Discovering Natural Product Modulators to Overcome Multidrug Resistance in Cancer Chemotherapy

Abstract

Multidrug resistance caused by the overexpression of ABC drug transporters is a major obstacle in clinical cancer chemotherapy. For several years, it appeared that direct inhibition of ABC transporters would be the cheapest and most efficient way to combat this problem. Unfortunately, progress in finding a potent, selective inhibitor to modulate ABC transporters and restore drug sensitivity in multidrug-resistant cancer cells has been slow and challenging. Candidate drugs should ideally be selective, potent and relatively non-toxic. Many researchers in recent years have turned their attention to utilizing natural products as the building blocks for the development of the next generation of inhibitors, especially after the disappointing results obtained from inhibitors of the first three generations at the clinical trial stage. The first step is to discover natural substances (distinct from the first three generation inhibitors) that are potent, selective and relatively non-toxic in order to be used clinically. Here, we present a brief overview of the prospect of using natural products to modulate the function of ABC drug transporters clinically and their impact on human physiology and pharmacology.

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.…”

Acridone suppresses the proliferation of human breast cancer cells in�vitro via ATP-binding cassette subfamily G member 2

“…This ATP-binding cassette transporter serves a crucial function in mediating drug efflux and is associated with the primary or acquired drug resistance presented in clinical settings. A number of studies have attempted to develop specific inhibitors targeting ABCG2 (24,25). In consideration of the potent inhibitory effect of acridone, the present study further explored whether ABCG2 is associated with the underlying mechanism of the inhibitory effect of acridone.…”

Beneficial Pharmacokinetic Drug Interactions

“…Over-expression of PGP has been reported in several different types of cancer leading to resistance to a wide spectrum of structurally unrelated anticancer compounds. As a result of these observations, considerable research has been conducted into strategic drug interactions in which anticancer drugs are co-administered with a PGP inhibitor to overcome resistance by allowing more effective uptakeby cancer cells [40][41][42]. It was recognized almost 30 years ago that drugs such as verapamil and cyclosporine inhib it PGP and early attempts to identify specific PGP inhibitors were based on finding more potent and specific analogues of these drugs.…”

“…There is also considerable interest in the use of natural products as PGP inhibitors [41,42]. There are a diverse range of bioactive compounds in fruits and vegetables that presumably have minimal toxicity since they are consumed as food on a regular basis.…”