Ratzon Einav, Najajreh Yousef, Salem Rami, Khamaisie Hazem, Ruthardt Martin, Mahajna Jamal
Cancer Drug Discovery Program, Migal, Galilee Research Institute, P.O. Box 831, Kiryat Shmona, 11016, Israel.
Anticancer Drugs Research Lab, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Abu-Dies, Palestinian Authority.
BMC Cancer. 2016 Feb 23;16:140. doi: 10.1186/s12885-016-2182-8.
Platinum-based drugs are used as cancer chemotherapeutics for the last 40 years. However, drug resistance and nephrotoxicity are the major limitations of the use of platinum-based compounds in cancer therapy. Platinum (IV) complexes are believed to act as platinum prodrugs and are able to overcome some of platinum (II) limitations.
A number of previously sensitized platinum (IV) complexes were evaluated for their anti-cancer activity by monitoring ability to affect proliferation, clonigenicity and apoptosis induction of Cisplatin sensitive and resistant cancer cells. In addition, the uptake of Cisplatin and the platinum (IV) derivatives to Cisplatin sensitive and resistant cancer cells was monitored.
The bis-octanoatoplatinum (IV) complex (RJY13), a Cisplatin derivative with octanoate as axial ligand, exhibited strong anti-proliferative effect on the Cisplatin resistant and sensitive ovarian cells, A2780cisR and A2780, respectively. Moreover, RJY13 exhibited good activity in inhibiting clonigenicity of both cells. Anti-proliferative activity of RJY13 was mediated by induction of apoptosis. Interestingly, a bis-lauratopaltinum (IV) complex (RJY6) was highly potent in inhibiting clonigenicity of both Cisplatin sensitive and Cisplatin resistant cells, however, exhibited reduced activity in assays that utilize cells growing in two dimensional (2D) conditions. The uptake of Cisplatin was reduced by 30% in A2780 in which the copper transporter-1 (Ctr1) was silenced. Moreover, uptake of RJY6 was marginally dependent on Ctr1, while uptake of RJY13 was Ctr1-independent.
Our data demonstrated the potential of platinum (IV) prodrugs in overcoming acquired and inherited drug resistance in cancer cell lines. Moreover, our data demonstrated that the uptake of Cisplatin is partially dependent on Ctr1 transporter, while uptake of RJY6 is marginally dependent on Ctr1 and RJY13 is Ctr1-independent. In addition, our data illustrated the therapeutic potential of platinum (IV) prodrugs in cancer therapy.
铂类药物在过去40年一直被用作癌症化疗药物。然而，耐药性和肾毒性是铂类化合物在癌症治疗中应用的主要限制因素。铂（IV）配合物被认为可作为铂前药，并且能够克服铂（II）的一些局限性。
通过监测对顺铂敏感和耐药癌细胞的增殖、克隆形成能力及凋亡诱导能力的影响，评估了一些先前已致敏的铂（IV）配合物的抗癌活性。此外，还监测了顺铂和铂（IV）衍生物对顺铂敏感和耐药癌细胞的摄取情况。
双辛酰铂（IV）配合物（RJY13），一种以辛酸盐作为轴向配体的顺铂衍生物，分别对顺铂耐药和敏感的卵巢癌细胞A2780cisR和A2780表现出强烈的抗增殖作用。此外，RJY13在抑制这两种细胞的克隆形成能力方面表现出良好活性。RJY13的抗增殖活性是通过诱导凋亡介导的。有趣的是，双月桂酰铂（IV）配合物（RJY6）在抑制顺铂敏感和耐药细胞的克隆形成能力方面非常有效，然而，在利用二维（2D）条件下生长的细胞的实验中活性降低。在铜转运蛋白-1（Ctr1）沉默的A2780细胞中，顺铂的摄取减少了30%。此外，RJY6的摄取对Ctr1的依赖性很小，而RJY13的摄取不依赖于Ctr1。
我们的数据证明了铂（IV）前药在克服癌细胞系中获得性和遗传性耐药方面的潜力。此外，我们的数据表明顺铂的摄取部分依赖于Ctr1转运蛋白，而RJY6的摄取对Ctr1的依赖性很小，RJY13的摄取不依赖于Ctr1。此外，我们的数据说明了铂（IV）前药在癌症治疗中的治疗潜力。
