Yang Jie, Zeng Xin, Pei Junxia, Su Zhou, Liu Qi, Zhang Yamei, Yang Yixi, Li Rui, Zhou Fei, Deng Yu
Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China.
Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China.
Med Oncol. 2025 Jan 18;42(2):48. doi: 10.1007/s12032-025-02601-y.
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.
基于替莫唑胺（TMZ）的化疗是靶向治疗或免疫治疗失败的黑色素瘤患者的主要治疗方案。然而，基于TMZ的化疗低反应率对患者的预后构成挑战。BRAF突变是黑色素瘤中最常见的突变位点。本研究调查了原儿茶醛（PA）与替莫唑胺（TMZ）联合对BRAF突变黑色素瘤细胞和BRAF抑制剂耐药黑色素瘤细胞的杀伤协同作用及其潜在分子机制。我们报告PA协同增强TMZ对BRAF抑制剂敏感和BRAF抑制剂耐药黑色素瘤细胞的细胞毒性。PA与TMZ联合增加DNA双链断裂并提高细胞凋亡率。机制研究表明，PA通过诱导FANCD2降解促进TMZ的细胞毒性。我们的结果表明，无论O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）状态如何，PA都是黑色素瘤联合化疗的潜在化合物。
