle arrest,
TYMS
65
— — ⬆miR-
1914* and miR-
1915; ⬇NFIX 66
(Continues)
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Gene therapy Chemical drugs Cell model
miR-
193a-
5p 5-
FU, L-
OHP SW480, LS180, and HT-
29
miR-
195-
5p 5-
FU 5-
FU-
resistant SW620 and HT-
29 cell lines
miR-
135b and miR-
182 5-
FU HCT-
8/5-
FU and LoVo/5-
FU cells
miR-
26b 5-
FU HT-
29/5-
FU and LOVO/5-
FU cell lines
LncRNAs
lncRNA CCAT1 5-
FU HCT116/5-
FU and HT29/5-
FU cells
LINC00689 5-
FU HCT116 and LoVo cell lines
MIR600HG L-
OHP Caco2 cell line
lnc-
AP L-
OHP HCT116/L-
OHP and SW480/L-
OHP cell lines
CircRNAs
Circ_0032833 FOLFOX HCT116/ FOLFOX cell line
Circ-
PRKDC 5-
FU SW480/5-
FU and SW620/5-
FU Cell lines
circ_0007031 5-
FU HCT116/5-
FU and SW480/5-
FU cell lines
circ_0094343 5-
FU, L-
OHP and Dox HCT116 cell lines
circ_0006174 DOX LoVo/DOX and HCT116/DOX cell lines
circCSPP1 DOX LoVo/DOX and HCT116/DOX cell lines
circ_0071589 CDDP HCT116/CDDP and LOVO/CDDP cell line
CircEXOC6B 5-
FU SW620 and HCT116 cell lines
Epigenetic therapy
Zebularine (DNMT inhibitor) L-
OHP hypoxia-
induced oxaliplatin resistance in HCT116 cell line
Tunicamycin (N-
glycosylation
inhibitor)
DOX LoVo/DOX cell line
METTL1 (mediates m7G
methylation)
CDDP HCT116, SW480 and SW620
Note: “⬆” means upregulation or activation; “⬇” means downregulation or inhibition.
Abbreviations: ABCB1, ATP binding cassette subfamily B member 1; ABCC5, ATP-
binding cassette subfamily C member 5; ADAM17, A disintegrin and
metalloproteinase 17; AKT, protein kinase B; ALDH1A3, aldehyde dehydrogenase 1 family, member A3; AOM, azoxymethane; AP-
1, activator protein-
1;
ASOs, antisense oligonucleotides; anti-
miR-
19a, antisense oligonucleotide of miR-
19a; ATG10, autophagy-
related 10BCRP, breast cancer resistance protein;
CAC1, CDK2-
associated cullin domain 1; CCAT1, colon cancer-
associated transcript 1; CCND2, cyclin D2; CDDP, cisplatin; CES-
2, carboxylesterase-
2;
CircRNAs, circular RNAs; CSPP1, centrosome and spindle pole associated protein 1; CXCR4, C-
X-
C Motif chemokine receptor 4; DNMT, DNA
methyltransferase; DOT1L, disruptor of telomeric silencing 1-
like; DOX, doxorubicin; EGFR, epidermal growth factor receptor; ERK, extracellular regulated
protein kinases; DSS, dextran sodium sulfate; FKBPs, FK506‑binding proteins; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FOXM1, Forkhead box
protein M1; 5-
FU, 5-
fluorouracil; FZD7, frizzled-
7; γ-
GCS, γ-
glutamylcysteine synthetase; GDPD5, glycerophosphodiester phosphodiesterase domain
containing 5; GEM, gemcitabine; γ-
GCS, gamma-
glutamylcysteine synthetase; GOLPH3, golgi phosphoprotein 3; HCPT, hydroxycamptothecin; HDAC2,
histone deacetylase 2; HIF-
1α, hypoxia inducible factor-
1α; KLK11, Kallikrein 11; KLF12, Krüppel-
like factor 12; L-
OHP, oxaliplatin; LncRNAs, long
non-
coding RNAs; MDR, multidrug resistance; MDR1, multidrug resistance protein 1; METTL1, methyltransferase-
like 1; METTL3, methyltransferase-
like 3;
m7G, 7-
methylguanosine; MiRNAs, micro RNAs; MRP, multidrug resistance-
associated protein; MSI1, musashi1; mTOR, mammalian target of rapamycin;
NFIX, nuclear factor I/X; p-
AKT, phosphorylated AKT; P-
gp, P-
glycoprotein; PI3K, phosphatidylinositol 3 kinase; PPP, pentose phosphate pathway; PTEN,
phosphatase and tensin homolog deleted on chromosome 10; PTX, paclitaxel; RBPJ, recombination signal binding protein for immunoglobulin Kappa J region;
RBX2, RING box protein 2; RNAi, RNA interference; Rz, ribozyme; RRAGB, Ras-
related GTP binding protein B; SH3GL1, Src homology 3 (SH3)-
domain
GRB2-
like protein 1; shRNA, short hairpin RNA; S6K1, S6 kinase 1; TALDO1, transaldolase 1; TIAM1, T-
lymphoma invasion and metastasis-
inducing
protein-
1; TRIM67, tripartite motif-
containing 67; TYMS, thymidylate synthase; Ufd1, ubiquitin fusion-
degradation 1-
like protein; VP-
16, etoposide; Yap,
yes-
associated protein.
TABLE 2 (Continued)
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| 11083
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Animal species Animal model Reversal mechanisms Reference
— — ⬆miR-
193a-
5p; ⬇CXCR4 68
— — ⬆MiR-
195-
5p; ⬇Notch2 and RBPJ 69
⬇miR-
135b, miR-
182, PI3K/AKT pathway;
⬆ST6GALNAC2
70
BALB/c-
nude mice (male,
4weeks)
Xenograft (HT-
29/5-
FU/miR-
26b- cells) ⬆miR-
26b; ⬇p-
gp 71
— — ⬇CCAT1 73
BALB/c-
nude mice (male,
4-
5weeks)
Xenograft (LINC00689+ and miR-
31-
5p-
stable HCT116 and LoVo cells)
⬆LINC00689; ⬇miR-
31-
5p, YAP/β-
catenin
pathway
74
athymic (nu/nu) mice
(female, 6weeks)
Caco2 cells ⬆MIR600HG; ⬇stemness, ALDH1A3 75
— — encoding short peptide pep-
AP, which
⬇TALDO1, PPP; ⬆ROS, apoptosis
76
— — ⬇circ_0032833; ⬆MSI1/miR-
125-
5p 78
Nude mice (5weeks) Xenograft (SW480/5-
with sh-
circ-
PRKDC)
⬇Circ-
PRKDC, wnt/β-
catenin pathway;
⬆FOXM1/miR-
375
79
BALB/c nude mice
(6weeks)
Xenograft (SW480/5-
with sh-
circ-
0007031)
⬇circ_0007031; ⬆ABCC5/miR-
133b 80
— — ⬆circ_0094343; ⬆TRIM67/miR-
766-
5p,
glycolysis
81
— — ⬆Circ_0006174; ⬇CCND2/miR-
1205 82
nude mice (6weeks) Xenograft (LoVo/DOX cells transfected
withsh-
circCSPP1)
⬇circCSPP1, ⬆FZD7/miR-
944 83
BALB/c nude mice (male,
5weeks)
Xenograft (HCT116/CDDP cells
transfected with sh-
circ_0071589)
⬇circ_0071589, KLF12; ⬆miR-
526b-
3p 84
— — competitively binding with RRAGB,
⬇HIF1A-
RRAGB-
mTORC1
85
BALB/c nude mice;
C57BL/6 mice
Xenograft (HCT116 cells); AOM/DSS-
induced CRC mouse models
⬇HIF-
1α 88
— — ⬇P-
gp and BCRP 92
— — ⬆METTL1, p53; ⬇miR-
149-
3p, S100A4 91
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3.5 | Micro-
RNAs
Micro-
RNAs (MiRNAs), defined as small ncRNAs con-
taining 21–
23 nucleotides, regulate gene expression at the
level of posttranscription by repressing mRNA transla-
tion and inducing mRNA degradation.57
Dysregulation of
miRNAs is associated with colorectal carcinogenesis, and
appropriate modulation of miRNAs is found to exert re-
versal effects in resistant CRC cells.58,59
Wu et al. found
that upregulation of miR-
200b-
3p could promote cell mi-
gration, induce apoptosis, inhibit cell growth, and reverse
L-
OHP resistance by downregulating the expression of
βIII-
tubulin protein through binding to 3′-
UTR of TUBB3
(encoding β III-
tubulin protein) in L-
OHP-
resistant
HT29/L-
OHP and HCT116/L-
OHP cell lines.60
Zhou et al.
reported that overexpression of miR-
506 improved che-
mosensitivity in HCT116/L-
OHP cell line by suppressing
P-
gp expression through downregulating Wnt/β-
catenin
pathway.61
Sun et al. indicated that miR-
27b-
3p could re-
verse chemoresistance by inhibiting autophagy via inhib-
iting the expression of autophagy-
related protein ATG10
in L-
OHP-
resistant SW480 cells.62
MiR-
195-
5p could
dramatically increase chemosensitivity in 5-
FU-
resistant
HCT116/5-
FU and SW480/5-
FU CRC cell lines by reduc-
ing the expression of glycerophosphodiester phosphodies-
terase domain containing 5 (GDPD5) that is involved in
the process of choline phospholipid metabolism.63
MiR-
133b reduced stemness and 5-
FU and L-
OHP chemore-
sistance in HT29 and SW620 cell lines by targeting and
suppressing the disruptor of telomeric silencing 1-
like
(DOT1L)-
mediated H3K79me2 modification and tran-
scription of stem cell genes.64
MiR-
375-
3p was discovered
to be downregulated in CRC tissues as well as HT29 and
HCT116 cell lines. It strengthened the sensitivity to 5-
FU
in CRC cells by inducing cell cycle arrest and apoptosis
via targeting TYMS.65
Upregulation of miR-
1914* and
miR-
1915 decreased chemoresistance in 5-
FU and L-
OHP
chemo-
resistantHCT116cellsbyrepressingtheexpression
of transcription factor nuclear factor I/X (NFIX).66
MiR-
138-
5p, which decreased in CRC tissues, could inhibit cell
migration and chemoresistance in CRC by targeting the
nuclear factor I/B (NFIB)-
Snail1 axis.67
Combined with
5-
FU and L-
OHP, miR-
193a-
5p reversed chemoresist-
ance in CRC by reducing C-
X-
C motif chemokine recep-
tor 4 (CXCR4, induces cell proliferation and metastasis)
expression.68
MiR-
195-
5p considerably increased tumor
cell apoptosis, reduced tumor sphere formation, and pre-
vented cell stemness and chemoresistance by decreasing
Notch signaling proteins Notch2 and recombination sig-
nal binding protein for immunoglobulin Kappa J region
(RBPJ).69
Suppression of miR-
135b and miR-
182 may re-
verse the 5-
FU resistance in HCT-
8/5-
FU and LoVo/5-
FU
cell lines by targeting sialyltransferase ST6GALNAC2 via
PI3K/AKT pathway.70
Overexpression of miR-
26b could
reverse 5-
FU chemoresistance by downregulation of P-
gp
in 5-
FU-
resistant HT-
2 and LOVO cell lines.71
3.6 | Long noncoding RNAs
Long noncoding RNAs (LncRNAs), which are transcripts
that exceed 200 nucleotides, can regulate CRC progres-
sion by acting as competitive endogenous RNAs (ceR-
NAs) by interacting with miRNAs or protein-
coding
mRNAs and encoding short peptides.72
A growing num-
ber of studies has indicated that abnormally expressed
lncRNAs confer to drug resistance in CRC and the condi-
tion can be overcome by re-
modulating the expression of
the aberrant lncRNAs. Downregulation of lncRNA colon
cancer-
associated transcript 1 (CCAT1) could effectively
inhibit CCAT1 expression and reverse the 5-
FU resistance
in HCT116/5-
FU and HT29/5-
FU cells.73
Long intergenic
nonprotein-
coding RNA 689 (LINC00689) functioned as
a miR-
31-
5p sponge to inhibit tumor proliferation, metas-
tasis, and chemoresistance by upregulating large tumor
suppressor kinase (LATS2) and repressing yes-
associated
protein (YAP)/β-
catenin signaling pathway in CRC.74
LncRNA MIR600HG functioned as a tumor suppres-
sor and the overexpression of MIR600HG could inhibit
tumor invasion and enhance chemosensitivity by target-
ing ALDH1A3 (encodes an aldehyde dehydrogenase en-
zyme) in CRC.75
LncRNA lnc-
AP could sensitize the
HCT116/L-
OHP and SW480/L-
OHP cell lines to L-
OHP
by encoding short peptide pep-
AP, which suppressed pen-
tose phosphate pathway (PPP), increased ROS accumula-
tion and cell apoptosis through inhibiting transaldolase 1
(TALDO1, a key enzyme of PPP).76
3.7 | Circular RNAs
CircRNAs, a special subclass of ncRNAs, have a covalently
closed circular structure with no 5′ cap structure and 3′
polyA tail, which is associated with tumor recurrence and
chemotherapy resistance in CRC.77
CircRNAs could par-
ticipate in chemoresistance by acting as miRNAs sponges
or binding with proteins. Circ_0032833 downregulated
the expression of Musashi1 (MSI1), which promoted drug
resistance in cancer by sponging miR-
125-
5p. Knockdown
of circ_0032833 could sensitize folinic acid, fluorouracil,
and oxaliplatin (FOLFOX)-
resistant HCT116 cells to 5-
FU
and L-
OHP.78
Circ-
PRKDC knockdown suppressed 5-
FU
Resistance in SW480/5-
FU and SW620/5-
FU Cell lines by
directly targeting miR-
375, which negatively regulated the
expression of transcription factor forkhead box protein M1
(FOXM1).79
Knockdown of circ_0007031 could repress
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| 11085
MA et al.
tumor malignant progression and reverse 5-
FU resistance
in HCT116/5-
FU and SW480/5-
FU cell lines via regulat-
ing ATP-
binding cassette subfamily C member 5 (ABCC5)
expression by sponging miR-
133b.80
Circ_0094343 was
found to inhibit tumor proliferation, clone formation,
and glycolysis and improve the chemosensitivity to gem-
citabine (GEM), 5-
FU, L-
OHP, and DOX in HCT116
cells via the miR-
766-
5p/ tripartite motif-
containing 67
(TRIM67) axis.81
Circ_0006174 was highly expressed in
DOX-
resistant CRC tissues and cells. Downregulation of
circ_0006174 could inhibit chemoresistance and tumor
progression in DOX-
resistant CRC cells by upregulating
the miR-
1205-
mediated cyclin D2 (CCND2).82
CircCSPP1
knockdown inhibited tumor growth and increased drug
sensitivity of DOX-
resistant CRC cells by targeting miR-
944/frizzled-
7 (FZD7, a receptor of Wnt signaling proteins)
axis.83
Circ_0071589 knockdown suppressed chemore-
sistance in CDDP-
resistant CRC cells via miR-
526b-
3p/
Krüppel-
like factor 12 (KLF12) axis.84
CircEXOC6B could
enhance the sensitivity of SW620 and HCT116 cell lines
to 5-
FU by competitively binding with Ras-
related GTP
binding protein B (RRAGB, activator of mTORC1 path-
way), thus blocking the HIF1A-
RRAGB-
mTORC1 posi-
tive feedback loop.85
3.8 | Epigenetic therapy
Epigenetic therapy is a coping strategy to modify the ab-
errant epigenetic alterations in cancers, including CRC.
It has been found that epigenetic alterations like higher
DNA methylation and mRNA N6-
methyladenosine
(m6A) are related to the occurrence of chemoresistance
and tumor relapse in CRC.86
Block the epigenetic modi-
fication that occurred in resistant CRC can reverse the
resistance. Baharudin et al. found that recurrent CRC pa-
tients exhibited higher methylation levels and the recur-
rence of CRC compared to non-
recurrent CRC patients,
which might associate with the abnormal methylation of
CCNEI, CCNDBP1, CHL1, DDX43, and PON3. Treatment
of 5-
aza-
2′-
deoxycytidine (5-
azadC, a DNA methyla-
tion inhibitor) could restore the sensitivity to 5-
FU in
the SW48 cell line.87
Zebularine, a low-
toxicity DNA
methyltransferase (DNMT) inhibitor, could overcome
hypoxia-
induced CDDP resistance in HCT116 cells and
show the same efficacy in HCT116 xenograft models and
AOM/DSS-
induced CRC mouse models by downregulat-
ing HIF-
1α expression through hydroxylation.88
Zhang
et al. found that methyltransferase-
like 3 (METTL3)
and mRNA N6-
methyladenosine (m6A) were upregu-
lated in 5-
FU-
resistant HCT-
116 and SW480 cell lines.
Knockdown of METTL3 could restore the chemosensi-
tivity of HCT-
116/5-
FU, SW480/5-
FU, and SW620/5-
FU
cell lines mediated by downregulating the expression of
lactate dehydrogenase (LDH) A, which catalyzes pyru-
vate to lactate to promote glycolysis.89
Uddin et al. found
that silencing of METTL3 or inhibition of RNA methyla-
tion could restore the sensitivity to DOX in cells carrying
the mutation of R273H by suppressing the m6A modifi-
cation in the pre-
mRNA of p53 and increasing the phos-
phorylated level of p53 protein. In addition, suppression
of ceramide glycosylation was also found to combat drug
resistance by mechanisms of the suppression of METTL3
and m6A formation in p53 pre-
mRNA.90
Overexpression
of methyltransferase-
like 1 (METTL1) was found to sen-
sitize CDDP-
resistant colon cancer cells to chemoresist-
ance via modulating miR-
149-
3p/S100A4/p53 axis.91
Wojtowicz et al. found that tunicamycin, an inhibitor of
N-
glycosylation, might reverse MDR in LoVo/DOX cell
line by blocking the first-
step N-
glycosylation and trans-
location of P-
gp.92
4 | PROTEIN INHIBITORS
In the treatment of CRC chemoresistance, except for
gene-
level therapy, direct protein inhibitors also play an
important role. Various inhibitors, including inhibitors
of classical resistance-
related proteins, EGFR inhibitors,
and sphingosine 1-
phosphate receptor (S1PR) modula-
tors have been found to reverse chemoresistance in
CRC.
4.1 | Inhibitors of classical resistance-
related proteins
An increment in drug efflux could reduce drug concen-
tration and accumulation in tumor cells, which leads to
drug resistance. Targeting ATP-
binding cassette (ABC)
transporters like breast cancer resistance protein (BCRP)
and P-
gp provides a potential approach to eliminating
drug resistance during the treatment of CRC. GF120918,
a potent P-
gp and BCRP inhibitor, markedly increased
the oral bioavailability of topotecan from 40% to 97% in
cancer patients.93
Compound WS-
10, a P-
gp inhibitor,
could overcome P-
gp-
mediated MDR in SW620/Ad300
cells by binding with P-
gp, thus enhancing the intracel-
lular accumulation of PTX.94
The protein kinase C (PKC)
family, deemed as oncoprotein historically, is comprised
of a group of serine or threonine kinases and is incorpo-
rated in tumor progression.95
It has been indicated that
PKC could reduce intracellular drug concentration by ac-
tivating ATP-
dependent efflux pumps, which contributes
to drug resistance in CRC.96
Go6976, a specific inhibitor
of classical PKC, can be used to reverse DOX resistance
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in human colon cancer DOX-
resistant HCT15 cell line by
reducing MDR expression and increasing DOX-
induced
apoptosis.97
4.2 | EGFR Inhibitors
EGFR is a transmembrane receptor belonging to a family
of receptor tyrosine kinases that mediates a series of in-
tracellular pathways that promote tumor proliferation,
invasion, metastasis, and neovascularization.98
EGFR
inhibitors application has been found to overcome
chemoresistance in CRC. Saptinib, an EFGR inhibitor,
could increase 3H-
PTX accumulation in tumor cells and
reverse MDR in SW720/Ad300 cells through stimulating
ATPase which competitively inhibits 3H-
PTX uptake.99
Erlotinib, a specific inhibitor of EGFR, could effectively
strengthen the antitumor effect of 5-
FU via modulating
the EGFR-
FGD5-
AS1-
miR-
330-
3p-
hexokinase 2 (HK2)
pathway.100
4.3 | S1PR modulators
Sphingosine-
1-
phosphate (S1P), one of the sphingolipids,
could regulate cancer survival by binding sphingosine
1-
phosphate receptors (S1PRs), which activate multiple
cell growth-
related pathways.101
Inhibition of S1PR has
been found to reverse chemoresistance in several cancers
including CRC. JTE-
013, an S1P and S1PR2 inhibitor,
could overcome 5-
FU resistance in CRC by lowering the
expression of dihydropyrimidine dehydrogenase (DPD or
DPYD).102
S1PR2 antagonists compound 40 could mark-
edly reverse the drug resistance in HCT116/5-
FU and
SW620/5-
FU cell lines by evading the expression of dihy-
dropyrimidine dehydrogenase (DPD). It significantly en-
hanced the inhibitory effect of 5-
FU in the SW620/5-
FU
cells xenograft murine model without significant liver
toxicity.103
4.4 | Others
Notch and Wnt signaling-
associated proteins were
upregulated in HCT116/5-
FU and HCT116/L-
OHP
cells, including Notch1 receptor intracellular do-
main NICD1 and nonphosphorylated β-
catenin and
Notch target gene HES1. Wnt inhibitor XAV939 and
Notch inhibitor RO4929097 could restore cell viabil-
ity in L-
OHP-
treated HCT116 cells.104
Regorafenib, a
multikinase inhibitor, which targets the RAS/RAF/
MEK/ERK pathway, could overcome the ABCB1-
mediated MDR and increase 3H-
PTX accumulation in
ABCB1-
overexpressing tumor cells by suppressing the
efflux activity of ABCB1.105
5 | NATURAL HERBAL
COMPOUNDS
Natural herbal compounds have become putative ad-
juncts of conventional chemotherapy in CRC and are able
to reverse acquired drug resistance by different mecha-
nisms.106
Natural herbal compounds can be classified into
polyphenols, terpenoids, quinones, alkaloids, sterols, and
others according to the chemical structures (Table 3).
5.1 | Polyphenols
Dihydromyricetin, a flavonoid compound (belonging
to polyphenols) extracted from the Japanese raisin tree
(Hovenia dulcis), could inhibit both MRP2 expression and
its promoter activity by inhibiting NF-
κB-
Nrf2 signaling
in HCT116/L-
OHP and HCT-
8/VCR cell lines, contribut-
ing to the reversal of L-
OHP/VCR-
resistant CRC cells.107
Curcumin, as a lipophilic polyphenol, was effective in the
inhibition of cell proliferation, increment of cell apopto-
sis, block of G0/G1 phase, and downregulation of 10 and
11 translocation (TET1, a DNA demethylase), and naked
cuticle homolog 2 (NKD2, a negative regulator of Wnt
signaling), suggesting that curcumin might exert antire-
sistance effect 5-
FU-
resistant HCT116 cells by modulating
the TET1-
NKD2-
Wnt signaling pathway, thus inhibiting
the EMT progress.108
Moreover, Fan et al. found that cur-
cumin could evade tumor progression and reverse MDR
in the HCT-
8/5-
FU cells line by suppressing the expres-
sion of P-
gp and heat shock protein-
27.109
Resveratrol,
a naturally occurring polyphenol, could induce chemo-
sensitization to 5-
FU in HCT116/5-
FU and SW480/5-
FU
cell lines by inhibiting EMT via enhancing intercellular
junctions and suppressing NF-
κB pathway.110
Resveratrol
could also reverse L-
OHP resistance by increasing drug
accumulation, inhibiting MDR1, NF-
κB pathway, and the
transcriptional activity of cAMP-
responsive elements in
L-
OHP-
resistant HCT116 cells.111
5.2 | Terpenoids
β-
elemene, a sesquiterpene compound isolated from the
Chinese herb Curcumae Rhizoma, could significantly
inhibit cell proliferation and reverse the resistance of
HCT116 p53−/−−
to 5-
FU by inducing cyclin D3-
dependent
cycle arrest and autophagy.112
Atractylenolide II, a sesquit-
erpenoid monomer, which is extracted from traditional
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| 11087
MA et al.
T
A
B
L
E
3
Natural
herbal
medicine
applied
in
the
reversal
of
chemoresistance
in
CRC
(2011–
2
022)
Chemical
structure
Drug
Reversal
Mechanisms
Resistant
cell
line
Reference
Polyphenols
Dihydromyricetin
(flavonoid)
Inhibit
MRP2
expression
and
its
promoter
activity
by
preventing
NF-
κ
B-
N
rf2
signaling
HCT116/L-
O
HP,
HCT8/VCR
103
Curcumin(non-
f
lavonoid)
Inhibition
of
proliferation,
inducement
of
apoptosis,
block
of
G0/G1
phase
and
expression
of
TET1
and
NKD2;
inhibit
proliferation,
increase
apoptosis,
downregulate
P-
g
p
and
HSP-
2
7
HCT-
1
16/5-
F
U;
HCT-
8
/5-
F
U
104,105
Resveratrol(non-
f
lavonoid)
Inhibiting
EMT
via
up-
r
egulation
of
intercellular
junctions
and
down-
r
egulation
of
NF-
κ
B
pathway;
downregulating
MDR1,
inhibiting
NF-
k
B
pathway
and
the
transcriptional
activity
of
CRE
HCT116/5-
F
U
and
SW480/5-
F
U;
HCT116/L-
O
HP
106,107
Terpenoids
β-
e
lemene
(sesquiterpene)
Inhibit
proliferation,
induce
pro-
d
eath
autophagy
and
Cyclin
D3-
d
ependent
cycle
arrest
HCT116
(p53
−/−
)/5-
F
U
108
Atractylenolide
II
(sesquiterpenoid)
Inhibit
cell
proliferation
and
alleviate
chemoresistance
Lovo,
SW480/5-
F
U,
mitomycin,
adriamycin
and
CDDP
109
Quinones
Emodin
(anthraquinone
derivative)
Inhibit
proliferation,
invasion,
migration,
and
induce
cell
apoptosis
and
downregulate
PI3K/Akt
pathway
SW480/5-
F
U
110
Tanshinone
IIA
(diterpene
quinone)
Decrease
the
levels
of
Bcl-
2
,
p-
A
kt
and
p-
E
RK,
and
increase
the
levels
of
Bax
and
active
caspase
3
by
inhibiting
ERK/Akt
Signaling
Pathway
SW480/L-
O
HP
112
Cryptotanshinone
Inhibit
tumor
growth
through
induction
of
autophagic
cell
death
and
p53-
i
ndependent
cytotoxicity
SW620
Ad300
113
Dihydrotanshinone
Hypericin
(anthraquinone)
Downregulation
of
MRP2
level,
GSH-
r
elated
detoxification
and
NER-
m
ediated
DNA
repair
mediated
by
ROS
HCT8/L-
O
HP
and
HCT116/L-
O
HP
114
Alkaloids
Evodiamine
Inhibit
cell
growth,
induce
apoptosis,
suppress
the
expression
of
ABCG2
and
inhibit
p50/p65
NF-
κ
B
Pathway
HCT-
1
16/L-
O
HP
115
Sterols
Ginsenoside
Rh2
Inhibit
cell
proliferation
and
migration,
induce
apoptosis,
and
decrease
the
expression
of
MRP1,
MDR1,
LRP
and
GST
LoVo/5-
F
U,
HCT-
8
/5-
F
U
CRC
116
β-
S
itosterol
Suppress
BCRP,
activate
p53,
and
enhance
apoptosis
HCT116/L-
O
HP
117
Others
Salvianolic
acid
B
(phenolic
acid)
Increase
ROS
levels,
promote
apoptosis
and
downregulate
the
expression
of
P-
g
p
HCT‑8/VCR
118
Abbreviations:
ABCG2,
ATP-
b
inding
cassette
superfamily
G
member
2;
AKT,
protein
kinase
B;
BCRP,
breast
cancer
resistance
protein;
CAFs,
cancer-
a
ssociated
fibroblasts;
CDDP,
cisplatin;
CSCs,
colorectal
cancer
stem
cells;
CRC,
colorectal
cancer;
CRE,
cAMP-
r
esponsive
element;
DOX,
doxorubicin;
EGFR,
epidermal
growth
factor
receptor;
ERK,
extracellular
regulated
protein
kinases;
EMT,
epithelial-
m
esenchymal
transition;
5-
F
U,
5-
f
luorouracil;
GSH,
glutathione;
GST,
glutathione
S-
t
ransferase;
HCPT,
hydroxycamptothecin;
HIF-
1
α,
hypoxia-
i
nducible
factor;
Hsp27,
heat
shock
protein
27;
LncRNAs,
long
non-
c
oding
RNAs;
L-
O
HP,
oxaliplatin;
LRP,
lung
resistance-
r
elated
protein;
MDR1,
multidrug
resistance
protein
1;
miRNAs,
micro
RNAs;
MRP1,
multidrug
resistance-
a
ssociated
protein
1;
MRP
2,
multidrug
resistance-
a
ssociated
protein
2;
ncRNAs,
noncoding
RNAs;
NER,
nucleotide
excision
repair;
NF-
κ
B,
nuclear
factor-
k
appa
B;
NKD2,
naked
cuticle
homolog
2;
Nrf2,
nuclear
factor
E2-
r
elated
factor
2;
NSAIDs,
nonsteroidal
anti-
i
nflammation
drugs;
p-
A
KT,
phosphorylated
AKT;
PCD,
programmed
cell
death;
p-
E
RK,
phosphorylated
ERK;
P-
g
p,
P-
g
lycoprotein;
PI3K,
phosphatidylinositol
3
kinase;
PTEN,
phosphate
and
tension
homology
deleted
on
chromsome
ten;
RNAi,
RNA
interference;
ROS,
reactive
oxygen
species;
shRNAs,
short
hairpin
RNAs;
siRNAs,
small
interfering
RNAs;
TAMs,
tumor-
a
ssociated
macrophages;
TET1,
ten-
e
leven
translocation;
TGF-
β
2,
tumor
growth
factor-
β
2;
VCR,
vincristine.
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Chinese medicine atractylodes macrocephala, could in-
hibit tumor proliferation and increase chemosensitivity of
Lovo, SW480 cell lines to 5-
FU, CDDP, mitomycin, and
adriamycin.113
5.3 | Quinones
Emodin, a natural anthraquinone derivative, could re-
verse 5-
FU resistance in SW480/5-
FU cells by blocking
cell proliferation, invasion, and migration as well as in-
creasing cell apoptosis and downregulating the PI3K/
Akt pathway.114
Tanshinones, diterpene quinones iso-
lated from the roots of Salviamiltiorrhiza bunge, owe
the properties of antioxidation, anti-
inflammation,
antitumor, and other pharmacological effects, and its
chemoresistance reversal effect has been found in re-
cent years.115
Tanshinone IIA, cryptotanshinone, and
dihydrotanshinone are three of the compounds of tan-
shinones, which reverse chemoresistance to some ex-
tent in CRC. Tanshinone IIA could combat L-
OHP
resistance in the SW480/L-
OHP cell line by the inhibi-
tion of the ERK/Akt signaling pathway. Tanshinone IIA
applied with L-
OHP could significantly downregulate
the expressions of Bcl-
2, p-
ERK, and p-
Akt, and up-
regulate the expressions of Bax and active caspase 3.116
Cryptotanshinone and dihydrotanshinone could pre-
vent the growth of MDR-
resistant SW620/Ad300 cells
by inducing autophagic cell death and p53-
independent
cytotoxicity.117
Hypericin, a natural anthraquinone, is a
well-
studied photosensitizer. Hypericin-
mediated pho-
todynamic therapy could resensitize CRC-
resistant cells
including HCT-
8/L-
OHP and HCT116/L-
OHP cell lines
toward L-
OHP, which is associated with decreased drug
efflux (downregulation of MRP2 level), GSH-
related
detoxification, and nucleotide excision repair (NER)-
mediated DNA repair.118
5.4 | Alkaloids
Evodiamine, an alkaloid, could inhibit cell growth and
induce apoptosis and suppress ABCG2-
mediated MDR
resistance in HCT116/L-
OHP cells by inhibiting p50/p65
NF-
κB pathway.119
5.5 | Sterols
Ginsenoside Rh2 could inhibit cell proliferation and
migration, induce apoptosis, and decrease the drug-
resistant correlated genes expression like MRP1, MDR1,
lung resistance-
related protein (LRP), and glutathione
S-
transferase (GST), which reverses chomoresistance in
HCT-
8/5-
FU and LoVo/5-
FU cell lines.120
β-
Sitosterol, a
phytosterol, could reverse L-
OHP MDR in HCT116/L-
OHP cells via breast cancer resistance protein (BCRP/
ABCG2) suppression by disrupting murine double min-
ute 2 (MDM2, an E3 ubiquitin ligase) binding to p53,
thus evading protein degradation and ubiquitination,
and resulting in the activation of p53 and apoptosis
enhancement.121
5.6 | Others
Salvianolic acid B, a phenolic acid isolated from the dried
root and rhizome of Salvia miltiorrhiza Bge. (Labiatae),
could reverse MDR in HCT-
8/VCR cells through elevating
ROS levels, which promoted apoptosis and lowered the
expression of P-
gp, which increased the chemosensitivity
of drug-
resistant cancer cells.122
6 | NEW DRUG DELIVERY
SYSTEM
The low solubility and bioavailability, off-
target, and cy-
totoxicity to normal tissues of chemotherapy decreases
the therapeutic effect and promotes drug resistance in
CRC, which causes relapse and poor prognosis of CRC
patients. To deal with it, a new drug delivery system
including nanocarriers, liposomes, exosomes, and hy-
drogels has been used to overcome chemoresistance in
CRC.
6.1 | Nanocarriers
Lower toxicity and fewer side effects in blood and non-
cancerous tissues, increased aqueous solubility and bio-
availability, specific target feature and multifunctional
drug combination make nanoparticle-
based formulations
become an effective strategy to overcome drug resistance
in CRC combined with conventional chemotherapy.123
Chen et al reported that codelivery 5-
FU with epidermal
growth factor (EGF) grafted hollow mesoporous silica na-
noparticles (EGF-
HMSNs) can augment cytotoxicity and
reverse MDR by enhancing drug accumulation in tumor
cells, inducing S phase arrest and inducing cell death in
5-
FU-
resistant SW480 cells.124
Using aptamer-
conjugated
grapefruit-
derived nanovectors (GNVs) loaded with DOX
and P-
gp siRNA also showed MDR reversal effect, which
could effectively inhibit proliferation and enhance apop-
tosis in MDR Lovo cells and the effect might be related
to the downregulation of P-
gp.125
Other multifunctional
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| 11089
MA et al.
codelivery systems, like mesoporous silica-
coated gold
nanorods (GNRs/mSiO2) loaded with DOX, conjugated
with pH-
responsive poly-
histidine (PHIS), and covered
with d-
α-
tocopherol polyethylene glycol 1000 succinate
(TPGS) was discovered to increase the drug accumulation
and promote photothermal conversion in tumor resistant
CRC cells and exert better anticancer effects in SW620/
Ad300 xenograft mice without observed systemic toxic-
ity compared with other chemotherapy or photothermal
therapy alone.126
Combination use of sodium butyrate
and Fe3O4 magnetic nanoparticles (MNPs), coated with
folic acid (FA) and polyethylene glycol (PEG) (FA-
PEG@
MNPs), could decrease cell viability and increase FA-
PEG@MNPs intracellular uptake in Lovo cells, which in-
dicated that the combined use may exert MDR resistance
reversal effect in CRC.127
Due to the multiple advantages
of nanocarriers, recently, more studies are focusing on na-
nocarriers and trying to find different ways to overcome
chemoresistance.128,129
6.2 | Liposomes
Liposomes, artificial colloidal vesicles with unique lipid
bilayered membranes, can target tumor cells after chemi-
cal modification or physical treatment and have been used
in the targeted therapy of cancer.129
Liposomes, as one
kind of nanocarriers, own the advantages like biocom-
patibility and low systematic toxicity as well, which also
contribute to drug resistance reversal. Xu et al found that
bifunctional liposomes loaded with hypoxia-
inducible
factor-
1(HIF-
1) inhibitors, acriflavine (ACF), and DOX
(DOX-
ACF@Lipo) can reduce the chemoresistance to
DOX in advanced CRC.130
Combining 5-
FU with a bio-
chemical modulator in one same stealth liposome can ex-
hibit significant antiproliferative activity and reverse drug
resistance in resistant CRC cells.131
Liposome encapsula-
tion of VCR and monoclonal antibody or verapamil can
effectively overcome MDR in human colon cancer cells.132
Injectable PEGylated liposome encapsulating disulfiram
was found to reverse chemoresistance at low nanomolar
concentrations.133
6.3 | Exosomes
Exosomes are endocytic extracellular vesicles (EVs) rang-
ing from about 40–
160nm in diameter, which is associ-
ated with cancer proliferation, migration, invasion, and
drug resistance.134,135
Exomes induce drug resistance
mainly by exporting chemical drugs from tumors or im-
porting resistance-
associated small molecules to cancer
cells. CRC-
derived exosomes have been found to enhance
CRC chemoresistance by transferring cancer-
related miR-
NAs,136
lncRNAs,137
andcircRNAs.82,138
Duetotheirtarget-
ing specificity, high bioavailability, low immunogenicity,
low toxicity, and good cell–
cell communication capacity,
exosomes have been employed as a new drug delivery
system for drug resistance reversal in cancer treatment,
including CRC.139
Exosomes can overcome chemoresist-
ance by transferring therapeutic ncRNAs and chemical
drugs. It was reported that engineered exosomes contain-
ing miR-
21i and 5-
FU can effectively overcome drug resist-
ance and dramatically elevated the cytotoxicity of 5-
FU in
the HCT-
116/5-
FU cell line, compared to the single use of
either miR-
21i or 5-
FU.34
Exosomal miR-
204-
5p sustained
released by human-
constructed HEK293T cells enhanced
the 5-
FU sensitivity of LoVo and HCT116 cell lines, and
inhibited neoplasm growth in HCT116 xenograft mice.140
Engineered exosomes loaded with lncRNA PGM5-
AS1
and L-
OHP realized by electroporation reversed L-
OHP resistance in DLD1/L-
OHP cell line and xenograft
mice.141
Exosomes-
carried circ_0094343 improved the
chemosensitivity to5-
FU, L-
OHP, and DOX via regulating
the miR-
766-
5p/TRIM67 axis.81
Circular RNA F-
box and
WD repeat domain containing 7 (circ-
FBXW7) encapsu-
lated in exosomes by electroporation could enhance the
chemosensitivity of SW480/L-
OHP and HCT116/L-
OHP
cells to L-
OHP, increase apoptosis and inhibit EMT by
binding to miR-
18b-
5p, the reversal effect was also found
in the HCT116/L-
OHP xenograft mice.142
Kim et al. found
that encapsulation of PTX to exosomes released from
macrophages (exoPTX) by means of sonication could
overcome MDR in resistant cancer cells by delivering the
anticancer drug into the cancer cells directly, increasing
drug accumulation and cytotoxicity, and bypassing the
P-
gp-
mediated drug efflux. This effect was also verified
in the murine model of lung metastases, exoPTX could
significantly inhibit the tumor growth in the pulmonary.
They also found that exosomes incorporated with doxoru-
bicin (exoDOX) promoted the accumulation of DOX in re-
sistant cancer cells.143
After a modification of PTX-
loaded
exosomes with aminoethylanisamide-
polyethylene glycol
(AA-
PEG) vector moiety, PTX exhibited more potent an-
ticancer effect in lung metastasis compared to the single
administration of exoPTX or PTX.144
6.4 | Hydrogels
Hydrogels, an emerging drug carrier, are three-
dimensional (3D) frameworks comprised of cross-
linked
hydrophilic polymers. Due to their excellent biocompat-
ibility and biodegradability, hydrogels have been exten-
sively utilized for the treatment of cancer chemoresistance
and relapse in recent years.145
Hydrogels could modulate
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drug release when exposed to external stimuli includ-
ing light, temperature, pH, and electrical and magnetic
fields.146
It has been found that hydrogel carriers loaded
with drugs could overcome chemoresistance in many can-
cers, mainly including breast cancer,147–
149
ovarian can-
cer,150,151
gastric cancer,152
and CRC.
5-
FU loaded in a thermal sensitive hydrogel system (a
biodegradable PEG-
polycaprolactone (PCL)-
PEG (PECE)
triblock copolymer), prolonged drug release time and
markedly inhibited the growth and dissemination of
CT26 cells in colorectal peritoneal carcinomatosis (CRPC)
murine model.153
An alginate nanocomposite hydrogel
coloaded with CDDP and gold nanoparticles (AuNPs),
combining photothermal therapy with chemotherapy, dra-
matically inhibited the growth of 90% colorectal tumors
of control and dramatically improve the animal survival
studied in CT26 colorectal xenograft murine model. This
chemophotothermal therapy based on hydrogel could di-
rectly transport high-
dose drugs and heat to tumors with
neglectable side effects, which elevated the antitumor
efficiency of CDDP and had the potential to evade CRC
relapse.154
A thermo-
sensitive hydrogel coloaded with
L-
OHP and tannic acid (TA) polymeric nanoparticles (L-
OHP/TA NPs), an injectable drug delivery system, could
evade the growth of tumors and prolonged the survival
time of the CT26 peritoneal CRC murine model.155
An in-
jectable thermal-
sensitive poly(L-
glutamate)-
based hydro-
gel coloaded with CDDP and combretastatin A4 disodium
phosphate (CA4P), exerted enhanced antitumor efficacy
in C26 colon cancer-
bearing mice.156
7 | COMBINATION THERAPY
Combination therapy is the common treatment for CRC.
FOLFOX, capecitabine and oxaliplatin (CapeOX), and
leucovorin, fluorouracil, and irinotecan hydrochloride
(FOLFIRI) are the first-
line regimen for chemotherapy in
CRC. Combination therapy could enhance anticancer effi-
cacy, prolong survival, prevent drug resistance, and tumor
relapse, which always makes an effect of “1+1>2.”
Various combination therapies combating chemoresist-
ance have been clarified in the upper five sections, so the
combined therapies not belonging to these sections are il-
lustrated below.
7.1 | Combined with 5-
FU
Auranofin, a forkhead box 3 (FoxO3) agonist and thiore-
doxin reductase 1 (TR1) inhibitor, could enhance the
sensitivity of HCT-
8/5-
FU and SW620/5-
FU cells to
5-
FU in vitro and the sensitivity of SW620/5-
FU cells to
5-
FU treatment in vivo by inhibiting the nuclear factor
erythroid 2-
related factor 2 (Nrf2)/TR1 signaling path-
way. Auranofin in combination with 5-
FU induced the
most cell death compared to treatment with auranofin
or 5-
FU alone and suppressed tumor cell invasion obvi-
ously. In SW620/5-
FU cells xenograft nude mice, fewer
lung metastatic nodules were observed in auranofin plus
5-
FU group than in the 5-
FU or auranofin groups.157
It
has been found that Lactobacillus Plantarum Supernatant
(LP SN) combined with 5-
FU could reverse the resistance
to 5-
FU and enhance the therapeutic effect of 5-
FU in
5-
FU-
resistant HT29 cells and HCT116 cells by inactivat-
ing the Wnt/β-
catenin signaling, reducing CSCs, and in-
creasing apoptosis.158
Curaxins, a class of small molecules,
might overcome 5-
FU resistance in defective mismatch-
repair (dMMR) colorectal cancer patients by targeting
the histone chaperone facilitates chromatin transcription
(FACT) complex.159
7.2 | Combined with L-
OHP
Administration of Toll-
like receptor agonists R848
combined with L-
OHP reversed the functional orien-
tation of myeloid-
derived suppressor cells (MDSCs)
toward tumoricidal M1-
like macrophages and strength-
ened the antitumor effect of L-
OHP.160
Combinational
inhibition of YAP by a YAP-
specific inhibitor verte-
porfin and an inhibitor of EGFR/ErbB1 AG1478 syner-
gistically inhibited the CRC progression and overcame
chemoresistance.161
GW4064, a synthetic farnesoid X
receptor (FXR) agonist, could enhance the antineo-
plasm effects of L-
OHP by inducing BAX/caspase-
3/
gasdermin E (GSDME)-
mediated pyroptosis in HT26
and SW620 cells.162
7.3 | Combined with DOX
Tamoxifen, a selective estrogen receptor modulator, com-
bined with DOX can reverse MDR in CRC nude mice, re-
duced weight and volume of transplanted tumors, which
is independent of the expression of estrogen receptors and
has no influence on MDR1 expression.163
8 | CONCLUSION
CRC is one of the most prevalent cancers across the
world with increasing incidence in recent years, and the
chemoresistance caused by long-
term use has evaded the
therapeutic process of CRC. Chemical drugs, combined
with clinical common drugs, herbal medicine monomers,
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| 11091
MA et al.
gene therapy, and protein inhibitors, could restore the
chemosensitivity of tumors to chemodrugs. Nanocarriers,
liposomes, exosomes, and hydrogels, as drug delivery sys-
tems, could combine multiple drugs together well, trans-
port these drugs to the tumor site directly, and control
the drug release, which dramatically enhances the drug
effect and reverse the drug resistance occurred in mono-
drug therapy. Reversal drugs involved in drug repurpos-
ing and herbal medicinal compound are already marketed
drugs, and are the safest and fastest mean able to apply
in the clinic, thus more efforts should be contributed in
these fields. Gene therapy and protein inhibitors, belong-
ing to gene and protein levels, respectively, become a hot
spot in cancer treatment and chemoresistance. Moreover,
gene therapy in chemoresistance reversal still stays in the
early stage but own huge developmental potential. So far,
although various potential strategies have been found,
there is still a long way to go from laboratory to clinic.
Therefore, further and consistent investigation is required
to the realization of the victory in the chemoresistance
combat of CRC.
AUTHOR CONTRIBUTIONS
Shuchang Ma: Visualization (lead); writing – original
draft (lead); writing – review and editing (lead). Jiaqi
Zhang: Visualization (lead); writing – review and edit-
ing (lead). Tianhua Yan: Writing – review and editing
(equal). Mingxing Miao: Writing – review and editing
(equal). Yemin Cao: Writing – review and editing (equal).
Yongbing Cao: Writing – review and editing (equal).
Lichao Zhang: Writing – review and editing (equal).
Ling Li: Supervision (lead); validation (lead); visualiza-
tion (lead); writing – review and editing (lead).
FUNDING INFORMATION
This study was supported by grants from the National
Natural Science Foundation of China (No. 81973551),
the Science and Technology Commission of Shanghai
Municipality (No. 19ZR1451800, 21ZR1460400), the
Innovative projects of Shanghai University of Traditional
Chinese Medicine (Y2021030), the Future plan for
Traditional Chinese Medicine development ofSci-
ence, the Health Commission of Shanghai Municipality
(ZY(2021-
2023)-
0203-
04) and the Technology of Shanghai
Municipal Hospital of Traditional Chinese Medicine
(WL-
HBBD-
2021001K).
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data
were created or analyzed in this study.
ORCID
Shu-
Chang Ma https://orcid.org/0000-0002-4513-960X
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Cancer Medicine - 2023 - Ma - Novel strategies to reverse chemoresistance in colorectal cancer.pdf

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