Gossypin Blocks Melanoma Growth in Culture and Xenograft Models

Targeted therapy against BRAF-V600E 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. In addition to the abnormal BRAF gene, some melanomas have a mutation in the CDK4 (cyclin-dependent kinase 4) gene.

The protein encoded by the BRAF gene plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene have been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small-cell lung carcinoma, and lung adenocarcinoma. The protein encoded by the CDK4 gene is a member of the Ser/Thr protein kinase family. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. Mutations in this gene as well as in its related proteins have all been found to be associated with tumorigenesis of a variety of cancers.

Investigators at the Texas Biomedical Research Institute (San Antonio, USA) tested gossypin on melanoma cell cultures, in a culture system that mimicked human skin, and in a mouse xenograft model. They reported in the April 2013 issue of the journal Molecular Cancer Therapeutics that gossypin acted as a potent antimelanoma agent. The substance inhibited human melanoma cell proliferation, in vitro, in melanoma cell lines that harbored both BRAF-V600E kinase and CDK4 as well as in cells with BRAF wild-type allele. Gossypin inhibited the kinase activities of BRAF-V600E and CDK4, in vitro, possibly through direct binding with these kinases, as confirmed by molecular docking studies. For cells harboring the BRAF-V600E mutation, 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.

Gossypin significantly inhibited melanoma growth in a three-dimensional skin culture mimicking human skin. Furthermore, gossypin treatment for 10 days in human melanoma cell xenograft tumors harboring BRAF-V600E significantly reduced tumor volume through induction of apoptosis and increased survival rate in mice, and the effect was significantly superior to that of PLX4032.

“We identified gossypin as a novel agent with dual inhibitory activity towards two common mutations that are the ideal targets for melanoma treatment,” said senior author Dr. Hareesh Nair, staff scientist at the Texas Biomedical Research Institute. “Our results indicate that gossypin may have great therapeutic potential as a dual inhibitor of mutations called BRAF-V600E kinase and CDK4, which occur in the vast majority of melanoma patients. They open a new avenue for the generation of a novel class of compounds for the treatment of melanoma.”

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Texas Biomedical Research Institute