Abstract
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. 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. [3H] Lopinavir uptake and VIVID™ assay further confirmed the functional activity of transcribed genes upon co-treatment. When the anticancer agent (doxorubicin, paclitaxel, tamoxifen or vinblastine) was 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.
Highlights
Despite complex nature of cancer, tremendous advancements in cancer treatment have been made in the recent years
The overexpression of efflux transporters and metabolizing enzymes was diminished when cells were co-treated with ritonavir. [3H] Lopinavir uptake and VIVIDTM assay further confirmed the functional activity of transcribed genes upon co-treatment
When the anticancer agents 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
Summary
Despite complex nature of cancer, tremendous advancements in cancer treatment have been made in the recent years. Chemotherapy represents the most common treatment modalities for cancer treatment. A major impediment to successful chemotherapy is the development of multidrug resistance (MDR) where resistance to one drug often confers resistance to several structurally and functionally unrelated drugs [1,2,3]. Many treatment modalities impose three to four drugs simultaneously. Patients in the early stage of cancer respond quickly, due to the development of drug resistance, cancer cells adapt treatment and relapse by overcoming therapy. Resistance to chemotherapy can either be intrinsic (resistance exists before the drug treatment is initiated) or acquired (resistance develops during drug treatment) [4]. Mechanisms of drug resistance are very complex. Several possible mechanisms and molecular alterations have been implicated in the development of MDR, including activation of drug transporters and metabolizing enzymes, mutation and amplification of drug targets, tumor microenvironment conditions (hypoxic conditions leading to vascularization) and genetic rewiring leading to cellular repair mechanisms (activation of DNA repair, mutant p53 and impaired apoptosis) [5]
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