Platinum-Paeonol Complexes as ERK Inhibitors To Restrain Melanoma and Relieve Cancer Pain

Melanoma is a refractory skin cancer with a poor response to chemotherapy and immunotherapy. Activation of the ERK pathway drives cell proliferation, metastasis, and pain in melanoma. Platinum-paeonol complexes PAP and DPAP were synthesized to inhibit melanoma and alleviate the associated pain. DPAP showed significant antimelanoma activity in vitro and vivo. It damaged DNA and mitochondria, triggering apoptosis via the mitochondrial pathway; moreover, it inhibited the expression of p-MEK1/2 and p-ERK1/2, thereby suppressing the metastasis and angiogenesis of melanoma. Uncommonly, DPAP showed the potential to relieve cancer pain by inhibiting the expressions of p-ERK1/2 and COX-2 in nerve cells and inactivating microglia and astrocytes in the spinal cord of mice. Contrary to conventional ERK inhibitors, DPAP upregulated programmed cell death ligand 1 (PD-L1), creating a unique susceptible tumor microenvironment for immunotherapy with anti-PD-1 monoclonal antibody. The combined therapy of DPAP and anti-PD-1 antibody remarkably improved their respective antitumor efficacy.