Flavonoids overcome drug resistance to cancer chemotherapy by epigenetically modulating multiple mechanisms

2021 ◽  
Vol 21 ◽  
Author(s):  
Kenneth K.W. To ◽  
William C.S. Cho
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Chemotherapy ◽  
Animal Studies ◽  
Multiple Drug Resistance ◽  
Resistance Mechanisms ◽  
Multiple Drug ◽  
Full Potential ◽  
Cancer Proliferation ◽  
Genes Encoding

Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been an increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings about the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.

scholarly journals Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells

Biochimie ◽  
2016 ◽  
Vol 124 ◽  
pp. 53-64 ◽  
Author(s):  
Geetika Chakravarty ◽  
Aditi Mathur ◽  
Pallavi Mallade ◽  
Samantha Gerlach ◽  
Joniece Willis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multiple Drug Resistance ◽  
Resistance Mechanisms ◽  
Multiple Drug ◽  
Mcf 7

Abstract C216: Small molecule antitubulin drugs that evade multiple drug resistance mechanisms.

2011 ◽  
Author(s):  
Markos Leggas ◽  
Eleftheria Tsakalozou ◽  
Tamer Ahmed ◽  
Kuei-Ling Kuo ◽  
Jamie Horn ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Small Molecule ◽  
Multiple Drug Resistance ◽  
Resistance Mechanisms ◽  
Multiple Drug

scholarly journals 3,3′-Diindolylmethane Promotes Gastric Cancer Progression via β-TrCP-Mediated NF-κB Activation in Gastric Cancer-Derived MSCs

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Shi ◽  
Yaoxiang Sun ◽  
Hongru Ruan ◽  
Cheng Ji ◽  
Jiahui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Multiple Drug Resistance ◽  
Cancer Drug ◽  
Multiple Drug ◽  
High Morbidity ◽  
Related Factors ◽  
Anti Cancer

Gastric cancer is a malignant tumor characterized by high morbidity and invasion. Surgery combined with chemo-radiotherapy is the most common treatment for gastric cancer, while multiple drug resistance always results in treatment failure. Once the anti-tumor drugs enter the tumor foci, tumor cells as well as those found in the microenvironment are affected. However, the effects of drugs on tumor microenvironment (TME) are easily overlooked. In this study, we investigated the effects of the anti-cancer drug 3,3’-diindolylmethane (DIM) on gastric cancer-derived mesenchymal stem cells (GC-MSCs) and their subsequent impact on cancer progression. Surprisingly, we found that the therapeutic concentration of DIM upregulated the expression level of tumor-related factors such as CCL-2, IL-6, and IL-8 in GC-MSCs. The conditioned medium of DIM-treated GC-MSCs promoted the proliferation, invasion, and migration of gastric cancer cells in vitro and tumor growth in vivo. Mechanistically, DIM enhanced the expression of β-TrCP, an E3 ubiquitin ligase leading to IκBα degradation and NF-κB activation in GC-MSCs. The β-TrCP knockdown partially eliminated positive results caused by DIM. Our results showed that the therapeutic dosage of DIM induced cell death in cancer cells, while enhancing MSC paracrine functions in the stroma to offset the original DIM effect on cancer cells. These findings provide a new mechanism of anti-cancer drug resistance and remind us to adjust the chemotherapeutic scheme by combining the anti-cancer drug with an appropriate signaling pathway inhibitor to block the side effects of drug on targeted TME cells.

Different Efflux Transporter Affinity and Metabolism of 99mTc-2-methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer Cells

2018 ◽  
Author(s):  
Masato Kobayashi ◽  
Takafumi Tsujiuchi ◽  
Yuya Okui ◽  
Asuka Mizutani ◽  
Kodai Nishi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Human Liver ◽  
High Stability ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Labeled Compounds ◽  
Cancer Resistance ◽  
99Mtc Mibi

Objectives: Little is known about the affinity of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for multiple drug resistance in cancer cells. Additionally, if 99mTc-labeled compounds are metabolized immediately after injection, imaging with these compounds may not allow monitoring of multiple drug resistance in cancer cells. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability in vivo. Methods: 99mTc-MIBI or 99mTc-TF was incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability of 99mTc-labeled compounds was evaluated in mice and human liver S9 fractions. Results: In vesicles, 99mTc-labeled compounds had affinity for MDR1 and MRP1. 99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99mTc-labeled compounds. 99mTc-MIBI uptake with inhibitors was higher than 99mTc-TF uptake with inhibitors. 99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99mTc-MIBI was metabolized after a 30-min incubation in SK-N-SH cells, mouse liver, human liver S9 fractions, and plasma. 99mTc-TF had high stability. Conclusion: 99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Although 99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.

scholarly journals Ciclopirox Olamine Treatment Affects the Expression Pattern of Candida albicans Genes Encoding Virulence Factors, Iron Metabolism Proteins, and Drug Resistance Factors

2003 ◽  
Vol 47 (6) ◽  
pp. 1805-1817 ◽  
Author(s):  
Markus Niewerth ◽  
Donika Kunze ◽  
Michael Seibold ◽  
Martin Schaller ◽  
Hans Christian Korting ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Resistance Genes ◽  
Mode Of Action ◽  
Multiple Drug Resistance ◽  
Expression Patterns ◽  
Multiple Drug ◽  
Ciclopirox Olamine ◽  
Genes Encoding ◽  
In Cells

ABSTRACT The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concentration (0.6 μg/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl3 to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.

scholarly journals S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

2021 ◽  
Vol 22 (17) ◽  
pp. 9286
Author(s):  
Laura Mosca ◽  
Martina Pagano ◽  
Luigi Borzacchiello ◽  
Luigi Mele ◽  
Annapina Russo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Defense Mechanism ◽  
Multiple Drug Resistance ◽  
Nutritional Supplement ◽  
Multi Drug Resistance ◽  
Multiple Drug ◽  
Cell Defense ◽  
P Glycoprotein

Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.

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