Recently, Pt prodrugs have attracted much attention as the next generation of platinum-based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt prodrug that is among the most cytotoxic Pt prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC values in the nanomolar range in both cisplatin-sensitive and -resistant cells; these IC values are up to 422-fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter-mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.
Recently,P t IV prodrugs have attracted mucha ttention as the next generation of platinum-based antineoplastic drug candidates.H ere we report the discovery and evaluation of monochalcoplatin, amonocarboxylated Pt IV prodrug that is among the most cytotoxic Pt IV prodrugs to date.C ompared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells,w hich is not ascribed to its lipophilicity.T he prodrug is quickly reduced, causes DNAdamage,and induces apoptosis,resulting in superior cytotoxicity with IC 50 values in the nanomolar range in both cisplatin-sensitive and -resistant cells;t hese IC 50 values are up to 422-fold higher than that of cisplatin. Adetailed mechanistic study reveals that monochalcoplatin actively enters cells through at ransporter-mediated process.M oreover,m onochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies apractical strategy for the design of more effective Pt IV prodrugs to conquer drug resistance by tuning both cellular uptake pathwaysa nd activation processes.
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