Inhibition of prostatic tumor cell proliferation by suramin: alterations in TGF alpha-mediated autocrine growth regulation and cell cycle distribution.
Suramin is a trypanocidal drug that has generated recent interest as an antineoplastic agent because of its ability to inhibit the binding of growth factors to their cell surface receptors. Our studies, and others, suggest that the androgen-independent human prostatic carcinoma cell lines PC3 and DU145 proliferate via autocrine growth mechanisms mediated by transforming growth factor alpha (TGFa) and its receptor, the epidermal growth factor (EGF) receptor. The present studies were designed to evaluate the ability of suramin to inhibit PC3 and DU145 proliferation by interfering with TGFa-mediated autocrine growth. Suramin induced a dose-dependent reduction of prostatic tumor cell proliferation which was reversed by removal of suramin from the culture medium. 3H-thymidine release studies showed that suramin had little direct cytotoxicity to either cell line. These findings suggest that the effects of suramin are mediated by cytostatic, rather than cytotoxic, mechanisms. Suramin also interfered with TGFa-mediated growth mechanisms. Specifically, suramin reduced the specific binding of TGFa to PC3 and DU145 cells. Additionally, the inhibitory effect of suramin on DU145 was reversed by cultivation of cells in the presence of excess TGFa. Further investigations revealed that suramin increased the percentage of cells in the S phase of the cell cycle for both cell lines. These studies show that the inhibitory effect of suramin on PC3 and DU145 cell growth is mediated, in part, by alteration of TGFa-mediated autocrine growth mechanisms and cell cycle kinetics.
Kim
J H
JH
Department of Urology, Northwestern University Medical School, Chicago, Illinois 60611.
Sherwood
E R
ER
Sutkowski
D M
DM
Lee
C
C
Kozlowski
J M
JM
D000970:Antineoplastic Agents; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013498:Suramin / Q000627:therapeutic use*; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D016211:Transforming Growth Factor alpha; D013498:Suramin; D066246:ErbB Receptors