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Progress on Multidrug Resistance Mechanisms in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 11341

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Prof. Dr. Chung-Pu Wu

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Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan 333, Taiwan
Interests: multidrug resistance mechanisms; ATP-binding cassette proteins; protein kinase inhibitors; medicinal chemistry; natural products chemistry
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Dear Colleagues,

A high proportion of cancer patients will develop multidrug resistance (MDR) during the course of chemotherapy, and they will no longer be responsive to anticancer agents that are structurally and functionally distinctive. Multiple molecular mechanisms are known to contribute to the development of multidrug resistance in cancer, including but not limited to reduced drug uptake and increased drug efflux, enhanced cellular repair mechanisms, and alterations of drug metabolism or drug targets. These resistance mechanisms can work both independently and collaboratively. In the past few years, new therapeutic targets and drug resistance mechanisms have been discovered; innovative therapeutic approaches and interventions have also been experimented with to overcome these resistance mechanisms. This Special Issue on “Progress in Multidrug Resistance Mechanisms in Cancer” invites researchers to contribute original research articles, review articles, and short communications related to all aspects of drug development and therapeutic approaches against multidrug-resistant cancers, as well as molecular mechanisms of multidrug resistance in cancer.

Prof. Chung-Pu Wu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

cancer
multidrug resistance
mechanisms of acquired drug resistance
anticancer drugs
drug development
drug discovery
combined therapy
translational medicine
therapeutic targets

Published Papers (4 papers)

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Research

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12 pages, 1478 KiB

Open AccessArticle

A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

by Shoji Kokubo, Shinobu Ohnuma, Megumi Murakami, Haruhisa Kikuchi, Shota Funayama, Hideyuki Suzuki, Taiki Kajiwara, Akihiro Yamamura, Hideaki Karasawa, Norihiko Sugisawa, Kosuke Ohsawa, Kuniyuki Kano, Junken Aoki, Takayuki Doi, Takeshi Naitoh, Suresh V. Ambudkar and Michiaki Unno

Int. J. Mol. Sci. 2021, 22(22), 12502; https://doi.org/10.3390/ijms222212502 - 19 Nov 2021

Cited by 6 | Viewed by 1749

Abstract

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC₅₀ of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy. Full article

(This article belongs to the Special Issue Progress on Multidrug Resistance Mechanisms in Cancer)

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16 pages, 3241 KiB

Open AccessArticle

The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

by Chung-Pu Wu, Yan-Qing Li, Ya-Chen Chi, Yang-Hui Huang, Tai-Ho Hung and Yu-Shan Wu

Int. J. Mol. Sci. 2021, 22(17), 9440; https://doi.org/10.3390/ijms22179440 - 30 Aug 2021

Cited by 4 | Viewed by 2252

Abstract

Human ATP-binding cassette (ABC) subfamily G member 2 (ABCG2) mediates the transport of a wide variety of conventional cytotoxic anticancer drugs and molecular targeted agents. Consequently, the overexpression of ABCG2 in cancer cells is linked to the development of the multidrug resistance (MDR) phenotype. TP-3654 is an experimental second-generation inhibitor of PIM kinase that is currently under investigation in clinical trials to treat advanced solid tumors and myelofibrosis. In this study, we discovered that by attenuating the drug transport function of ABCG2, TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic ABCG2 substrate drugs topotecan, SN-38 and mitoxantrone. Moreover, our results indicate that ABCG2 does not mediate resistance to TP-3654 and may not play a major role in the induction of resistance to TP-3654 in cancer patients. Taken together, our findings reveal that TP-3654 is a selective, potent modulator of ABCG2 drug efflux function that may offer an additional combination therapy option for the treatment of multidrug-resistant cancers. Full article

(This article belongs to the Special Issue Progress on Multidrug Resistance Mechanisms in Cancer)

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17 pages, 4711 KiB

Open AccessArticle

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

by Laura Mosca, Martina Pagano, Luigi Borzacchiello, Luigi Mele, Annapina Russo, Giulia Russo, Giovanna Cacciapuoti and Marina Porcelli

Int. J. Mol. Sci. 2021, 22(17), 9286; https://doi.org/10.3390/ijms22179286 - 27 Aug 2021

Cited by 16 | Viewed by 1898

Abstract

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 116^p53+/+ 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. Full article

(This article belongs to the Special Issue Progress on Multidrug Resistance Mechanisms in Cancer)

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Review

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28 pages, 1094 KiB

Open AccessReview

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

by Erin R. Scheidemann and Ayesha N. Shajahan-Haq

Int. J. Mol. Sci. 2021, 22(22), 12292; https://doi.org/10.3390/ijms222212292 - 14 Nov 2021

Cited by 27 | Viewed by 4527

Abstract

Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment. Full article

(This article belongs to the Special Issue Progress on Multidrug Resistance Mechanisms in Cancer)

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