Protocatechuic aldehyde sensitizes BRAF-mutant melanoma cells to temozolomide through inducing FANCD2 degradation.

Temozolomide (TMZ)-based chemotherapy is a primary regimen for melanoma patients who have failed targeted therapy or immunotherapy. However, the low response rate of TMZ-based chemotherapy challenges the patients' prognosis. BRAF mutation is the most frequently mutated site in melanoma. This study investigates the synergistic effect of protocatechuic aldehyde (PA) and temozolomide (TMZ) in killing BRAF mutant melanoma cells and BRAF inhibitor-resistant melanoma cells as well as the underlying molecular mechanisms. We report that PA synergistically promoted TMZ cytotoxicity to both BRAF inhibitor-sensitive and BRAF inhibitor-resistant melanoma cells. Combination of PA and TMZ increased DNA double-strand breaks and elevated apoptosis. Mechanism study reveals that PA promoted TMZ cytotoxicity through inducing FANCD2 degradation. Our results suggest that PA is a potential compound for melanoma combinational chemotherapy, regardless of O-6-methylguanine-DNA methyltransferase (MGMT) status.