dihydropyridines and Skin-Neoplasms

Antitumor potential of a 1,4-dihydropyridine derivative (DHP-8) has been successfully studied previously in a number of cancer cell lines including the human melanoma cells, A375. In order to validate its anticancer activity, DMBA induced tumor in Swiss Albino mice was considered for this study. DMBA causes skin carcinoma in murine systems and is an important in vivo model for evaluating the efficacy of any new chemical entity against skin cancer. Topical administration of DHP-8 at the dose rate of 33.3 and 50.0 mg/kg body weight showed a significant reduction in tumor parameters. It also prevented the progression and differentiation of squamous cell carcinoma, as evidenced from histopathological studies. Immunohistochemical analysis for the expression of Ki67 indicated that it also reduced cancer cell proliferation. Additionally, it induced apoptosis in the tumor cells by activation of Caspase3. Our results indicated that DHP-8 efficiently attenuated DMBA induced tumor progression and it could be a potent therapeutic agent for skin cancer treatment.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Calcium Channel Blockers; Carcinogens; Carcinoma, Squamous Cell; Cell Proliferation; Dihydropyridines; Male; Mice; Organ Size; Skin Neoplasms; Tumor Cells, Cultured

Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

Topics: Amino Acid Sequence; Animals; Azirines; Binding Sites; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromatin; Dihydropyridines; Female; Humans; Mice; Mice, Nude; Models, Molecular; Molecular Sequence Data; Nuclear Proteins; Protein Binding; Protein Structure, Tertiary; Recombinant Proteins; Sequence Alignment; Skin Neoplasms; Stereoisomerism; Transcription Factors