Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

Abstract

The dysregulation of apoptosis and DNA damage repair are two leading mechanisms of cisplatin resistance. Two anticancer Pt^IV prodrugs with the formulas [Pt(NH₃)₂Cl₂(L₁)₂] (1, L₁ = 3-chloro-benzo[b]thiophene-2-carboxylic acid) and [Pt(NH₃)₂Cl₂(L₂)₂] (2, L₂ = 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid) were designed to target myeloid cell leukemia-1 (Mcl-1), a protein responsible for inhibiting apoptosis and promoting DNA damage repair. Complexes 1 and 2 exhibited high cytotoxicity against various cancer cell lines, especially cisplatin-resistant non-small-cell lung and ovarian cancer cells. The resistance factors of both complexes for cisplatin-resistant cancer cells also decreased markedly as compared with that of cisplatin. Both 1 and 2 could enter cancer cells effectively and cause DNA damage while simultaneously downregulating Mcl-1 to prompt a conspicuous apoptotic response. Complex 2 also downregulated the DNA damage repair proteins RAD51 and BRCA2 as well as inhibited the formation of RAD51 foci, which is regarded as a critical step and functional biomarker in homologous recombination. The acute toxicity of 1 and 2 to mice is lower than that of cisplatin, and more importantly, they show much stronger inhibition towards the growth of non-small-cell lung cancer in nude mice than cisplatin. Complexes 1 and 2 are the first Mcl-1-targeted Pt^IV prodrugs, and the latter could synchronously inhibit apoptosis and DNA repair related proteins in cisplatin-resistant cancer cells. The strategy of tuning both apoptosis and DNA repair pathways opens a promising window to overcoming resistance to cisplatin in anticancer chemotherapy, and is also a breakthrough in the design of multitalented platinum-based anticancer drugs.