Chronic exposure to bryostatin-1 increases the radiosensitivity of U937 leukaemia cells ectopically expressing Bcl-2 through a non-apoptotic mechanism

• Published in: International journal of radiation biology 2000, Vol.76 (10), p.1323-1333
• Main Author: Cartee, C. Davis, Peck-Sun Lin, S. Grant, L.
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Apoptosis - radiation effects; Biological and medical sciences; Bryostatins; Cell Cycle - drug effects; Cell Cycle - radiation effects; Hematologic and hematopoietic diseases; Humans; Lactones - therapeutic use; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Macrolides; Medical sciences; Mitochondria - drug effects; Mitochondria - radiation effects; Proto-Oncogene Proteins c-bcl-2 - physiology; Radiation therapy and radiosensitizing agent; Radiation-Sensitizing Agents - therapeutic use; Space life sciences; Treatment with physical agents; Treatment. General aspects; Tumors; U937 Cells
• ISSN: 0955-3002; 1362-3095
• DOI: 10.1080/09553000050151592

Purpose : Ionizing radiation (IR) produced a dose-dependent increase in apoptosis in U937/pCEP4 cells which was attenuated by the stable over expression of Bcl-2 (U937/Bcl-2). A dose of 2 Gy IR was selected for further analyses to determine if subsequent exposure to 10 n m bryostatin-1 would overcome the resistance to IR-induced apoptosis conferred by Bcl-2 over expression. Methods and results : Although bryostatin-1 did not increase IR-induced apoptosis in U937/pCEP4 or U937/Bcl-2 cells, it impaired mitochondrial function and increased the antiproliferative effects of IR in both cell lines. The effects were more pronounced in U937/Bcl-2 cells. Bryostatin-1 also exerted differential effects on cell-cycle distributions of U937 transfectant cells, producing a significant G 0 /G1 arrest in U937/Bcl-2 cells, while decreasing IR-induced G 2 /M arrest in U937/pCEP4 cells. Although Bcl-2 over expression attenuated IR-induced apoptosis, clonogenic survival was similar in U937/pCEP4 and U937/Bcl-2 cells following 2Gy IR treatment. Treatment with 10nm bryostatin-1 after 2 Gy IR further reduced clonogenic survival in both cell lines. Moreover, U937/Bcl-2 cells were more susceptible to the growth-inhibitory effects of IR/bryostatin-1 than U937/pCEP4 cells. Conclusions : Bryostatin-1 increased the radiosensitivity of U937 transfectant cell lines without enhancing apoptosis; furthermore, U937/Bcl-2 cells were more susceptible to IR/bryostatin1-mediated antiproliferative effects than their empty-vector counterparts.