Role of the mitochondrial bc1-complex in the cytotoxic action of diethylstilbestrol-diphosphate toward prostatic carcinoma cells.

Abstract

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.

• Authors: P Schulz, T A Link, L Chaudhuri, F Fittler
• Journal: Cancer research (Cancer Res) Vol. 50 Issue 16 Pg. 5008-12 (Aug 15 1990) ISSN: 0008-5472 [Print] United States
• PMID: 2165852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Culture Media
• Diethylstilbestrol
• fosfestrol
• Acid Phosphatase
• Electron Transport Complex III

Topics

• Acid Phosphatase (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Cattle
• Cell Line
• Cell Survival (drug effects)
• Culture Media
• Diethylstilbestrol (analogs & derivatives, pharmacology)
• Electron Transport Complex III (antagonists & inhibitors, metabolism)
• Hot Temperature
• Humans
• Kinetics
• Male
• Mitochondria, Heart (enzymology)
• Mitochondria, Liver (drug effects, metabolism)
• Oxygen Consumption (drug effects)
• Prostatic Neoplasms
• Rats
• Tumor Cells, Cultured (cytology, drug effects, enzymology)