Apoptosis and clonogenic cell death in PC3 human prostate cancer cells after treatment with gamma radiation and suramin.
Suramin is a novel cytostatic/cytotoxic agent that is currently undergoing clinical trials in the treatment of hormone- and chemo-refractory tumors. Its unusual mechanism of action and its activity against prostate cancer raise the possibility that it could be particularly suitable for combined-modality treatment of prostate cancer. PC3 human prostate cancer cells were used as an in vitro model to test the possible interaction between suramin and ionizing radiation. Treatment with gamma radiation resulted in detachment of PC3 cells from the monolayer, and the detached cells exhibited internucleosomal DNA fragmentation characteristic of apoptosis. Low concentration of suramin (50-100 micrograms/ml, 35-70 microM) increased spontaneous as well as radiation-enhanced apoptosis. However, suramin inhibited spontaneous and radiation-enhanced apoptosis at 300 micrograms/ml (210 microM), a concentration that is more commonly used in the clinic. At this concentration suramin inhibited DNA fragmentation induced by chemotherapeutic drugs as well. The effect of suramin on inhibition of DNA fragmentation was reversible if the suramin was removed 24 h after irradiation. Despite inhibition of radiation-induced apoptosis by 300 micrograms/ml suramin (from 5% to 2.9% at 48 h), clonogenic cell death was enhanced by the combination of suramin and radiation. The effects of radiation and suramin on clonogenic cell survival appeared to be additive by isobologram analysis at clinically relevant radiation doses. Continuous exposure to a lower concentration of suramin (100 micrograms/ml) during the clonogenic assay period was as effective in decreasing clonogenic survival as 48 h exposure to 300 micrograms/ml suramin in decreasing clonogenic survival. Our data indicate that, when used in combination with radiation, suramin may be effective at concentrations that are lower than those required for efficacy as a single agent.
Palayoor
S T
ST
Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02215, USA.
Bump
E A
EA
Teicher
B A
BA
Coleman
C N
CN
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D053938:DNA Fragmentation; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D013498:Suramin