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  • Cx platin could improve the level of cellular uptake and

    2019-07-11

    Cx-platin could improve the level of cellular uptake and DNA platination, hence triggering distinct DNA damage repair pathways. The data (Fig. 3B, C and D) demonstrated that Cx-platin could increase the foci number of γH2AX in cancer cells, preventing the efficient DSBs repair. This gives a good explanation that the high cellular uptake and DNA platination could lead to severe DNA damage of DSBs, but low cellular uptake of cisplatin only caused SSBs to induce ATM activation to DNA repair response. Notably, the decreased recruitment of Aprataxin with MDC1 (Fig. 5A) and a little phosphrylation of p-XRCC1 at CK2-specific sites (Fig. S5) were observed in Cx-platin due to its inhibition on DNA damage repair. More importantly, Cx-platin presents its antitumor activity via inhibiting the CK2-mediated MDC1 in DSBs repair response thoroughly (Fig. 5B and C). In vivo studies with nude mice bearing SGC-7901 xenografts confirmed that Cx-platin exhibited the increased antitumor efficacy compared with those of cisplatin alone and the corresponding mixture group. It is of interest to note that Cx-platin, containing the constituent of cisplatin in approximate the half dose as cisplatin, displayed nearly 1.5-folds tumor growth inhibition rate greater than cisplatin, and furthermore it hardly exhibited toxic effects on apparent body weight growth in Cx-platin-treated mice group. The blood stability assay of Cx-platin with rat plasma reveals that the Medroxyprogesterone acetate time of Cx-platin is significantly longer than that of cisplatin, contributing to the promising stability of Cx-platin in rat plasma. The pharmacokinetics studies exhibited that Cx-platin had longer blood retention as compared to cisplatin, which could dramatically promote Pt accumulation in tumor tissues. Cx-platin with longer circulation time could significantly ameliorate in vivo pharmacokinetics of cisplatin and increase its bioavailability. In addition to the DNA repair response, CK2 regulates a list of other cellular processes that are also established for the sensitivity to DNA-targeted chemotherapeutics, including PI3K/AKT/mTOR signaling, NF-kB transcription, Hsp90 machinery activity, hypoxia, inhibition of apoptosis and IL-6 expression. Moreover, sensitization of head and neck cancer cells to cisplatin by genetic manipulation of CK2 expression has been finally contributed to the suppression of Akt and NF-kB activity, respectively. Therefore, Cx-platin could possibly enhance its antitumor activity by modulating PI3K/Akt and NF-kB signaling besides the suppression of DNA repair response [12], [13]. Previous researches have ever reported the enhancement of therapeutic activity induced by suppression of CK2, indicating that CK2 represents a promising pharmacologic target [47]. In summary, introduction of a CK2 inhibitory agent, CX-4945, to the Pt(IV) framework derived from cisplatin has resulted in the formation of a novel Pt(IV) prodrug, Cx-platin, which presented potent cytotoxicity against a number of cancer cell lines including a cisplatin resistant cell line. Cx-platin was found to be highly accumulated in tumor cells for its high lipophilicity and stability as a Pt(IV) complex, which can be readily reduced by ascorbic acid to release active drugs, cisplatin and CX-4945. Its enhanced cellular uptake of Pt and subsequently platinated DNA can cause severe DSBs and SSBs damage, inducing cell cycle arrest and apoptosis. With the increased extent of the cellular uptake of Pt, severe DSBs were detected in Cx-platin-treated cancer cells. The coordinated CX-4945 to the platinum moiety was able to significantly inhibit DNA damage repair including both DSBs and SSBs repairs with MDC1/Aprataxin and XRCC1, respectively, activated by CK2, which related to the resistance mediated by DNA damaging platinum-based chemotherapy drugs. These results imply that Cx-platin could increase the sensitivity of the tumor cells to cisplatin released from prodrugs and reverse cisplatin-mediated resistance via increasing its cellular uptake and suppressing of CK2-related recruitments of Aprataxin to co-localize with MDC1 in DSBs repairs. An in vivo antitumor assay indicated that Cx-platin possessed significant antitumor activity with no toxic effect compared with cisplatin, revealing a novel strategy for the enhancement of sensitivity and the weakness of resistance by combing traditional clinic drugs with the small molecule targeting inhibitor for potential clinical application in future.