Germano Antonina, Rapa Ida, Volante Marco, De Francia Silvia, Migliore Cristina, Berruti Alfredo, Papotti Mauro, Terzolo Massimo
Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
Department Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
Mol Cell Endocrinol. 2015 Feb 5;401:105-10. doi: 10.1016/j.mce.2014.11.027. Epub 2014 Dec 9.
The anti-proliferative activity of mitotane (o,p'DDD) in adrenocortical cancer is mediated by its metabolites o,p'DDE and o,p'DDA. We previously demonstrated a functional link between ribonucleotide reductase M1(RRM1) expression and o,p'DDD activity, but the mechanism is unknown. In this study we assessed the impact of RRM1 on the bioavailability and cytotoxic activity of o,p'DDD, o,p'DDE and o,p'DDA in SW13 and H295R cells. In H295R cells, mitotane and its metabolites showed a similar cytotoxicity and RRM1 expression was not influenced by any drug. In SW13 cells, o,p'DDA only showed a cytotoxic activity and did not modify RRM1 expression, whereas the lack of sensitivity to o,p'DDE was associated to RRM1 gene up-modulation, as already demonstrated for o,p'DDD. RRM1 silencing in SW13 cells increased the intracellular transformation of mitotane into o,p'DDE and o,p'DDA. These data demonstrate that RRM1 gene interferes with mitotane metabolism in adrenocortical cancer cells, as a possible mechanisms of drug resistance.
米托坦（邻，对二氯二苯二氯乙烷，o,p'DDD）在肾上腺皮质癌中的抗增殖活性由其代谢产物邻，对二氯二苯二氯乙烯（o,p'DDE）和邻，对二氯二苯乙酸（o,p'DDA）介导。我们之前证明了核糖核苷酸还原酶M1（RRM1）表达与o,p'DDD活性之间存在功能联系，但具体机制尚不清楚。在本研究中，我们评估了RRM1对SW13和H295R细胞中o,p'DDD、o,p'DDE和o,p'DDA的生物利用度和细胞毒性活性的影响。在H295R细胞中，米托坦及其代谢产物表现出相似的细胞毒性，且RRM1表达不受任何药物影响。在SW13细胞中，o,p'DDA仅表现出细胞毒性活性，且不改变RRM1表达，而对o,p'DDE缺乏敏感性与RRM1基因上调有关，这与o,p'DDD的情况已得到证实一致。在SW13细胞中敲低RRM1会增加米托坦向o,p'DDE和o,p'DDA的细胞内转化。这些数据表明，RRM1基因干扰肾上腺皮质癌细胞中的米托坦代谢，这可能是耐药的一种机制。
