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Disruption of Cellular Energy Balance by Suramin in Intact Human Prostatic Carcinoma Cells, a Likely Antiproliferative Mechanism

Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792 [R. R., J. M., A-L. C., G. W.]; Departments of Medicine and Pathology, Wm. S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin 53705 [R. R., J. M., T. O., G. W.]

The antiparasitic drug, suramin, has antiproliferative effects in human carcinoma cells. It has been suggested that this occurs through blockade of growth factor-receptor interactions. Three types of evidence that suramin rapidly inhibits cellular respiration or disrupts cellular energy balance in intact cells of the human prostate carcinoma cell line, DU145, are presented. Beginning at approximately 10^-4 M, suramin rapidly causes dose-dependent inhibition of tetrazolium conversion by mitochondrial dehydrogenases in intact cells, demonstrating an inhibition of respiration. This effect is reversed by exchange with suramin-free media but not by pretreatment with serum, epidermal growth factor, insulin-like growth factor I, acidic and basic fibroblast growth factors, or calcium. Rhodamine 123 (10 µg/ml) uptake by mitochondria in intact DU145 cells is inhibited in the presence of 10^-3 M suramin. Treatment with 10^-4–10^-3 M suramin causes the loss of rhodamine 123 from cells with mitochondria prestained with rhodamine 123, indicating that suramin is acting as an ionophore or respiratory poison. Also shown by electron microscopy are progressive toxic changes in mitochondria of DU145 cells within 1 h after treatment with 10^-4 M suramin.

These data indicate that in intact DU145 cells 10^-4 M suramin rapidly disrupts cellular energy balance or respiration as seen by three studies of mitochondrial state. Disruption of energy balance or respiration represents a likely antiproliferative mechanism, as is thought to be a primary mechanism for the action of suramin in parasitic diseases. This proposed mechanism of action for suramin can explain the most prominent observed clinical toxicities of nephrotoxicity, adrenal toxicity, coagulopathy, and demyelinating neuropathy.

¹ Fellowship recipient under grant T32 CA09614.

² Current address: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

³ Recipient of an American Cancer Society Career Development Award and supported in part by National Cancer Institute grant CA50590 and the Veterans Administration. To whom requests for reprints should be addressed, at Department of Human Oncology, University of Wisconsin Clinical Cancer Center, K4/666 CSC, 600 Highland Avenue, Madison, WI 53792.

Received 6/ 3/91. Accepted 10/ 4/91.

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