nitrophenols and Mouth-Neoplasms

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.. 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.. 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.. 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.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Blotting, Western; Cell Line, Tumor; Cell Survival; Drug Therapy, Combination; Humans; Mouth Neoplasms; Niacinamide; Nitrophenols; Phenylurea Compounds; Piperazines; Sorafenib; Staining and Labeling; Sulfonamides

We investigated the effects of recombinant human bone morphogenetic protein-7 (rhBMP-7) on the behaviour of oral keratinocytes and head and neck squamous cell carcinoma (SCC) cells in vitro. Expression of all three BMP receptors was high (p<0.01), and rhBMP-7 exhibited significant dose-related inhibitory effects on the doubling time and viability of cancer cells (p<0.01), but not on the proliferation or viability of oral keratinocytes. It elicited no significant effect on the invasion of Matrigel in SCC of the head and neck. Results indicate that in cell culture, rhBMP-7 exerts antineoplastic effects. This should be tested in an orthotopic animal model to more closely replicate in vivo effects.

Topics: Antineoplastic Agents; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Protein Receptors, Type II; Carcinoma, Squamous Cell; Cell Culture Techniques; Cell Death; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cellular Senescence; Culture Media, Serum-Free; Humans; Indicators and Reagents; Keratinocytes; Mouth Neoplasms; Neoplasm Invasiveness; Nitrophenols; Organophosphorus Compounds

Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1-dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC.

Topics: 4-Nitroquinoline-1-oxide; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy-Related Protein 5; Autophagy-Related Protein 7; bcl-X Protein; Beclin-1; Biphenyl Compounds; Carcinoma, Squamous Cell; Celecoxib; Cell Line, Tumor; Cyclooxygenase 2 Inhibitors; Female; Gossypol; Humans; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Mitophagy; Mouth Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Proto-Oncogene Proteins; Quinolones; Random Allocation; RNA Interference; RNA, Small Interfering; Sulfonamides; Ubiquitin-Activating Enzymes; Xenograft Model Antitumor Assays

To date, many different chemotherapeutic agents have been widely used as common treatments for oral cancers. However, their therapeutic effects have been disappointing, and these agents may have unwanted side effects. Among the many regulatory factors, overexpression of pro-survival Bcl-2 family members may promote resistance to chemotherapeutic drugs in many tumors. The BH3 domain-only proteins effectively antagonize their apoptotic activities. Therefore, there is substantial interest in developing chemotherapeutic drugs that directly target pro-survival Bcl-2 proteins by mimicking the BH3 domain and unleashing pro-apoptotic molecules in tumor cells. Among the numerous available small molecule BH3 mimetics, ABT-737, a potent small molecule that binds to Bcl-2/Bcl-xL with high affinity, has anti-tumor activity in a wide variety of cancer cells. However, the effects of ABT-737 on human oral cancers and the underlying molecular mechanisms have not previously been elucidated. In the present study, we observed that inactivation of the ERK1/2 signaling pathway using ABT-737 dramatically increased the expression of pro-apoptotic protein Bim via transcriptional and/or posttranslational regulation, in a cell type-dependent manner, inducing mitochondria-mediated apoptosis of human oral cancer cells. To the best of our knowledge, this is the first demonstration of the antitumor effects of ABT-737 on human oral cancers.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; BH3 Interacting Domain Death Agonist Protein; Biomimetics; Biphenyl Compounds; Carcinoma, Mucoepidermoid; Carcinoma, Squamous Cell; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Membrane Proteins; Molecular Targeted Therapy; Mouth Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides