Lee-Han Kim1, Ji-Ae Shin2, Boonsil Jang1, In-Hyoung Yang1, Dong-Hoon Won1, Joseph H Jeong3, Tae-Ho Chung4, Nam-Pyo Cho1, Sung-Dae Cho5. 1. Department of Oral Pathology, School of Dentistry, Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Jeonju 54986, Republic of Korea. 2. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Alkek Building for Biomedical Research, Houston, TX, 77030, USA. 3. Department of Urology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. 4. Department of Animal Resources Science, Joongbu University, Chungnam, 32713, Republic of Korea. 5. Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea. Electronic address: efiwdsc@gmail.com.
Abstract
OBJECTIVE: The mimetic BH3 ABT-737, a potent inhibitor of anti-apoptotic Bcl-2 family proteins, has potential as anti-cancer drug in many cancers. Recently, patients treated with ABT-737 have developed drug tolerance during cancer therapy. Therefore, we examined whether ABT-737 is effective in killing MC-3 and HSC-3 human oral cancer cells either alone or in combination with the oncogenic kinase inhibitor, sorafenib. DESIGN: The potentiating activities of sorafenib in ABT-737-induced apoptosis were determined using trypan blue exclusion assay, DAPI staining, cell viability assay and Western blot analysis. RESULTS: Combined use of ABT-737 and sorafenib synergistically suppressed cell viability and induced apoptosis compared with either compound individually. The combination of ABT-737 and sorafenib altered only Bax and Bak proteins and their activations, resulting in mitochondrial translocation of Bax from the cytosol. Additionally, combination treatment-mediated apoptosis may be correlated with ERK and STAT3 pathways. CONCLUSIONS: These results suggest that sorafenib may effectively overcome ABT-737 resistance to apoptotic cell death, which can be a new potential chemotherapeutic strategy against human oral cancer. Copyright Â
OBJECTIVE: The mimetic BH3ABT-737, a potent inhibitor of anti-apoptotic Bcl-2 family proteins, has potential as anti-cancer drug in many cancers. Recently, patients treated with ABT-737 have developed drug tolerance during cancer therapy. Therefore, we examined whether ABT-737 is effective in killing MC-3 and HSC-3humanoral cancer cells either alone or in combination with the oncogenic kinase inhibitor, sorafenib. DESIGN: The potentiating activities of sorafenib in ABT-737-induced apoptosis were determined using trypan blue exclusion assay, DAPI staining, cell viability assay and Western blot analysis. RESULTS: Combined use of ABT-737 and sorafenib synergistically suppressed cell viability and induced apoptosis compared with either compound individually. The combination of ABT-737 and sorafenib altered only Bax and Bak proteins and their activations, resulting in mitochondrial translocation of Bax from the cytosol. Additionally, combination treatment-mediated apoptosis may be correlated with ERK and STAT3 pathways. CONCLUSIONS: These results suggest that sorafenib may effectively overcome ABT-737 resistance to apoptotic cell death, which can be a new potential chemotherapeutic strategy against humanoral cancer. Copyright Â
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