This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Colon cancer is the third most common cancer, accounts for 9% of all cancer deaths and is notoriously chemoresistant. One of the reasons for poor response to treatment and/or patient death is the phenomenon of multiple drug resistance (MDR). One of the mechanisms of multiple drug resistance in tumors is upregulation of mdr1 gene which encodes an efflux pump known as Phospho-glycoprotein (P-gp). P-gp protein acts as an efflux pump and pump out chemotherapeutic agents, lowering the intracellular effective dose of the drug and requiring administration of even higher doses of drugs. Presence of P-gp in many human cancers is a negative prognostic factor and highest levels f expression seen in renal and colon cancers. The current methods employed to overcome MDR are plagued by detrimental side effects and too high toxicity to be used in patients. The search for P-gp inhibitors has expanded into flora-based natural health products. The leaf extract from bitter melon (Momordica charantia) was found to cause inhibition of P-gp activity in the multidrug-resistant human cervical cancer. The main objectives of this study are to examine the effect of bitter melon leaf extracts on mdr1 gene expression, P-gp protein function, potential role of the leaf extract as an efflux pump inhibitor and the ability of the leaf extract to potentiate the action of known chemotherapeutic drugs against multiple drug resistant colorectal cancer cells. The two varieties of bitter melons that will be used are Taiwan White (Momordica charantia var. charantia) which exhibits superior fruit traits and low content of phytochemicals and an advanced breeding line CBM-12 (Momordica charantia var. muricata) which has inferior fruit traits but a high content of phytochemicals. The leaf extracts will be used on colon cancer cell lines and their effect on mdrl1 gene expression and function of P-p protein will be determined using PCR, RT-PCR and staining methods. The data generated from the experiments will be analyzed and compared between the two varieties. The long-term goals of the proposed project are to isolate and characterize the active component/s in the leaf extract, examine the role of purified product/s in effecting P-gp function, determine the effect of different ratios of leaf/root/fruit on efflux pump inhibition and in vivo studies. The preliminary data generated from this research will help validate the beneficial role of bitter melon and apply for NIH or USDA grants. This project will have a broader impact in helping advance knowledge in the field of cancer therapy and phytomedicine. As we are comparing popular cultivar Taiwan White and an advancing breeding line CBM12 varieties of bitter melon, cultivation of improved varieties with better medicinal properties will foster the growth of small-scale industries leading to generation of employment and strengthening of local economies.
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