Gold(iii) complexes inhibit growth of cisplatin-resistant ovarian cancer in association with upregulation of proapoptotic PMS2 gene

Abstract

Various gold complexes have been known to overcome cisplatin resistance in cancer cells. Yet, their in vivo anti-tumor efficacies and detailed action mechanisms in overcoming this resistance remain largely unexplored. In this work we have established a xenograft model simultaneously consisting of both cisplatin-sensitive and cisplatin-resistant tumors by inoculating human ovarian cancer cells A2780 and its cisplatin-resistant variant A2780cis into different flanks of the same nude mouse. Towards this model, a gold(III) porphyrin complex [Au^III(TPP)]Cl (gold-1a, wherein [TPP]²⁻ = meso-tetraphenylporphyrinato ligand) was found to effectively inhibit the growth of both kinds of tumors, while cisplatin failed to suppress the growth of A2780cis tumors under similar conditions. In both A2780 and A2780cis cells, gold-1a was found to transcriptionally upregulate postmeiotic segregation increased 2 (PMS2) which has DNA mismatch repair and proapoptotic functions. Suppression of PMS2 by RNA interference in A2780cis cells partially rescued the gold-1a-induced death of the cells, indicating that gold-1a inhibited growth of cisplatin-resistant ovarian cancer in association with upregulation of this gene. Two other stable gold(III) analogues including gold(III) octaethylporphyrin (2) and gold(III)-NHC (3) complexes also displayed similar anti-cancer activities on A2780cis cells and capability in PMS2 regulation. In contrast, a gold(I) phosphine complex (4), a gold(I) thiourea complex (5), KAu^IIICl₄ and cisplatin all displayed a preferential cytotoxicity only towards the cisplatin-sensitive A2780 cells. Taken together, this work has demonstrated the prospect of gold(III) complexes for the treatment of cisplatin-resistant/relapsed ovarian cancers.