Abstract 4829: Plumbagin amplifies the pro-apoptotic and anti-tumorigenic activities of vemurafenib in BRAF-mutant melanoma

Abstract

Abstract Melanoma, the deadliest form of skin cancer, originates from the pigment-producing cells in the skin known as melanocytes. The incidence of melanoma is increasing at a more alarming rate than any other cancer worldwide. BRAF mutations occur in ~50% of melanomas that drive oncogenic activation of the BRAF-MEK-ERK resulting in cell proliferation and tumorigenesis. BRAF and MEK inhibitors either alone or in combination have improved the overall survival of melanoma patients with BRAF mutations. However, these patients inevitably develop resistance to these treatments. Thus, there is a need for exploring novel agents to enhance the therapeutic efficacy of these inhibitors for the management of melanoma. Phytochemicals offer promising new options for the development of more effective strategies because of their relatively low toxicities on normal cells. Plumbagin, a naturally occurring naphthoquinone found in flowers and roots of the Plumbaginaceae family, exhibits potent anti-proliferative and anti-tumorigenic properties. Recently, we have shown that plumbagin reduces proliferation and induces apoptosis in melanoma cells by downregulating PI3K signaling. Studies have unequivocally demonstrated that BRAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways play major roles in melanoma development and therapy resistance. Therefore, the objective of this study is to determine whether plumbagin in combination with vemurafenib could offer therapeutic benefit over an individual agent for the treatment of the BRAF-mutant melanoma. Treatment of BRAF-mutant human melanoma cells with plumbagin and vemurafenib in combination more effectively reduced cell growth and colony formation than individual agents. Combination treatment (plumbagin + vemurafenib) also resulted in increased apoptosis as revealed by cleaved caspase-3 and PARP. Furthermore, combination treatment resulted in enhanced expression of Bax and Bak, and increased inhibition of Bcl2 and Mcl-1. We also found that combination treatment was more effective in inhibiting the phosphorylation of MEK1/2 ERK1/2, AKT, and mTOR as well as the protein expression of PI3K. In athymic nude mice subcutaneously implanted with A375 melanoma cells, combination treatment resulted in greater inhibition of tumor growth, when compared to individual agents. Combination treatment also resulted in (i) decreased phosphorylation of MEK1/2, ERK1/2, AKT, and mTOR (ii) decreased proliferation, and (iii) increased apoptosis in tumor samples than individual agents.These data encourage the need for further advanced in vivo studies to evaluate the effects of plumbagin as an adjuvant to current therapies for the management of BRAF-mutant melanoma. Citation Format: Pooja Sharma, Mary Katherine Montes de Oca, Ross L. Pearlman, Farrukh Afaq. Plumbagin amplifies the pro-apoptotic and anti-tumorigenic activities of vemurafenib in BRAF-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4829.