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

Chemical Science Pub Date: 2020-03-09 DOI: 10.1039/D0SC00197J

Abstract

The dysregulation of apoptosis and DNA damage repair are two leading mechanisms of cisplatin resistance. Two anticancer PtIV 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 PtIV 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.

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