New ferrocene modified retinoic acid with enhanced efficacy against melanoma cells via GSH depletion

Malignant melanoma is a highly lethal disease, and advanced stages of melanoma have proven to be resistant to many chemotherapeutic drugs. Cancer stem cells (CSCs) and high levels of intracellular glutathione (GSH) have been proven to play important roles in drug resistance. Retinoic acid (RA) is a promising anticancer agent, which can inhibit proliferation and induce differentiation of CSCs, but its clinical use has been limited by its water insolubility and weak cancer cell killing effect when used alone. Herein, by combining RA and ferrocene, a new type of derivative of retinoic acid (FCRA) was synthesized and then oxidized by FeCl3. The oxidized FCRA (FCRA+) was exploited as a novel anticancer agent. Compared with RA, FCRA+ not only has improved water solubility and stronger anti-cancer effect to melanoma cells through depleting intracellular GSH of the cancer cells, but also can inhibit proliferation and induce differentiation of melanoma CSCs, such as free RA. Therefore, FCRA+ has better application prospects than RA and may replace RA for clinical applications.