The combination of gamma ionizing radiation and 8-Cl-cAMP induces synergistic cell growth inhibition and induction of apoptosis in human prostate cancer cells.
The antiproliferative and cytotoxic potential of the nucleotide analog 8-Cl-cAMP was tested in PC-3 and DU145 metastatic human prostate cancer cells. The drug was examined as the only therapeutic agent and in combination with ionizing irradiation (IR). Highly synergistic effects of IR and 8-Cl-cAMP were observed in both cell lines when examined by the MTT viability and BrdU proliferation assays. The combination of IR and 8-Cl-cAMP at clinically relevant doses exerted substantial growth inhibition. The combination of IR and 8-Cl-cAMP caused a significant disturbance in the distribution of cell cycle phases. Cell cycle arrest in the sub-G0/G1 phase predominated in both cell lines. The most striking observation was a significant increase in apoptotic PC-3 and DU145 cells. The DU145 cells were three times more sensitive to the combined treatment than PC-3 cells. The initial resistance to IR-induced apoptosis in these p53-deficient prostate cancer cell lines was overcome through an alternative proapoptotic pathway induced by 8-Cl-cAMP. Considering the low effective doses of treatments, improved tumor eradication rates and minimal undesirable side effects, the combination of IR and 8-Cl-cAMP could be the therapy of choice in treating prostate cancer.
Department of Molecular Biology and Endocrinology, Institute for Nuclear Sciences Vinca, P.O. Box 522, 10001 Belgrade, Republic of Serbia.
Vesna
V
Vucić
Ana
A
Nićiforović
Miroslav
M
Adzić
Marija B
MB
Radojcić
Sabera
S
Ruzdijić
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005720:Gamma Rays / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*
D000970:Antineoplastic Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate