Molecular impacts of rapamycin-based drug combinations: Combining rapamycin with gemcitabine or imatinib mesylate (Gleevec) in a human leiomyosarcoma model

Drug combinations may provide a therapeutic benefit in treating cancer patients. However when considering a drug combination, it is important to assess how the molecular impact of the combination relates to the effects manifested by each drug alone and whether or not it varies depending on the tumor type. In this study, we have analyzed the molecular impact on a human leiomyosarcoma cell line (SK-LMS-1) of a combination consisting of the mTOR inhibitor rapamycin and either the anti-metabolite drug gemcitabine (Gemzar) or the protein tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571). We show that imatinib mesylate depolarizes the mitochondrial membrane potential (ΔΦm) and inhibits protein tyrosine phosphorylation, but displays only minor effects on cell proliferation when added alone or in combination with rapamycin. Gemcitabine or rapamycin, when added alone, inhibit protein tyrosine phosphorylation as well as phosphorylation of the MAP kinases ERK1/2. Both drugs also affect the cell cycle, arresting the cells at the S or G1 phase respectively. Rapamycin elevates significantly ΔΦm but produces only a moderate effect on cell growth. Gemcitabine inhibits considerably cell growth but exerts no effect on ΔΦm. Combining gemcitabine and rapamycin produces a major effect on the cell cycle, elevates the ΔΦm even further and maintains the molecular impacts exerted by each single drug. Therefore, consistent with our clinical observation, these results suggest that combining gemcitabine and rapamycin may be beneficial in treating leiomyosarcoma patients.