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 the basis of its ability to exert a cytostatic effect on human prostate carcinoma cells. Radiotherapy for the treatment of prostate cancer has long been known as an alternative medical therapeutic approach, but the molecular mechanism involved in radiation-induced toxicity in prostatic tumors is poorly defined. In these studies, the antitumor effect of suramin and irradiation, either as individual treatments or in combination, was investigated in human prostate cancer cells. Two androgen-independent prostate cancer cell lines, DU-145 and PC-3, were used as in vitro model systems to study the underlying molecular mechanisms of these two therapeutic modalities. A cytostatic effect on cell growth was observed when cells were exposed to suramin alone, while treatment with irradiation alone resulted in significant cell death as determined by the Trypan blue exclusion assay. Suramin treatment prior to irradiation inhibited this radiation-induced cell death. In contrast, exposure of cells to suramin following irradiation enhanced the cytotoxic effect of ionizing radiation. Temporal analysis of the molecular events involved in radiation-induced toxicity revealed the characteristic fragmentation of DNA into a nucleosomal ladder (a hallmark of apoptosis) and enhanced expression of specific programmed cell death-associated genes (TRPM-2 and TGF-beta), preceding the dramatic decrease in cell number. These results indicate that radiation-induced cell death proceeds via the apoptotic pathway. Further studies have demonstrated that activation of programmed cell death by ionizing radiation is substantially inhibited by pretreatment of the cells with suramin. This study suggests that the relative timing of this combination treatment may have significant therapeutic implications in the treatment of advanced prostate cancer.
Sklar
G N
GN
Department of Surgery, University of Maryland School of Medicine, Baltimore.
Eddy
H A
HA
Jacobs
S C
SC
Kyprianou
N
N
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051152:Clusterin; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000032:analysis; D013498:Suramin / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014407:Tumor Cells, Cultured
C495242:CLU protein, human; D051152:Clusterin; D004273:DNA, Neoplasm; D006023:Glycoproteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013498:Suramin