1) The study explored two strategies to inhibit P-glycoprotein (P-gp) mediated drug resistance in multiple myeloma (MM) cells: directly targeting P-gp with a P-gp inhibitor (Tariquidar), and indirectly targeting the genetic regulator of P-gp, hypoxia-inducible factor 1-alpha (HIF-1α), with an HIF-1α inhibitor (Px-478).
2) They found that under hypoxic conditions, inhibiting P-gp with Tariquidar, but not inhibiting HIF-1α with Px-478, increased intracellular accumulation of the fluorescent P-gp substrate Rhodamine 123 in MM cells, restoring levels
Description on definition of pharmacogenetics, role of pharmacogenetics in drug response, role of polymorphism in drug metabolism, drug transporters and drug targets.
Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.
This is a set of powerpoint slides with self-assessment questions interspersed throuought on drug metabolism and pharmacogenetics. The aim is to understand the mechanism of clinically significant drug interactions, recognize potentially clinically significant genetic influences on drug efficacy and toxicity, and genetic predispositions to disease due to altered drug metabolism or transport. This resource is appropriate for medical students or graduate healthcare professionals such as nursing students.
Description on definition of pharmacogenetics, role of pharmacogenetics in drug response, role of polymorphism in drug metabolism, drug transporters and drug targets.
Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.
This is a set of powerpoint slides with self-assessment questions interspersed throuought on drug metabolism and pharmacogenetics. The aim is to understand the mechanism of clinically significant drug interactions, recognize potentially clinically significant genetic influences on drug efficacy and toxicity, and genetic predispositions to disease due to altered drug metabolism or transport. This resource is appropriate for medical students or graduate healthcare professionals such as nursing students.
Event Details
This webinar will introduce the Advanced MethylDetox Profile, discuss the scientific underpinnings of methylation and detoxifications, and explain how this test can benefit your patients. Our speakers have a diverse range of backgrounds from research to clinical practice.
Key Learning Points
-Discover the critical genes in the methylation pathway
-Understand each gene’s role in patient methylation function
-See how the MethylDetox Profile can be used clinically
-Learn how to monitor treatment progress
Event Details
This webinar will introduce the Advanced MethylDetox Profile, discuss the scientific underpinnings of methylation and detoxifications, and explain how this test can benefit your patients. Our speakers have a diverse range of backgrounds from research to clinical practice.
Key Learning Points
-Discover the critical genes in the methylation pathway
-Understand each gene’s role in patient methylation function
-See how the MethylDetox Profile can be used clinically
-Learn how to monitor treatment progress
RNA Interference(RNAi) is a conserved biological response of eukaryotes against double-stranded RNA causing silencing of the gene expression. This mechanism has an important role in defending cells against viral genes and transposons. RNAi technology has become the latest "next big thing," progressing from a barely understood colour silencing mechanism found in flowers to a powerful tool that is going to become a new therapeutic tool for treating illnesses ranging from AIDS to cancer to Huntington’s disease. Even more exciting is the potential of RNAi in agriculture where it has provided a way to control pests and diseases as well as increase nutritional value of food.
RNA interference (RNAi) is a mechanism that inhibits gene expression at the stage of translation or by hindering the transcription of specific genes.
RNAi targets include RNA from viruses and transposons.
Pharmacogenetics is the study of influences of a gene on therapeutic and adverse effects of drugs.
Pharmacogenetics plays an important role in drug development and drug safety.
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...daranisaha
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...eshaasini
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...semualkaira
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...semualkaira
: Prolyl 4-hydroxylase, beta polypeptide (P4HB)
and Glucose‑regulated protein 78 (GRP78) represent for poor
prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer
Polymer therapeutics: an smart drug delivary systemAlok kumar Soni
The development of polymer therapeutics has emerged as an exciting field of research for improving the therapeutic potential of low-molecular-weight drugs and proteins. this presentation depicted overview of nanomedicine in healthcare industry
Medical Technology Tackles New Health Care Demand - Research Report - March 2...pchutichetpong
M Capital Group (“MCG”) predicts that with, against, despite, and even without the global pandemic, the medical technology (MedTech) industry shows signs of continuous healthy growth, driven by smaller, faster, and cheaper devices, growing demand for home-based applications, technological innovation, strategic acquisitions, investments, and SPAC listings. MCG predicts that this should reflects itself in annual growth of over 6%, well beyond 2028.
According to Chris Mouchabhani, Managing Partner at M Capital Group, “Despite all economic scenarios that one may consider, beyond overall economic shocks, medical technology should remain one of the most promising and robust sectors over the short to medium term and well beyond 2028.”
There is a movement towards home-based care for the elderly, next generation scanning and MRI devices, wearable technology, artificial intelligence incorporation, and online connectivity. Experts also see a focus on predictive, preventive, personalized, participatory, and precision medicine, with rising levels of integration of home care and technological innovation.
The average cost of treatment has been rising across the board, creating additional financial burdens to governments, healthcare providers and insurance companies. According to MCG, cost-per-inpatient-stay in the United States alone rose on average annually by over 13% between 2014 to 2021, leading MedTech to focus research efforts on optimized medical equipment at lower price points, whilst emphasizing portability and ease of use. Namely, 46% of the 1,008 medical technology companies in the 2021 MedTech Innovator (“MTI”) database are focusing on prevention, wellness, detection, or diagnosis, signaling a clear push for preventive care to also tackle costs.
In addition, there has also been a lasting impact on consumer and medical demand for home care, supported by the pandemic. Lockdowns, closure of care facilities, and healthcare systems subjected to capacity pressure, accelerated demand away from traditional inpatient care. Now, outpatient care solutions are driving industry production, with nearly 70% of recent diagnostics start-up companies producing products in areas such as ambulatory clinics, at-home care, and self-administered diagnostics.
Deep Leg Vein Thrombosis (DVT): Meaning, Causes, Symptoms, Treatment, and Mor...The Lifesciences Magazine
Deep Leg Vein Thrombosis occurs when a blood clot forms in one or more of the deep veins in the legs. These clots can impede blood flow, leading to severe complications.
One of the most developed cities of India, the city of Chennai is the capital of Tamilnadu and many people from different parts of India come here to earn their bread and butter. Being a metropolitan, the city is filled with towering building and beaches but the sad part as with almost every Indian city
Empowering ACOs: Leveraging Quality Management Tools for MIPS and BeyondHealth Catalyst
Join us as we delve into the crucial realm of quality reporting for MSSP (Medicare Shared Savings Program) Accountable Care Organizations (ACOs).
In this session, we will explore how a robust quality management solution can empower your organization to meet regulatory requirements and improve processes for MIPS reporting and internal quality programs. Learn how our MeasureAble application enables compliance and fosters continuous improvement.
India Clinical Trials Market: Industry Size and Growth Trends [2030] Analyzed...Kumar Satyam
According to TechSci Research report, "India Clinical Trials Market- By Region, Competition, Forecast & Opportunities, 2030F," the India Clinical Trials Market was valued at USD 2.05 billion in 2024 and is projected to grow at a compound annual growth rate (CAGR) of 8.64% through 2030. The market is driven by a variety of factors, making India an attractive destination for pharmaceutical companies and researchers. India's vast and diverse patient population, cost-effective operational environment, and a large pool of skilled medical professionals contribute significantly to the market's growth. Additionally, increasing government support in streamlining regulations and the growing prevalence of lifestyle diseases further propel the clinical trials market.
Growing Prevalence of Lifestyle Diseases
The rising incidence of lifestyle diseases such as diabetes, cardiovascular diseases, and cancer is a major trend driving the clinical trials market in India. These conditions necessitate the development and testing of new treatment methods, creating a robust demand for clinical trials. The increasing burden of these diseases highlights the need for innovative therapies and underscores the importance of India as a key player in global clinical research.
Navigating Challenges: Mental Health, Legislation, and the Prison System in B...Guillermo Rivera
This conference will delve into the intricate intersections between mental health, legal frameworks, and the prison system in Bolivia. It aims to provide a comprehensive overview of the current challenges faced by mental health professionals working within the legislative and correctional landscapes. Topics of discussion will include the prevalence and impact of mental health issues among the incarcerated population, the effectiveness of existing mental health policies and legislation, and potential reforms to enhance the mental health support system within prisons.
CRISPR-Cas9, a revolutionary gene-editing tool, holds immense potential to reshape medicine, agriculture, and our understanding of life. But like any powerful tool, it comes with ethical considerations.
Unveiling CRISPR: This naturally occurring bacterial defense system (crRNA & Cas9 protein) fights viruses. Scientists repurposed it for precise gene editing (correction, deletion, insertion) by targeting specific DNA sequences.
The Promise: CRISPR offers exciting possibilities:
Gene Therapy: Correcting genetic diseases like cystic fibrosis.
Agriculture: Engineering crops resistant to pests and harsh environments.
Research: Studying gene function to unlock new knowledge.
The Peril: Ethical concerns demand attention:
Off-target Effects: Unintended DNA edits can have unforeseen consequences.
Eugenics: Misusing CRISPR for designer babies raises social and ethical questions.
Equity: High costs could limit access to this potentially life-saving technology.
The Path Forward: Responsible development is crucial:
International Collaboration: Clear guidelines are needed for research and human trials.
Public Education: Open discussions ensure informed decisions about CRISPR.
Prioritize Safety and Ethics: Safety and ethical principles must be paramount.
CRISPR offers a powerful tool for a better future, but responsible development and addressing ethical concerns are essential. By prioritizing safety, fostering open dialogue, and ensuring equitable access, we can harness CRISPR's power for the benefit of all. (2998 characters)
Health Education on prevention of hypertensionRadhika kulvi
Hypertension is a chronic condition of concern due to its role in the causation of coronary heart diseases. Hypertension is a worldwide epidemic and important risk factor for coronary artery disease, stroke and renal diseases. Blood pressure is the force exerted by the blood against the walls of the blood vessels and is sufficient to maintain tissue perfusion during activity and rest. Hypertension is sustained elevation of BP. In adults, HTN exists when systolic blood pressure is equal to or greater than 140mmHg or diastolic BP is equal to or greater than 90mmHg. The
CHAPTER 1 SEMESTER V PREVENTIVE-PEDIATRICS.pdfSachin Sharma
This content provides an overview of preventive pediatrics. It defines preventive pediatrics as preventing disease and promoting children's physical, mental, and social well-being to achieve positive health. It discusses antenatal, postnatal, and social preventive pediatrics. It also covers various child health programs like immunization, breastfeeding, ICDS, and the roles of organizations like WHO, UNICEF, and nurses in preventive pediatrics.
Explore our infographic on 'Essential Metrics for Palliative Care Management' which highlights key performance indicators crucial for enhancing the quality and efficiency of palliative care services.
This visual guide breaks down important metrics across four categories: Patient-Centered Metrics, Care Efficiency Metrics, Quality of Life Metrics, and Staff Metrics. Each section is designed to help healthcare professionals monitor and improve care delivery for patients facing serious illnesses. Understand how to implement these metrics in your palliative care practices for better outcomes and higher satisfaction levels.
How many patients does case series should have In comparison to case reports.pdfpubrica101
Pubrica’s team of researchers and writers create scientific and medical research articles, which may be important resources for authors and practitioners. Pubrica medical writers assist you in creating and revising the introduction by alerting the reader to gaps in the chosen study subject. Our professionals understand the order in which the hypothesis topic is followed by the broad subject, the issue, and the backdrop.
https://pubrica.com/academy/case-study-or-series/how-many-patients-does-case-series-should-have-in-comparison-to-case-reports/
Therapeutic Strategies Aimed to Circumvent P-Glycoprotein-Mediated Resistance in Multiple Myeloma
1. THERAPEUTIC STRATEGIES AIMED TO CIRCUMVENT P-GLYCOPROTEIN-MEDIATED
RESISTANCE IN MULTIPLE MYELOMA
Nicholas Potter1,2
, Pharm.D. Candidate 2017, Benjamin Minch1,2
, Pharm.D. Candidate 2017, Barbara Muz2
,Ph.D., Noha N. Salama1
, Ph.D., and Abdel Kareem Azab2
,Ph.D.
1
St. Louis College of Pharmacy, Department of Pharmaceutical and Administrative Sciences, St. Louis, MO.
2
Washington University Medical School, Department of Radiation Oncology, St. Louis, MO.
ABSTRACT
Introduction: Multiple myeloma (MM) is a malignant neoplastic cancer of the
plasma cells that involves the bone marrow (BM). Generally, patients respond
initially to treatment, but become refractory later-on. With novel therapeutic
agents, the median survival of MM patients is estimated to be about 7 years;
however, patients that are refractory to these drugs (such as proteasome
inhibitors) have an overall average survival of 9 months. Hypoxia develops in
the BM niche during MM progression and plays a major role in MM cell
dissemination to new BM niches. Additionally, hypoxia has long been linked to
chemoresistance. Hypoxia-Inducible Factor (HIF-1α) is upregulated in many
hypoxic cells, and is the key regulator of a cell’s hypoxic response. Increased
expression of efflux proteins, such as P-glycoprotein (P-gp), is a major reason
for drug resistance in MM because many MM drugs are P-gp substrates (such
as proteasome inhibitors). MDR1, the gene encoding P-gp, is a target gene of
HIF-1α. We hypothesize that inhibition of the hypoxic response in MM cells by
inhibition of the HIF-1α pathway will prevent P-gp induction and re-sensitize
MM cells to therapy. We explored two strategies to inhibit or minimize the
development of P-gp mediated drug resistance in MM: 1) a direct approach
through targeting P-gp efflux using a P-gp inhibitor and 2) an indirect
approach through targeting the genetic regulation of HIF-1α .
Methods: MM1s cells (n =3/treatment), MM cell line, were incubated under
normoxic and hypoxic conditions for 24 hrs. with 1) Tariquidar, a P-gp
inhibitor, 2) Px-478, a HIF-1α inhibitor or 3) Tariquidar and Px-478. The cells
were then treated with Rhodamine 123 (Rh123, a fluorescent model P-gp
substrate) for 1 hr. at 1 ug/mL. The intracellular Rh123 concentration was
measured by flow cytometry and compared statistically using ANOVA and
Bonferroni pairwise comparisons at P<0.05 (SPSS 20).
Results: We did not detect a significant difference in the cellular Rh123
content in the absence or presence of any agent under normoxic conditions.
However, under hypoxic conditions, incubation of the cells with either
Tariquidar or Tariquidar/Px-478 caused a significant increase in the amount of
Rh123 accumulating inside the cells. When comparing the effect of hypoxia to
normoxia on Rh123 accumulation intracellularly with and without inhibitors,
there was a substantially lower (P <0.05) Rh123 intracellular content in MM1s
cells incubated under hypoxic conditions in the absence and presence of Px-
478. In contrast, the extent of Rh123 intracellular accumulation following
treatment of the cells with Tariquidar or Tariquidar/Px-478 was not significantly
different under normoxic and hypoxic conditions.
Conclusions: The extent of Rh123 intracellular accumulation is a measure of
P-gp efflux. In this study, we detected an increase in the extent of Rh123
effluxed out of the MM1s cells under hypoxic conditions, which suggests P-gp
upregulation and is consistent with recent studies reported by our research
group. HIF inhibition was recently reported to be a successful strategy to
prevent P-gp upregulation in hypoxia and subsequently interfere with drug
resistance in other types of cancer. However, in our study, HIF-1α inhibition
had no effect on Rh123 efflux under hypoxic conditions. The co-incubation of
Tariquidar with Px-478 did not provide an enhanced effect beyond that
observed with Tariquidar incubation alone. Future studies will focus on
exploring higher concentrations of Px-478 as well as other HIF-1α inhibitors.
On the contrary, inhibition of P-gp-mediated Rh123 efflux by Tariquidar had no
effect in normoxia (limited or no P-gp expression) but significantly increased
the extent of intracellular Rh123 accumulation under hypoxic conditions where
P-gp is upregulated. Hence, P-gp inhibition proved to be a successful strategy
to interfere with the development of P-gp mediated drug resistance in MM.
CONCLUSIONS
Our research group reported enhanced MM drug resistance to
current therapies when MM cells are hypoxic.3
In the study
described herein, we used the accumulation of the P-gp substrate
Rh123 as an indicator of the change in P-gp activity in cells under
hypoxic versus normoxic conditions. We documented a 43.4%
decrease in Rh123 intracellular content under hypoxia compared
to normoxic conditions, which is comparable to earlier findings.9
Because HIF-1α targets MDR1 (the gene encoding P-gp) we
expected that inhibition of HIF-1α would restore Rh123
intracellular accumulation under hypoxic conditions. However,
using Px-478 at 25uM did not prove effective in minimizing P-gp-
mediated drug resistance under hypoxia in the tested MM cell
lines. Future studies will explore additional or alternative specific
HIF-1α inhibitors at a range of concentrations. The extent of
contribution of other cellular mechanisms of drug resistance to the
decline in Rh123 intracellular content remains elusive.
On the contrary, inhibition of P-gp via Tariquidar under hypoxic
conditions restored the extent of Rh123 intracellular accumulation
to the levels detected under normoxia. Combining both Px-478
and Tariquidar provided no synergistic effects when compared to
Tariquidar treatment alone. This observation suggests that
Tariquidar was the sole contributor to the restoration of Rh123
cellular levels and hence, P-gp inhibition is an effective strategy to
prevent the development of resistance to P-gp substrates such as
the MM drugs, Carfilzomib, Doxorubicin, and Melphalan in
hypoxia-induced resistant MM cells lines.
REFERENCES
1.Abraham J et al. The role of P-glycoprotein in drug resistance in multiple
myeloma. Leuk Lymphoma. 2015;56(1):26-33.
2.Azab A et al. Hypoxia promotes dissemination of multiple myeloma through
acquisition of epithelial to mesenchymal transition-like features. Blood.
2012;119(24):5782-5794.
3.Muz B et al. Hypoxia promotes stem cell-like phenotype in multiple myeloma
cells. Blood Cancer Journal. 2014;4(12):e262.
4.De la Puente P et al. Molecularly Targeted Therapies in Multiple
Myeloma. Leukemia Research and Treatment. 2014;2014:976567.
5.Welsh Set al. Antitumor activity and pharmacodynamic properties of PX-478, an
inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004;3(3):233-44.
6.Thomas H and Coley H. Overcoming multidrug resistance in cancer: an update
on the clinical strategy of inhibiting P-glycoprotein. Cancer Control. 2003;10(2):159-
65.
7.Mistry P et al. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug
resistance by a novel potent modulator, XR9576. Cancer Res. 2001;61:749-758
8.Chen J et al. HIF-1α inhibition reverses multidrug resistance in colon cancer cells
via downregulation of MDR1/P-Glycoprotein. Zmijewski M, ed. PLoS ONE.
2014;9(6):e98882.
9.Abraham J et al. Hypoxia induces up-regulation of p-glycoprotein and promotes
resistance to carfilzomib in multiple myeloma. AAPS Annual Meeting and
Exposition, November 2-6, 2014, San Diego, CA.
BACKGROUND
Multiple Myeloma (MM) is a type of malignant cancer of bone
marrow plasma cells. There are 20,000 new cases yearly with
10,000 deaths attributed to this disease.1
The median survival for patients with MM is about 4-5 years with
advancements to 7 years with newer therapy.1
This low survival
rate is attributed to the development of resistance mechanisms
that render MM unresponsive to previously efficacious
therapies.1
Regions of low blood concentration (hypoxia) arise in cancerous
tumors due to enhanced cell activity and division, coupled with
insufficient angiogenesis.2
Hypoxia is also a desirable
therapeutic target for MM as it has a potentially high therapeutic
index.
Several studies have concluded that hypoxia promotes cancer
cell progression and survival through various transcription
factors.2
Azab, et al. reported enhanced MM drug resistance to
current therapies when MM cells are hypoxic.3
Hypoxia-Inducible Transcription Factor-1 (HIF-1) is a
heterodimer; consisting of the HIF-1α and HIF-1β subunits, with
HIF-1α playing a major role in a cell’s hypoxic response.4
Studies have demonstrated that the inhibition of HIF-1α blocks
MM angiogenesis, tumor burden, and bone destruction in vivo.4
Px-478 is reported to be an effective HIF-1α inhibitor in many
forms of cancer.5
P-glycoprotein (P-gp) is a drug transporter, induced by the
MDR1 gene1
. It effluxes its substrates from inside the cell to the
extracellular space. Treatment with chemotherapeutic agents
(e.g. doxorubicin, carfilzomib) was associated with P-gp
upregulation in MM cells, leading to decreased drug efficacy.
Tariquidar is a third-generation P-gp inhibitor that non-
competitively binds with high affinity to this efflux pump.6
It was
shown to inhibit P-gp activity for 22 hours in vitro after the drug
was removed from the culture medium.7
MDR1, the gene encoding P-gp, is a target gene of HIF-1α.
Recent studies involving colon cancer reported that HIF-1α
inhibition reverses drug resistance via downregulation of
MDR1/P-gp.8
A similar correlation has not been confirmed in
MM.
HYPOTHESIS
We hypothesize that inhibition of the hypoxic response in MM
cells by inhibition of the HIF-1α pathway will prevent P-gp
induction and re-sensitize MM cells to therapy.
OBJECTIVES
We explored two strategies to inhibit the development of P-gp
mediated drug resistance in MM: 1) a direct approach through
targeting P-gp efflux using a P-gp inhibitor and 2) an indirect
approach through targeting the genetic regulation of HIF-1α.
METHODS
MM1s cell line was used as a biological model for MM. The cells
(5x 105
cells/ well) were incubated for 24 hours under either
normoxic (37 o
C, 5% CO2, 21% O2) or hypoxic (37 o
C, 5% CO2,
1% O2) conditions with/without one of the following treatments:
1)RPMI 1640 growth medium with L-glutamine
2)Px-478 (25 uM, HIF-1α inhibitor) in RPMI 1640 medium
3)Tariquidar (1 uM, P-gp inhibitor) in RPMI 1640 medium
4)Px-478 (25uM) and Tariquidar (1uM) in RPMI 1640 medium
The fluorescent P-gp substrate; Rhodamine 123 (Rh123,
1ug/mL) was subsequently incubated with the cells for 1 hour.
The MM1s cells were then washed 3 times by PBS 1x.
The mean fluorescence intensity (MFI) for the intracellular Rh123
was measured by flow cytometry.
Control wells (without Rh123) were used to measure the
background/noise.
Statistical analysis: The different treatments were compared
statistically using ANOVA and Bonferroni pairwise comparisons
at P<0.05 (SPSS 20).
RESULTS
Under normoxic conditions, we did not detect a significant
difference between the intracellular concentrations of Rh123
under any treatment in normoxic conditions. The untreated, Px-
478-treated, Tariquidar-treated, and Px-478/Tariquidar- treated
cells showed intracellular Rh123 concentrations of 2.71 ± 0.16,
2.31 ± 0.20, 2.30 ± 0.07, and 2.42 ± 0.38 respectively (p>0.05).
Under hypoxia, Rh123 intracellular concentrations were not
significantly different when comparing Px-478 treated cells to the
control untreated cells.
RESULTS
The intracellular concentrations of Rh123 in Tariquidar-treated
and Px-478/Tariquidar-treated hypoxic cells were not statistically
different from each other. However, their Rh123 intracellular
content was significantly (p<0.05) higher than the levels
detected with the untreated and Px-478 treated cells.
When comparing incubation under hypoxic and normoxic
conditions, we detected a significant decrease (43.4%) in Rh123
intracellular concentrations in untreated hypoxic cells (1.89 ±
0.08) compared to untreated normoxic cells (2.71 ± 0.16). This
observation was reported earlier by our research group.9
Similarly, treatment of the cells with Px-478 resulted in
significantly lower (22.9%) Rh123 intracellular content in hypoxic
cells (1.88 ± 0.13) compared to normoxic cells (2.31 ± 0.20).
On the contrary, treatment of the cells with Tariquidar or with Px-
478/Tariquidar did not show any substantial differences in
Rh123 intracellular content under hypoxic versus normoxic
conditions.
Intracellular Rh123 Concentrations Under Hypoxia
Untreated Px-478 Tariquidar Px-478/Tariquidar
1.89 ± 0.08
(100%)
1.88 ± 0.13
(99.5%)
2.35 ± 0.16 *
(124.3%)
2.53 ± 0.08 *
(133.9%)
* p<0.05
ACKNOWLEDGEMENTS
This research was supported by the Washington University
Institute of Clinical and Translational Sciences grant
UL1TR000448 from the National Center for Advancing
Translational Sciences (NCATS) of the National Institutes of
Health (NIH). The content is solely the responsibility of the
authors and does not necessarily represent the official view of
the NIH. Additional resources were provided through Federal
work Study and Departmental Research Assistantship Funds.
Fig 1. The intracellular Rhodamine 123 concentrations in
MM1s cells, in the presence and absence of P-gp and HIF-1α
inhibitors under hypoxic and normoxic conditions.
0
20
40
60
80
100
120
Control PX-478 Tariquidar PX-478/Tariq
IntracellularcontentofRh123
(%ofuntreatedcomtrolMM1s)
Normoxia
Hypoxia
**
* p<0.05