Vemurafenib, an inhibitor of mitogen-activated protein kinase signaling downstream of BRAFV600E, can be successfully used to treat patients with metastatic melanoma. However, it produces a high incidence of therapeutic resistance. New strategies are needed to treat vemurafenib-resistant melanoma, so researchers used two bioactive compound libraries and identified two possible targets: deguelin and rotenone.
"Breakthroughs in understanding the molecular basis for the disease have led to a couple of different drugs, vemurafenib and dabrafenib, that elicit dramatic clinical responses in patients with metastatic melanoma containing a mutation in a certain gene," noted one of the study authors, Arup Indra, PhD, Associate Professor at the College of Pharmacy at Oregon State University, "but the drugs' effectiveness is limited by a high incidence of resistance, which inevitably leads to disease relapse in six or eight months. The current five-year survival rate of stage IV metastatic melanoma is less than 50%."
For this study, which was published in Molecular Carcinogenesis, the researchers conducted high-throughput screening of two bioactive compound libraries against a metastatic melanoma cell line. They identified the compounds deguelin and rotenone from a cell viability assay. Deguelin is a derivative of rotenone, and both compounds are classified as rotenoids of the flavonoid family. Deguelin acts as a mitochondrial complex I inhibitor, and it hinders oxygen consumption in cellular metabolism assays. When metastatic melanoma cells are treated with deguelin, AMPK signaling is activated, inhibiting mTORC1 signaling. This causes deguelin to effectively deprive the cancer cells of energy.
The study authors concluded, "These data posit that treatment with metabolic regulators, such as deguelin, can lead to energy starvation, thereby modulating the intracellular metabolic environment and reducing survival of drug-resistant melanomas harboring BRAFV600E mutations."
For More Information
Carpenter EL, Chagani S, Nelson D, et al (2019). Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAFV600E mutation bearing metastatic melanoma cells. Mol Carcinog. [Epub ahead of print] DOI:10.1002/mc.23068
Image Courtesy of Creative Commons. Licensed Under CC BY-SA 4.0