Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance

J Pharm Sci. 2013 Dec;102(12):4444-54. doi: 10.1002/jps.23753. Epub 2013 Oct 15.


Recently, we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells toward DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2, and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy.

Keywords: ABC transporters; PXR; colon cancer; drug interaction; drug interactions; drug resistance; drug transport; drug-food interaction; efflux pumps; efflux transporters.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biological Availability
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy
  • Cucurbitaceae / chemistry*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology*
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Multidrug Resistance-Associated Protein 2
  • Plant Extracts / chemistry
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*


  • ABCC2 protein, human
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Protein 2
  • Plant Extracts
  • Doxorubicin