A study of the effects of xanthine derivatives including caffeine on cancer cells. It is a study for potential cancer chemotherapy adjuncts.

1. XANTHINES AND
CANCER
BY:
ENOMA, DAVID OSARIEME

2. CANCER
■ Cancer is a genetic disease that is chiefly
caused by alterations in the genome or
epigenome of a cell, ranging from point
mutations to insertions, deletions and
chromosomal aberrations.
■ These genetic changes can lead to
abnormal growth of cells and tissues that
characterize the neoplastic phenotype of
cancer (Stransky & Galante, 2010).
2

3. RELEVANT CANCER
STATISTICS
■ In 2008, an estimated 12.7 million new cancer cases
and 7.6 million cancer deaths occurred, (Ferlay et al.,
2010).
■ There was an increase in these statistics and
globally, there were 14.1 million new cases and 8.2
million deaths relating to cancer in 2012 (Ferlay et
al., 2015).
■ The most common cancers in Nigeria were breast
and cervical cancers in females and prostate cancer
in males (Jedy-Agba et al., 2012).
3

4. 4
Figure 1. Estimated counts of cancer incidence and
mortality rates of men and women within the ages of 0-
69 in 2012 (Bray et al., 2012).

5. 5
Figure 2: Hallmarks of cancer (Hanahan & Weinberg,
2000)

6. 6Figure 3. A typical growth factor induced signalling
cascade (Hejmadi, 2009).

7. 7
Figure 4. Stages of metastatic progression (Gupta & Massagué, 2006).

8. CANCER CHEMOTHERAPY
■ Cancer chemotherapy is the treatment of
cancer using anticancer drugs.
■ These drugs are used along with surgery
and/or radiotherapy to achieve and maintain
remission from cancer (Airley, 2009).
■ Chemotherapeutic agents include alkylation
agents, antimetabolites, mitotic inhibitors,
vinca alkaloids, camptothecins, hormonal
antagonists and antitumour antibiotics
(Pecorino, 2012;Baquiran, 2001).
8

9. CHEMOTHERAPY DRUG CLASSES
■ Alkylating agents: Alkylating agents have the ability to
form DNA adducts by covalent bonds via an alkyl group.
■ Examples of alkylating agents are Busulfan, Ifosfamide.
Carboplatin, Melphalan, Chlorambucil, Cisplatin.
■ Antimetabolites: They are compounds that are
structurally similar to endogenous molecules.(Lind,
2008).
■ Examples include Capecitabine, 5-Fluorouracil, Cytosine
arabinoside, Gemcitabine, Deoxycoformycin, 6-
Mercaptopurine, Floxuridine, Methotrexate.
9

10. CHEMOTHERAPY DRUG
CLASSES CONTD.
■ Mitotic Inhibitors: Mitotic inhibitors target tubulins thus
meddle with the dynamics of the mitotic spindle.
■ Taxanes (Docetaxel, Paclitaxel), Epipodopyllotoxins
(Etoposide, Teniposide) and Vinca Alkaloids (Vinblastine,
Vincristine, Vindesine, Vinorelbine) (Baquiran, 2001;
Lehne, 2013).
■ Topoisomerase Inhibitors: These enzymes as cellular
targets for several clinically active anticancer drugs.
Example:
■ Camptothecins act in the S phase and inhibit
topoisomerase I. Some camptothecins are Irinotecan and
Topotecan
10

11. 11
Figure 5. Structure of some anticancer drugs
(Pecorino, 2012).

12. TYPE OF
CANCER
CHEMOTHERAPEUTIC ANTICANCER DRUGS
Breast Cyclophosphamide, methotrexate, 5-fluorouracil
(Corrie, 2008).
Doxorubicin, cyclophosphamide(Corrie, 2008)
Lung Cyclophosphamide, doxorubicin, vincristine
(etoposide) (Corrie, 2008).
Carboplatin, Etoposide, Ifosfamide, Mesna
(Baquiran, 2001).
Prostate Flutamide, Leuprolide acetate (Airley, 2009)
Flutamide, Goserelin acetate (Baquiran, 2001)
Lymphoma
(Hodgkin's)
Doxorubicin, Bleomycin. Vinblastine, Dacarbazine
(Baquiran, 2001).
Etoposide, Vinblastine, Doxorubicin (Baquiran,
2001).
12

13. 13
TYPE OF CANCER CHEMOTHERAPEUTIC ANTICANCER DRUGS
Anal Cancer 5-Fluorouracil, Mitomycin
5-Fluorouracil, Cisplatin(Salvage
Chemotherapy)
(Chu, 2008).
Bladder Cancer Ifosfamide, Paclitaxel, Cisplatin (Chu, 2008)
Gemcitabine, Carboplatin (Chu, 2008).
Cervical cancer Paclitaxel, Cisplatin
Cisplatin, Topotecan
Bleomycin, Ifosfamide, Mesna, Cisplatin (Chu,
2008)
Acute lymphocytic
leukemia (ALL)
Cyclophosphamide, Daunorubicin, Vincristine,
Prednisone (Baquiran, 2001)

14. PURINE AND XANTHINE DERIVATIVES
USED IN CHEMOTHERAPY
■ 6-mercaptopurine remains a standard drug for
maintenance and remission in childhood acute
lymphocytic leukaemia, in combination with
methotrexate. (Chabner & Longo, 2013).
■ According to a study by Motegi et al. (2013) both
caffeine and theophylline induced apoptosis, and the
treated cells expressed annexin V and caspase 3/7;
both drugs enhanced doxorubicin-induced cytotoxicity.
■ The effects of 1-methyl-3-propyl-7-butylxanthine
(MPBX), a xanthine derivative, on idarubicin (IDA)-
induced antitumor activity against P388 leukemia
cells (P388) and bone marrow suppression were
examined by Sadzuka et al. (2000).
14

15. XANTHINES
■ Xanthine is a purine base that is found in most
human body tissues and fluids. Three xanthines
are pharmacologically important: caffeine,
theophylline, and theobromine (Craig & Stitzel,
2004).
15
Figure 7.
Methylated
purine
derivatives of
xanthine (Voet
et al., 2016).

16. PURINES AND XANTHINES
■ The most common purines are adenine (A)
and guanine (G) in the human body system
and they occur in the DNA (Voet et al.,
2016).
■ The starting material for purine
biosynthesis is ribose-5-phosphate which is
a product of the pentose phosphate
pathway.
■ Xanthines are purine bases that are found
in most human body tissues and fluids.
16

17. ORIGIN OF PURINES
17
Figure 6. Origin Of The Carbon And Nitrogen Of A Purine
Ring & First Step Of Purine Biosynthesis (Nelson & Cox,
2012; Voet et al., 2016).

18. STRUCTURE 0F XANTHINE
DERIVATIVES
18Figure 9. Inosine Monophosphate And Xanthine
Derivatives.

19. USES OF XANTHINES
■ They have legitimate therapeutic uses but the
greatest public exposure to them is in xanthine
(caffeine) containing beverages.
■ Xanthines (usually caffeine) are frequently
combined with aspirin in the treatment of
headaches.
■ Theophylline is frequently used as a
bronchodilator in the treatment of asthma.
(Craig & Stitzel, 2004).
19

20. USES OF XANTHINES CONTD.
■ Theophylline, given as the soluble
ethylenediamine salt aminophylline, offers
some help in relieving the paroxysmal dyspnea
that is often associated with left heart failure.
■ Theophylline also has shown some benefit in
the treatment of neonatal apnea syndrome.
■ Methylxanthines, including theophylline and
aminophylline have been used in the
management of asthma and chronic
obstructive pulmonary disease (DiPiro, 2010).
20

21. CAFFEINE’S ABOLISHMENT OF
DNA DAMAGE CHECKPOINT
■ Caffeine has been shown to abolish the mammalian G-
2/M DNA damage checkpoint by inhibiting Ataxia-
Telangiectasia-mutated (ATM) Kinase activity (Zhou et al.,
2000).
■ It was found that treatment of gamma irradiated cells by
caffeine inhibited the activation of Chk2/Cds1.
■ ATM is a direct kinase for Chk2/Cds1 which suggests that
caffeine is an inhibitor of cell cycle arrest by inhibiting the
phosphorylation of Chk2/Cds1 by ATM
■ A study also reported that caffeine inhibits ATM kinase
activity directly in vitro (Blasina et al., 1999).
21

22. 22
Figure 10. The eukaryotic cell cycle. Cells may enter a
quiescent phase (G0) rather than continuing about the cycle
(Voet et al., 2016)

23. CAFFEINE’S TUMOUR
DECREASING ABILITY
■ In a work done by Lou et al. (1999), Oral administration
of caffeine alone (0.44 mg/ml) as the sole source of
drinking fluid to lab mice for 18-23 weeks inhibited the
formation of non-malignant and malignant tumours.
■ Chung et al. (1998) examined the effect of black tea and
caffeine on lung tumorigenesis in F344 rats induced by
the nicotine-derived carcinogen 4-(methylnitrosamino)-l-
(3-pyridyl)-l-butanone (NNK) in a 2-year bioassay.
■ This study demonstrated for the first time that black tea
protects against lung tumorigenesis in F344 rats, and
this effect appears to be attributed, to a significant
extent, to caffeine as an active ingredient of tea.
23

24. CAFFEINE ENHANCES THE CYTOTOXIC
EFFECTS OF ANTI-CANCER AGENTS
■ Tomita and Tsuchiya (1989) studied the
effects of several combinations of several
anticancer agents (including cisplatin, 4-
hydroxyperoxycyclophophamide, mitomycin C,
adriamycin, vincristine and methotrexate) with
caffeine against cultured human sarcoma
cells.
■ They suggested that cisplatin,
cyclophosphamide, mitomycin C and
Adriamycin had their DNA-damaging effects
enhanced by caffeine.. 24

25. CAFFEINE’S INDUCTION OF
APOPTOSIS
■ Caspase-3 activation studies have demonstrated
that the presence of caffeine increased the
cisplatin-induced apoptosis in both HTB182 and
CRL5985 lung cancer cells (Wang et al., 2015).
■ A study by Liu et al. (2017) examined the
anticancer effects of caffeine on gastric cancer
cells in vitro.
■ Their results indicated that caffeine treatment
significantly suppressed gastric cancer cell growth
and viability and induced apoptosis by activating
the caspase-9/-3 pathway.
25

26. CONCLUSION
■ Finally, xanthine derivatives can be
experimented against different cancer
cells,
■ Different modifications of xanthines can
be tested against cancer cell lines and
■ More work can be done to ascertain the
anti-cancer effects of xanthines in
combination with established
chemotherapeutic drugs.
26

27. REFERENCES
■ Stransky, B., & Galante, P. (2010). Application of Bioinformatics in Cancer
Research. In W. C. S. Cho (Ed.), An Omics Perspective on Cancer Research
(pp. 211-233). Dordrecht: Springer Netherlands.
■ Voet, D., Voet, J. G., & Pratt, C. W. (2016). Fundamentals of Biochemistry:
Life at the Molecular Level, 5th Edition: Life at the Molecular Level: Wiley.
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■ DiPiro, J. T. (2010). Concepts in Clinical Pharmacokinetics: American
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■ Airley, R. (2009). Cancer Chemotherapy: Basic Science to the Clinic: Wiley.
27

28. ■ Lehne, R. A. (2013). Pharmacology for Nursing Care: Elsevier/Saunders.
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human gastric cancer cells by activating the caspase-9/caspase-3 signalling
pathway. Molecular Medicine Reports, 16(2445-2454). doi:
https://doi.org/10.3892/mmr.2017.6894
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29. THANK YOU FOR
YOUR ATTENTION.
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