Sorafenib potentiates ABT-737-induced apoptosis in human oral cancer cells
Lee-Han Kim1, Ji-Ae Shin2, Boonsil Jang1
1Department of Oral Pathology, School of Dentistry, Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Jeonju 54986, Republic of Korea.
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.
Insights
Sorafenib overcomes ABT-737 resistance in oral cancer cells by enhancing apoptosis. This combination therapy shows potential for treating human oral cancers resistant to ABT-737.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- ABT-737, a Bcl-2 family inhibitor, shows anti-cancer potential but drug tolerance develops.
- Drug resistance limits the efficacy of ABT-737 in cancer therapy.
- Investigating combination therapies is crucial for overcoming resistance.
Purpose of the Study:
- To evaluate the efficacy of ABT-737 alone and with sorafenib in oral cancer cells.
- To determine if sorafenib can overcome ABT-737 resistance.
- To explore the molecular mechanisms of the combination treatment.
Main Methods:
- Cell viability assays (trypan blue exclusion, viability assay).
- Apoptosis assessment (DAPI staining).
- Western blot analysis for protein expression and activation (Bax, Bak, ERK, STAT3).
Main Results:
- Combined ABT-737 and sorafenib synergistically reduced cell viability and increased apoptosis.
- The combination induced mitochondrial translocation of Bax.
- Apoptosis was correlated with alterations in ERK and STAT3 pathways.
Conclusions:
- Sorafenib can overcome ABT-737 resistance in oral cancer cells.
- The combination therapy demonstrates potential as a novel chemotherapeutic strategy.
- Targeting apoptotic pathways with combination therapy warrants further investigation.
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