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Role of the Mitochondrial bc₁-Complex in the Cytotoxic Action of Diethylstilbestrol-Diphosphate toward Prostatic Carcinoma Cells¹

Institut für Physiologische Chemie der Universität München, Schillerstr, 44, D-8000 München 2 [P. S., L. C., F. F.], and Institut für Therapeutische Biochemie, Zentrum für Biologische Chemie der Universität Frankfurt, Theodor-Stern-Kai 7, D-6000 Frankfurt 70 [T. A. L.], Federal Republic of Germany

In previous work (P. Schulz et al., Cancer Res., 48: 2867–2870, 1988) we have demonstrated that diethylstilbestrol (DES), DES-monophosphate, and DES-diphosphate (DESDP) are generally cytotoxic at concentrations attained in patients' sera during therapeutic DESDP infusions for progressed carcinoma of the prostate. We have extended this work and addressed two questions: (a) Is DESDP itself a completely nontoxic prodrug which has to be transformed into the active species DES by a phosphatase? (b) Which metabolic or regulatory mechanism in a cell is the target of DES action? Using cell cultures in phosphatase-depleted media we could provide evidence that DESDP exerts cytotoxic activity only after conversion to DES. Oxygen electrode experiments and difference spectra with intact mitochondria demonstrated that DES did not act as an uncoupler, but inhibited electron flow from ubiquinone to cytochrome c₁. Phenomena previously observed in DES-treated cells could be explained by distortion of the energy metabolism.

¹ This work was supported by Deutsche Forschungsgemeinschaft, Degussa Pharma Gruppe, and Fonds der Chemischen Industrie.

² Present address: Universitätsklinikum Großhadern, Klinik und Poliklinik für Hals-, Nasen- und Ohrenkranke, Marchioninistr. 15, D-8000 München 70, Federal Republic of Germany.

Received 11/ 1/89. Revised 4/10/90.

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