Development of resistance to a trinuclear platinum complex in ovarian carcinoma cells

作者：Paola Perego, Laura Gatti, Sabina Carla Righetti, Giovanni Luca Beretta, Nives Carenini, Elisabetta Corna, Laura Dal Bo, Stella Tinelli, Donato Colangelo, Roberto Leone, Piero Apostoli, Luciano Lombardi, Gino Beggiolin, Laura Piazzoni, Franco Zunino · 发表于：International Journal of Cancer · 年份：2003 · DOI：10.1002/ijc.11140 · 被引用次数：44 · 研究领域：Metal complexes synthesis and properties、Genetic factors in colorectal cancer、DNA Repair Mechanisms

BBR3464 is a trinuclear platinum complex that exhibits a potent cytotoxicity and efficacy against cisplatin-resistant tumors. To better understand the determinants of cellular resistance to BBR3464, we selected a resistant ovarian carcinoma cell line after exposure to the complex. The resistant cells (A2780/BBR3464) exhibited a high level of resistance to the selecting agent, but a marginal cross-resistance to cisplatin. Although cellular accumulation of BBR3464 was similar in parental and in resistant cells, DNA platination was decreased in A2780/BBR3464 cells, suggesting a reduced drug accessibility to DNA. This behavior reflected a partial drug inactivation at cytoplasmic level, as a consequence of increased levels of nucleophilic molecules including metallothioneins and human neurofilament low, but not glutathione. A2780/BBR3464 cells also exhibited a reduced susceptibility to apoptosis, which was consistent with reduced expression of Bax, and an alteration of DNA mismatch repair system, as reflected by lack of expression of MLH1 and PMS2, which could impair the recognition/repair of DNA lesions. Whereas both platinum drugs induced G2/M arrest in the parental cells, BBR3464, but not cisplatin, caused a late G1 arrest of resistant cells. Cisplatin induced an appreciable increase of p21(WAF1) levels in both models, in contrast to BBR3464 that produced a substantial upregulation of p21(WAF1) only in parental cells. An inverse relationship with p21(WAF1) modulation was found ...