COMBINED ANTITUMOR EFFECT OF SURAMIN PLUS IRRADIATION IN HUMAN PROSTATE-CANCER CELLS - THE ROLE OF APOPTOSIS

Suramin has recently surfaced as a potential antineoplastic agent on t he basis of its ability to exert a cytostatic effect on human prostate carcinoma cells. Radiotherapy for the treatment of prostate cancer ha s long been known as an alternative medical therapeutic approach, but the molecular mechanism involved in radiation-induced toxicity in pros tatic tumors is poorly defined. In these studies, the antitumor effect of suramin and irradiation, either as individual treatments or in com bination, was investigated in human prostate cancer cells. Two androge n-independent prostate cancer cell lines, DU-145 and PC-3, were used a s in vitro model systems to study the underlying molecular mechanisms of these two therapeutic modalities. A cytostatic effect on cell growt h was observed when cells were exposed to suramin alone, while treatme nt with irradiation alone resulted in significant cell death as determ ined by the Trypan blue exclusion assay. Suramin treatment prior to ir radiation inhibited this radiation-induced cell death. In contrast, ex posure of cells to suramin following irradiation enhanced the cytotoxi c effect of ionizing radiation. Temporal analysis of the molecular eve nts involved in radiation-induced toxicity revealed the characteristic fragmentation of DNA into a nucleosomal ladder (a hallmark of apoptos is) and enhanced expression of specific programmed cell death-associat ed genes (TRPM-2 and TGF-beta), preceding the dramatic decrease in cel l number. These results indicate that radiation-induced cell death pro ceeds via the apoptotic pathway. Further studies have demonstrated tha t activation of programmed cell death by ionizing radiation is substan tially inhibited by pretreatment of the cells with suramin. This study suggests that the relative timing of this combination treatment may h ave significant therapeutic implications in the treatment of advanced prostate cancer.