Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer.

The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The major contributing factor for this resistance is efflux of the drugs by the p-glycoprotein pump. Over the years, inhibitors of this pump have been discovered to administer them in combination with chemotherapeutic agents. The clinical failure of first and second generation P-gp inhibitors (such as verapamil and cyclosporine analogs) has led to the discovery of third generation potent P-gp inhibitors (tariquidar, zosuquidar, laniquidar). Most of these inhibitors are nitrogenous compounds and recently a natural alkaloid CBT-01 (tetrandrine) has advanced to the clinical phase. CBT-01 demonstrated positive results in Phase-I study in combination with paclitaxel, which warranted conducting it's Phase II/III trial. Apart from this, there exist a large number of natural alkaloids possessing potent inhibition of P-gp efflux pump and other related pumps responsible for the development of resistance. Despite the extensive contribution of alkaloids in this area, has never been reviewed. The present review provides a comprehensive account on natural alkaloids possessing P-gp inhibition activity and their potential for multidrug resistance reversal in cancer.