Gossypin as a Novel Selective Dual Inhibitor of v-raf Murine Sarcoma Viral Oncogene Homolog B1 and Cyclin-Dependent Kinase 4 for Melanoma
| Autor: | Shylesh Bhaskaran, Hareesh B. Nair, Mitch Klausner, Sathyaseelan S. Deepa, Naveen K. Krishnegowda, Chittalakkottu Sadasivan, Kalarikkal V. Dileep, Rajeshwar Rao Tekmal, John L. VandeBerg |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Cancer Research MAP Kinase Signaling System Transplantation Heterologous Cell Mice Cell Movement Cell Line Tumor medicine Animals Humans Melanoma neoplasms Flavonoids biology Cell growth Cyclin-dependent kinase 4 Kinase Cell Cycle Cyclin-Dependent Kinase 4 medicine.disease Tumor Burden Molecular Docking Simulation Transplantation Disease Models Animal medicine.anatomical_structure Oncology Cell culture Apoptosis Mutation Cancer research biology.protein Female Protein Binding |
| Zdroj: | Molecular Cancer Therapeutics. 12:361-372 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-12-0965 |
| Popis: | Mutation in the BRAF gene (BRAFV600E) exists in nearly 70% of human melanomas. Targeted therapy against BRAFV600E kinase using a recently identified RAF-selective inhibitor, PLX4032, has been successful in early clinical trials. However, in patients with the normal BRAF allele (wild-type), PLX4032 is protumorigenic. This conundrum identifies the unmet need for novel therapeutic agents to target BRAFV600E kinase that are not counterproductive. We have identified gossypin, a pentahydroxy flavone, as a potent antimelanoma agent. Gossypin inhibited human melanoma cell proliferation, in vitro, in melanoma cell lines that harbor both BRAFV600E kinase and cyclin-dependent kinase 4 (CDK4) as well as in cells with BRAF wild-type allele. Gossypin inhibited kinase activities of BRAFV600E and CDK4, in vitro, possibly through direct binding of gossypin with these kinases, as confirmed by molecular docking studies. For cells harboring the BRAFV600E, gossypin inhibited cell proliferation through abrogation of the MEK–ERK–cyclin D1 pathway and in cells with BRAF wild-type allele, through attenuation of the retinoblastoma–cyclin D1 pathway. Furthermore, gossypin significantly inhibited melanoma growth in an organotypic three-dimensional skin culture mimicking human skin. Gossypin (10 and 100 mg/kg) treatment for 10 days in human melanoma (A375) cell xenograft tumors harboring BRAFV600E significantly reduced tumor volume through induction of apoptosis and increased survival rate in mice, and the effect was significantly superior to that of PLX4032 (10 mg/kg) or roscovitine 10 mg/kg. In summary, this study identified gossypin as a novel agent with dual inhibitory effects for BRAFV600E kinase and CDK4 for treatment of melanoma. Mol Cancer Ther; 12(4); 361–72. ©2013 AACR. |
| Databáze: | OpenAIRE |
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