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Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor.
Oncogene. 2007 Feb 01; 26(5):652-61.O

Abstract

Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio- or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 microM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index <1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 microg/ml of the antioxidant alpha-tocopherol or 10 microM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspase-dependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments.

Authors+Show Affiliations

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA. jingan@burnham.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16909121

Citation

An, J, et al. "Overcoming the Radioresistance of Prostate Cancer Cells With a Novel Bcl-2 Inhibitor." Oncogene, vol. 26, no. 5, 2007, pp. 652-61.
An J, Chervin AS, Nie A, et al. Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. Oncogene. 2007;26(5):652-61.
An, J., Chervin, A. S., Nie, A., Ducoff, H. S., & Huang, Z. (2007). Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. Oncogene, 26(5), 652-61.
An J, et al. Overcoming the Radioresistance of Prostate Cancer Cells With a Novel Bcl-2 Inhibitor. Oncogene. 2007 Feb 1;26(5):652-61. PubMed PMID: 16909121.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. AU - An,J, AU - Chervin,A S, AU - Nie,A, AU - Ducoff,H S, AU - Huang,Z, Y1 - 2006/08/07/ PY - 2006/8/16/pubmed PY - 2007/3/9/medline PY - 2006/8/16/entrez SP - 652 EP - 61 JF - Oncogene JO - Oncogene VL - 26 IS - 5 N2 - Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio- or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 microM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index <1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 microg/ml of the antioxidant alpha-tocopherol or 10 microM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspase-dependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/16909121/Overcoming_the_radioresistance_of_prostate_cancer_cells_with_a_novel_Bcl_2_inhibitor_ L2 - https://doi.org/10.1038/sj.onc.1209830 DB - PRIME DP - Unbound Medicine ER -