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Arrest of the Proliferation of Renal and Prostate Carcinomas of Human Origin by Inhibition of Mitochondrial Protein Synthesis¹

Laboratory of Physiological Chemistry, State University, Bloemsingel 10, 9712 KZ Groningen [C. v. d. B., B. H. J. D., M. H., T. E. M., A. M. K.], and Laboratory of Experimental Urology, Erasmus University, Rotterdam [J. C. R., J. W. v. D.], The Netherlands

The results described in this paper demonstrate that proliferation arrest by low concentrations of tetracyclines, which has previously been shown in experiments with animal tumor systems, can also be achieved in tumor systems of human origin. Tetracyclines specifically inhibit mitochondrial protein synthesis. Prolonged and continuous impairment of protein synthesis inside the mitochondria leads to reduction of the cellular concentration of the polypeptide products which are coded and synthesized within mitochondria. These products are part of the oxidative phosphorylative system of the cell. Long-term tetracycline treatment leads to a decrease of oxidative ATP-generating capacity as monitored by cytochrome c oxidase activity. This may cause severe energetic or metabolic disturbances which explain the proliferation arrest observed. Proliferation arrest, provided that mitochondrial protein synthesis is blocked effectively, is found in vitro as well as in vivo. It is shown that the effect of doxycycline is not limited to cytostasis; prolonged doxycycline treatment is clearly cytotoxic for the tumor cells.

¹ Supported in part by grants of the Dutch Organization for the Advancement of Pure Research, ZWO, and the Dutch Cancer Foundation, the Koningin Wilhelmina Fonds.

² To whom requests for reprints should be addressed.

Received 7/31/85. Revised 12/11/85. Revised 3/25/85. Accepted 3/27/86.

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