Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance

Abstract

Multidrug resistance (MDR) in cancer caused due to overexpression of ABC drug transporters is a major problem in modern chemotherapy. Molecular investigations on MDR have revealed that the resistance is due to various transport proteins of the ABC superfamily which include Phosphoglycoprotein (P-gp/MDR1/ ABCB1), multidrug resistance-associated protein-1 (MRP1), and the breast cancer resistance protein (BCRP). They have been characterized functionally and are considered as major players in the development of MDR in cancer cells. These ATP-dependent transporter proteins cause MDR either by decreased uptake of the drug or increased efflux of the drug from the target organelles. Several MDR-reversing agents are being developed and are in various stages of clinical trials. The first three generations of ABC modulators such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 required to be administered in high doses to reverse MDR and were associated with adverse effects. Additionally, these modulators non-selectively inhibit ABC and adversely accumulate chemotherapeutic drugs in brain and kidney. Currently, research has stepped up towards reversing MDR by using natural products which exhibitted potential as chemosensitizers. Globally, there is a rich biodiversity of natural products which can be sourced for developing drugs. These products may provide more lead compounds with superior activity, foremost to the development of more effective therapies for MDR cancer cells. Here, we briefly review the status of natural products for reversing MDR modulators, and discuss the long term goal of MDR strategies in current clinical settings.

MDR1 in immunity: friend or foe?

“…22,23 The development of a fourth generation of inhibitors, even more specific and with lower toxicity, based on the use of natural products is still ongoing. 24,25 Other approaches to inhibit MDR1, like the use of the monoclonal antibodies (mAb) MRK-16 26 or UIC2, 27 have also been evaluated. However, UIC2 mAb inhibits only partially membrane expressed MDR1, due to its recognition of a conformational epitope only fully revealed in the presence of cyclosporin-A or valspodar.…”

Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways

“…It is well known that multidrug resistance (MDR) is a major obstacle in the chemotherapy of oral cancer. Clinically, several resistance proteins, including phosphoglycoprotein (P-gp), multidrug resistance associated proteins (MRPs), and breast cancer resistance protein (BCRP) are proved to be simultaneously involved in MDR of oral cancer [2]. Conventional single-agent chemotherapy treatment has potential risks of high toxicity for the reason that the high dosage of individual anticancer drugs.…”

“…We recently reported that natural compound including flavonoids, such as resveratrol inhibits MDR transport function directly in ABCB1 overexpressing NCI-H460 lung cancer cells [4]. Further, we have challenged to provide a recent update of the published work on the natural products which have shown promising chemosensitizing effects on ABCs drug transporters [2]. In our continuous search of naturally occurring cytotoxic compounds, we designed this study to assess the cytotoxicity of glaucarubinone (GLU), a quassinoid natural product first isolated from the seeds of Simarouba glauca , and later from numerous other species in the family Simaroubaceae [5].…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…However, in an evaluation of ABC drug transporters in a panel of tumor cell lines from the US National Cancer Institute, over half of the members that comprise the ABC drug transporter family have been implicated as playing a role in conferring MDR, suggesting multiple drug transporters are likely involved (Szakacs et al, 2004). As a means to combat MDR in cancer patients, targeting ABC drug transporters through pharmacological inhibition has been attempted for several years but with poor results (Turk and Szakacs, 2009;Karthikeyan and Hoti, 2015). Because of their clinical contribution to MDR, studies aimed at understanding the regulatory mechanisms of transporters focus heavily on changes in gene and protein expression.…”