Title:Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance
Volume: 15
Issue: 5
Author(s): Subburayan Karthikeyan and Sugeerappa Laxmanappa Hoti
Affiliation:
Keywords:
ABC transporters, chemotherapy, multidrug resistance, natural products, overexpression.
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.
