Melanoma is an aggressive
skin cancer that metastasizes to other organs. While
immune checkpoint blockade with anti-PD-1 has transformed the treatment of advanced
melanoma, many
melanoma patients fail to respond to anti-PD-1
therapy or develop acquired resistance. Thus, effective treatment of
melanoma still represents an unmet clinical need. Our prior studies support the anti-
cancer activity of the 17β-hydroxywithanolide class of natural products, including
physachenolide C (PCC). As single agents, PCC and its semi-synthetic analog demonstrated direct cytotoxicity in a panel of murine
melanoma cell lines, which share common driver mutations with human
melanoma; the IC50 values ranged from 0.19-1.8 µM. PCC treatment induced apoptosis of
tumor cells both in vitro and in vivo. In vivo treatment with PCC alone caused the complete regression of established
melanoma tumors in all mice, with a durable response in 33% of mice after discontinuation of treatment. T cell-mediated immunity did not contribute to the therapeutic efficacy of PCC or prevent
tumor recurrence in YUMM2.1
melanoma model. In addition to apoptosis, PCC treatment induced G0-G1 cell cycle arrest of
melanoma cells, which upon removal of PCC, re-entered the cell cycle. PCC-induced cycle cell arrest likely contributed to the in vivo
tumor recurrence in a portion of mice after discontinuation of treatment. Thus, 17β-hydroxywithanolides have the potential to improve the therapeutic outcome for patients with advanced
melanoma.