Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance
Deep Kwatra, David Standing, Anand Venugopal, Shrikant Anant
Department of Molecular and Integrative Physiology, University of Kansas Medical Center
Purpose: Bitter melon (BM) is a tropical and subtropical vine, widely grown in Asia, Africa, and the Caribbean for its edible fruit. The fruit is recommended in ancient Indian and Chinese medicine for prevention/treatment of diabetes. Recent publications have demonstrated that BM extracts inhibit the growth of breast and prostate cancers. Our previous studies also suggest that it can be used as a preventive/therapeutic agent in colorectal cancers (CC). Phytochemical usage and dietary supplementation can often lead to improved efficacy of conventional therapies but they may also lead to drug-drug interactions. Thus we studied the effects of bitter melon on the anticancer activity as well as bioavailability of doxorubicin (DOX) in CC cells (Sw-480 and HT-29)
Methods: Cell proliferation studies using DOX were carried out in CC cells either pretreated or co-treated with BM extract. To identify the effects of BM on active permeation of DOX drug uptake and efflux studies were carried out in CC cells. PCR and western blots were performed to determine the changes in major efflux protein levels involved in limiting the uptake of DOX in cancer cells. Further, activity assays for PXR, a xenobiotic sensing nuclear receptor were performed to identify the mechanism with which BM altered the efflux transporter expression.
Results: BM was found to enhance the effect of DOX as well as sensitize the cells towards DOX upon pretreatment. Combinatorial index was calculated to identify synergism between the therapeutics. This effect may be result of altered drug permeation into the cells as both drug uptake and efflux were found to reduce in the presence of BM pre- and co- treatment. The reduced efflux and uptake maybe due to inhibition of expression of efflux transporters as was observed with PCR and western blots. The BM extracts were seen to effect PXR activation as well as expression in CC cells which might be responsible for the altered efflux protein expression. Since AMPK pathway is the main target of BM we also studied the effect of other AMPK activators to see whether there is a correlation between AMPK pathway and efflux. Our results were interesting in showing potential correlation between AMPK pathway and drug efflux.
Conclusion: Taken together these results suggest that BM can be an efficient co therapeutic enhancing the bioavailability and efficacy of conventional chemotherapy. This can lead to reduction in minimum effective doses further resulting in reduced toxicity from chemotherapy.