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

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Abstract
The analogs of tiapamil are highly active modifiers of P-glycoprotein-mediated multidrug resistance (MDR) in vitro. The activity of three analogs of tiapamil, Ro 11-2933, Ro 44-5911 and Ro 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. Ro 44-5911 and Ro 44-5912 were not intrinsically more toxic than DL-verapamil and exhibited a significantly higher reversing effect. Ro 44-5912 was shown slightly more efficient than Ro 44-5911 for reversing daunorubicin cytotoxicity. Ro 11-2933 was found to be the most potent in modulating MDR but was not significantly more active than Ro 44-5912. These two compounds were able to achieve a near complete reversion (above 80%) at 5 mumol/I. However, the cytotoxicity of Ro 11-2933 was higher with an IC50 near 20 mumol/I in both K562 and MCF7 cell lines. Our results indicate that tiapamil derivatives are promising compounds for MDR modulation. Among them Ro 11-2933 and Ro 44-5912 seem to be particularly interesting for in vivo evaluations.

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