Targeting drivers of melanoma with synthetic small molecules and phytochemicals

Abstract

Melanoma is the least common form of skin cancer, but it is responsible for the majority of skin cancer deaths. Traditional therapeutics and immunomodulatory agents have not shown much efficacy against metastatic melanoma. Agents that target the RAS/RAF/MEK/ERK (MAPK) signaling pathway—the BRAF inhibitors vemurafenib and dabrafenib, and the MEK1/2 inhibitor trametinib—have increased survival in patients with metastatic melanoma. Further, the combination of dabrafenib and trametinib has been shown to be superior to single agent therapy for the treatment of metastatic melanoma. However, resistance to these agents develops rapidly. Studies of additional agents and combinations targeting the MAPK, PI3K/AKT/mTOR (PI3K), c-kit, and other signaling pathways are currently underway. Furthermore, studies of phytochemicals have yielded promising results against proliferation, survival, invasion, and metastasis by targeting signaling pathways with established roles in melanomagenesis. The relatively low toxicities of phytochemicals make their adjuvant use an attractive treatment option. The need for improved efficacy of current melanoma treatments calls for further investigation of each of these strategies. In this review, we will discuss synthetic small molecule inhibitors, combined therapies and current progress in the development of phytochemical therapies.

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

“…PI3K/AKT constitutive activation results in downstream expression of mesenchymal proteins, repression of E-cadherin, and enhanced migration of melanoma cells [9,44]. Elevated AKT activity is present in approximately 70% of malignant melanomas, and upregulation of the PI3K/AKT pathway plays an important role in melanocyte neoplasia [13,45]. AKT primarily acts as a protein kinase to promote cell survival by activating downstream effectors such as mTOR.…”

“…Fisetin is a flavonoid derived from strawberries, mangoes, apples, grapes, persimmons, onions, tomatoes, and cucumbers [13,139]. Recent studies show that fisetin interferes with key regulators of EMT and may induce MET.…”

“…In addition to synthetic agents, phytochemicals have garnered attention as potential preventive or adjuvant treatment options. Phytochemicals have demonstrated significant potential for treating melanoma by inhibiting tumor progression, invasion, and metastasis [13,14]. The low-toxicity of these compounds makes them especially good candidates for use in cancer therapy.…”

Modulation of Ras/ERK and Phosphoinositide Signaling by Long-Chain n-3 PUFA in Breast Cancer and Their Potential Complementary Role in Combination with Targeted Drugs

“…Moreover, new therapies are also being experimented by combining different targeted inhibitors or combining targeted inhibitors with other existing non-targeted anticancer agents. In particular, recent studies have addressed the possibility of combining anticancer targeted therapies with natural agents, known for their broad antineoplastic activities, and relatively low toxicity, including LCn-3 PUFA fatty acids [25,26]. …”

Phytochemicals for the Management of Melanoma

“…Epidemiologic studies have also addressed the role of dietary factors in melanoma prevention. Since these dietary phytochemicals are safe and carry minimal toxicity, they hold promising potential as complementary therapies for the treatment of melanoma as well [100–103]. In the present review, we have explored the protective and therapeutic potential of dietary phytochemicals against cell proliferation, apoptosis, invasion and metastasis by targeting signal transduction pathways (Table 1 and Fig.…”