Ludwig Boltzmann Cluster of Translational Oncology, Vienna, Austria.
Curr Cancer Drug Targets. 2014;14(1):46-58. doi: 10.2174/15680096113136660109.
Platinum-based chemotherapeutics are the mainstay of treatment of a range of tumors achieving high response rates but limited in the course of disease by appearance of drug resistance. Tumor cells respond with reduced uptake and increased intracellular inactivation of the drugs, as well as increased DNA repair and general resistance to chemotherapyinduced cell death. Cisplatin is known to induce expression of cyclophilins, a group of proteins that have peptidyl-prolyl cis-trans isomerase (PPIase) and molecular chaperone activities, as stress response. Cyclophilin A (CypA) and other members of this family are inhibited by cyclosporin A (CsA) which sensitized diverse drug-resistant tumor cell lines in vitro to cisplatin. This effect of CsA was attributed to metabolic changes, inhibition of DNA repair, enhancement of apoptosis, altered intracellular signal transduction or increased production of reactive oxygen species (ROS), although no definitive explanation was provided so far. Several clinical trials employing cisplatin/carboplatin in combination with CsA yielded unsatisfactory results. Since viral replication was found to be dependent on cyclophilins of the host cells, effective new inhibitors, different from CsA or with low or absent immunosuppressive activity, are in development or clinical trials. Sanglifehrins are more potent than CsA and proved to increase toxicity of cisplatin against hepatocellular cancer cells in vitro. These novel cyclophilin inhibitors may offer new opportunities to achieve reversal of resistance to platinumbased drugs in refractory patients. Responsive cancer patients may be enriched in clinical trials by an identification of the downstream targets of Cyps responsible for chemoresistance.
铂类化疗药物是多种肿瘤治疗的基础，能达到较高的缓解率，但在疾病过程中会出现耐药性。肿瘤细胞通过减少药物摄取和增加细胞内失活、增加 DNA 修复以及对化疗诱导的细胞死亡的普遍抵抗来做出反应。顺铂已知能诱导亲环素的表达，亲环素是一组具有肽基脯氨酰顺反异构酶（PPIase）和分子伴侣活性的蛋白质，作为应激反应。亲环素 A（CypA）和该家族的其他成员被环孢素 A（CsA）抑制，CsA 能使体外多种耐药肿瘤细胞系对顺铂敏感。CsA 的这种作用归因于代谢变化、DNA 修复抑制、凋亡增强、细胞内信号转导改变或活性氧（ROS）产生增加，尽管迄今为止没有提供明确的解释。几项联合使用顺铂/卡铂和 CsA 的临床试验结果并不令人满意。由于病毒复制被发现依赖于宿主细胞的亲环素，因此正在开发或临床试验中寻找与 CsA 不同或具有低免疫抑制活性或无免疫抑制活性的有效新型抑制剂。桑利福林比 CsA 更有效，并已被证明能增加顺铂对肝癌细胞的体外毒性。这些新型亲环素抑制剂可能为克服耐铂类药物的耐药性提供新的机会。通过鉴定负责化疗耐药的 Cyps 的下游靶点，可以在临床试验中富集有反应的癌症患者。
