Abstract
Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.
Highlights
Multidrug resistance (MDR) refers to the resistance of a wide spectrum of structurally and mechanistically unrelated drugs across the membrane
We summarize the recent progress of the most clinically significant ATP binding cassette (ABC) transporters ABCB1, ABCG2, and ABCC1 that cause multi-drug resistance during cancer therapy, with the emphasis on novel small molecule compounds that are Clinically Relevant ABC Transporter tested in preclinical and clinical studies, mainly on natural products, synthetic compounds, aiming to provide a wider perspective to understand the multidrug resistance and new strategies targeting ABC transporters in cancer treatment
ABCG2 locates in the plasma membrane of the cell and expresses in normal tissues like placenta, prostate, kidney, blood-brain barrier, liver, ovary, small intestine, and seminal vesicle (Jackson et al, 2018), which is responsible for regulating the intracellular levels of hormones, lipids, ion and intracellular organelles such as mitochondrion (Ding et al, 2019), lysosome (Chapuy et al, 2008), endoplasmic reticulum (Kashiwayama et al, 2009), Golgi apparatus (Tsuchida et al, 2008)
Summary
Multidrug resistance (MDR) refers to the resistance of a wide spectrum of structurally and mechanistically unrelated drugs across the membrane. The critical role of P-gp in the blood-brain barrier ( known as BBB), was first illustrated by Schinkel et al (Schinkel et al, 1994) They found the deletion of Abcb1a and Abcb1b can lead to CNS toxicity from ivermectin, despite its defensive role in protecting cells, the overexpression of P-gp mRNA and protein in clinical specimens in breast, kidney, and lung cancers portends a poor response to chemotherapy, resulting in low survival rates (Robey et al, 2010; Amiri-Kordestani et al, 2012). ABCG2 locates in the plasma membrane of the cell and expresses in normal tissues like placenta, prostate, kidney, blood-brain barrier, liver, ovary, small intestine, and seminal vesicle (Jackson et al, 2018), which is responsible for regulating the intracellular levels of hormones, lipids, ion and intracellular organelles such as mitochondrion (Ding et al, 2019), lysosome (Chapuy et al, 2008), endoplasmic reticulum (Kashiwayama et al, 2009), Golgi apparatus (Tsuchida et al, 2008). The MYCN oncogene, a driver of tumorigenesis in neuroblastoma, can regulate ABCC1 drug transporter at the level of transcription (Weiss et al, 1997; Porro et al, 2010; Henderson et al, 2011)
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