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Purpose: A major impediment to successful drug therapy is the development of multidrug resistance (MDR). Drug resistance in HIV patients is also well known. The introduction of highly active antiretroviral therapy (HAART) has substantially reduced HIV resistance and fatalities. It appears that ritonavir along with another protease inhibitor regulates both drug efflux and metabolism to overcome resistance in HIV-infected patients. Therefore, we have examined a similar strategy of combining ritonavir with anticancer drugs to modulate drug efflux, metabolism and allow sufficient drug entry into tumor cells.
Methods: Cells were treated for 72 hours with anticancer drugs alone and in the presence of ritonavir. Quantitative gene expression studies, immunoblot analysis, radioactive uptake studies and Vivid™ fluorescent assay were performed on human colon adenocarcinoma cells (LS180) cells. Cell proliferation, migration and apoptosis assays were performed on human breast adenocarcinoma (T47D) cells and prostate cancer (PC-3) cells.
Results: The overexpression of efflux transporters and metabolizing enzymes was diminished when cells were co-treated with ritonavir. [3 H] Lopinavir uptake and VIVID™ assay further confirmed the functional activity of transcribed genes upon co-treatment. When the anticancer agents (doxorubicin, paclitaxel, tamoxifen or vinblastine) were combined with ritonavir, a significantly diminished cell proliferation and migration and augmented caspase activity leading to apoptosis was observed in T47D and PC-3 cells.
Conclusions: Combination therapy of anticancer drug with ritonavir may overcome drug resistance by deactivating the overexpression of efflux transporters and metabolizing enzymes. Therefore, drug regimens containing ritonavir would enhance therapeutic exposure of cancer cells to anticancer agents, potentially improving chemotherapeutic efficacy and consequently devoid of resistance.
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