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  • Recently several Pt IV complexes as prodrugs have been

    2020-03-25

    Recently, several Pt(IV) complexes as prodrugs have been designed and studied to enhance anti-tumor efficacy of traditional Pt(II) drugs, improving their cellular uptake and blood-circulation time [26], [27], [28], [29]. Compared with their Pt(II) counterparts, six-coordinated Pt(IV) complexes with octahedral geometry have higher coordination numbers with two extra axial ligands, which facilitate their kinetic inertness and low reduction potential till entering tumor 5959 [30], [31]. As the first bifunctional Pt(IV) complex, Mitaplatin with two dichloroacetate (DCA) moieties in the axial positions was found to attack both nuclear DNA and mitochondria, and expected to reduce drug resistance and heighten tumor cell apoptosis [32]. Inspired by that, vitamin E has also been coupled to a Pt(IV) complex that can cause simultaneous DNA and mitochondria damage [33]. Before long, a hybrid of Pt(IV)-aspirin, Platin-A, was designed to release aspirin, which exhibited anticancer and anti-inflammatory features better than the corresponding combination therapy [34]. Although the above-mentioned Pt(IV) complexes shown desirable ability to reduce platinum resistance via mitochondrial and other possible mechanisms [35], [36], specific DNA repair pathways that play a crucial role in the resistance response have not been explored. In this paper, CX-4945 has been designed in a Pt(IV) prodrug (Cx-platin) to occupy one of two axial positions of the Pt(IV) octahedral coordination sphere derived from cisplatin. It is anticipated that Cx-platin could reinforce cellular uptake of Pt and particularly suppress DNA repair response essential for aberrant CK2 activity to overcome cisplatin-induced resistance together with potent anticancer efficacy.
    Results
    Discussion DNA-damaged chemotherapeutics such as cisplatin are widely used in causing tumor regression. The DNA-targeted platinum drug cisplatin has been intensively studied for its antitumor efficacy with high levels of DNA damage causing cell-cycle arrest and cell death, which could be reduced by toxicity and innate or acquired resistance. The activities of most DNA repair pathways except mismatch repair could enable tumor cells to survive DNA damage, resulting in resistance to these DNA-targeted chemotherapeutics [7], [37]. The rational combinations of cisplatin and DNA repair-inhibitors to enhance tumor-cell killing have drawn much attention in the clinic. For instance, ABT-888, an inhibitor of PARP1 and PARP2, could be combined with platinum chemotherapy to potentiate the regression of established tumors [38], [39], [40], despite the full function of PARP in DNA repair is still unclear [41], [42]. UCN-01 is an anti-cancer agent that potentiates cisplatin toxicity via interfering with the interaction of ERCC1 and XPA, the components of the NER pathways which could repair cisplatin-induced intra-strand DNA damage [43], [44], [45]. Besides these specific DNA repair inhibitors, there is a more challenging treatment strategy to target a newly potential protein and disrupt a broader spectrum of DNA repair pathways to highly reverse the resistance and enhance the combination chemotherapy. CK2, a constitutively active Ser/Thr protein kinase over-expressed in cancer cells and recognized as its newly role in extensive DNA repairs induced by single and double strand breaks, could be inhibited by CX-4945 to strongly enhance the efficacy of cisplatin [46]. Thus, Cx-platin as a new Pt(IV) prodrug was designed and prepared by a fusion of cisplatin and CX-4945 that is a selective ATP-competitive CK2 inhibitor. Owing to the high lipophilicity and stability of the octahedral Pt(IV) structure, Cx-platin could increase cellular uptake, slow down reduction, and perform the enhanced DNA damage and antiproliferative activity compared with cisplatin and the mixture of cisplatin and CX-4945. And most significantly, it could overcome the cisplatin-induced resistance (Fig. 2). It is observed that the knockdown of CK2 in cancer cells shown in Fig. S4C could promote anticancer efficacy of cisplatin to reach the level of Cx-platin. This demonstrated that CK2 is a promising target of Cx-platin in the augmentation of anticancer activity in comparison with cisplatin and plays a crucial role in the DNA repair signal transductions that generate DNA-targeted agents-induced resistance in cancer cells.