Comparative in vitro evaluation of dithiane analogs of tiapamil, Ro 11-2933, Ro 44-5911 and Ro 44-5912 as multidrug resistance modulators

The analogs of tiapamil are highly active modifiers of P-glycoprotein-mediated multidrug resistance (Mon) in vitro, The activity of three analogs of tiapamil, no 11-2933, no 44-5911 and no 44-5912, was compared in K562/DXR and MCF-7/DXR cell lines, using flow cytometry for the determination of intracellular daunorubicin accumulation and MTT assays for the cytotoxic evaluation of the modulators combined or not with daunorubicin, no 44-5911 and no 44-5912 were not intrinsically more toxic than DL-verapamil and exhibited a significantly higher reversing effect, no 44-5912 was shown slightly more efficient than no 44-5911 for reversing daunorubicin cytotoxicity. no 11-2933 was found to be the most potent in modulating MDR but was not significantly more active than no 44-5912, These two compounds were able to achieve a near complete reversion (above 80%) at 5 mu mol/l. However, the cytoxicity of no 11-2933 was higher with an IC50 near 20 mu mol/l in both K562 and MCF7 cell lines. Our results indicate that tiapamil derivatives are promising compounds for MDR modulation. Among them no 11-2933 and no 44-5912 seem to be particularly interesting for in vivo evaluations.