Monochalcoplatin: An Actively Transported, Quickly Reducible, and Highly Potent Pt^IV Anticancer Prodrug

Abstract

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.

Pt(iv) antitumor prodrugs: dogmas, paradigms, and realities

“…Incidentally, it turned out to be more active than its symmetric Pt(IV) counterpart, containing two molecules of chalcone, a p53 activator. 139…”

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

“…20,21 This prodrug strategy has been widely used for the construction of multifunctional Pt complexes as illustrated in many studies. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] BRCA and RAD51 play essential roles in HR, and BRCA-procient tumors are usually refractory to CDDP due to effective HR. Recently, we designed two Pt IV -artesunate prodrugs, which inhibited HR via downregulating RAD51 and exhibited higher cytotoxicity against BRCA-procient cancer cells than CDDP.…”

Precisely Assembled Nanoparticles against Cisplatin Resistance via Cancer-Specific Targeting of Mitochondria and Imaging-Guided Chemo-Photothermal Therapy

“…Cisplatin resistance in tumor cells is a multifaceted impediment, and three well-acknowledged mechanisms have attracted most attention: decrease in the accumulation of platinum in cells by reduced uptake of platinum complexes and/or increased drug efflux capacity, detoxification by intracellular thiol-containing species especially glutathione (GSH), and regulation of nucleotides to prevent repair. − The side effect of cisplatin is mainly due to the lack of cancer specificity . A lot of efforts have been made to solve these problems, including development of Pt­(IV) prodrugs, consumption of intracellular GSH, changes of uptake mechanism and intracellular localization, multimodel synergistic therapy, and so on. − …”