MODULATION OF VINDESINE AND DOXORUBICIN RESISTANCE IN MULTIDRUG-RESISTANT PLEURAL MESOTHELIOMA CELLS BY TUMOR-NECROSIS-FACTOR-ALPHA

Tumor necrosis factor-alpha (TNF-alpha) has been shown to enhance the cytotoxicity of a variety of antineoplastic agents. To examine whether multidrug-resistant cells are targets of TNF-alpha, and whether TNF-a lpha is capable of modulating chemoresistance of these cells, a pleura l mesothelioma cell line (PXF1118L) and two multidrug-resistant sublin es thereof were used as experimental models. Drug resistance of these cells was due to P-glycoprotein expression, as confirmed by (1) staini ng with a monoclonal antibody (MRK16) specific for human P-glycoprotei n, (2) decreased accumulation of [H-3]vinblastine that was reversed by verapamil, and (3) enhanced cytotoxicity of vindesine in the presence of verapamil. Parental and multidrug-resistant cells exhibited little but comparable sensitivity to TNF-alpha alone. Combining TNF-alpha wi th vindesine or, to a lesser extent, with doxorubicin, but not with ci splatin, resulted in greater cytotoxicity towards multidrug-resistant cells than seen for each compound alone, indicating a synergism. In co ntrast, TNF-alpha failed to modulate vindesine or doxorubicin cytotoxi city in parental cells. [H-3]Vinblastine accumulation was unaffected b y TNF-alpha, and chemoresistance was reduced by TNF-alpha also in the presence of verapamil (10 mu M), indicating that TNF-alpha was acting in a way different from calcium-channel blockers. Though the molecular mechanism by which TNF-alpha was enhancing vindesine and doxorubicin cytotoxicity remained undefined in this study, the numbers of TNF-alph a binding sites on parental and on multidrug-resistant cells were simi lar, and P-glycoprotein expression was unmodulated during the entire 4 8 h incubation period. In conclusion, we show that TNF-alpha increases the cytotoxicity of anticancer drugs in multidrug-resistant tumor cel ls by a mechanism that differs from most chemosensitizing agents, incl uding verapamil. Further studies will be needed to clarify the mechani sm by which TNF-alpha synergizes with anticancer drugs.