Potentiation of paclitaxel cytotoxicity by inostamycin in human small celllung carcinoma, Ms-1 cells

In the present study, we found that inostamycin increased the ability of pa clitaxel to induce apoptosis in Ms-1 cells. A considerably higher concentra tion of paclitaxel was required for the induction of apoptosis in Ms-1 cell s than in other cell lines tested. Treatment of Ms-1 cells with inostamycin , an inhibitor of phosphatidylinositol (PI) synthesis, reduced the dosage o f paclitaxel required to induce cell death by apoptosis. This effect of ino stamycin is specific to Ms-1 cells, and inostamycin did not increase the cy totoxicity of other antitumor drugs such as adriamycin, vinblastine, methot rexate, cisplatin, etoposide, or camptothecin in Ms-1 cells, Addition of in ostamycin to paclitaxel-treated cells caused a significant increase in the sub G1 peak, representing apoptosis, which was accompanied by a decrease in the G2/M peak seen in paclitaxel-treated Ms-1 cells, without affecting pac litaxel-inhibited tubulin depolymerization, Moreover, paclitaxel did not en hance inostamycin-inhibited PI synthesis, The expression levels of Bcl-2, B ax, and Bcl-X-L were not changed following the co-treatment with inostamyci n plus paclitaxel, whereas the activated form of caspase-3 was markedly inc reased. Thus, inostamycin is a chemosensitizer of paclitaxel in small cell lung carcinoma Ms-1 cells.