Polyamine-Based Pt(IV) Prodrugs as Substrates for Polyamine Transporters Preferentially Accumulate in Cancer Metastases as DNA and Polyamine Metabolism Dual-Targeted Antimetastatic Agents

Diverse platinum drug candidates have been designed to
improve
inhibitory potency and overcome resistance for orthotopic tumors.
However, the antimetastatic properties have rarely been reported.
We herein report that homospermidineplatin (4a), a polyamine-Pt­(IV)
prodrug, can potently inhibit tumor growth in situ and reverse cisplatin resistance as expected, and more importantly, 4a displays remarkably elevated antimetastatic activity in vivo (65.7%), compared to those of cisplatin (27.0%)
and oxaliplatin (19.6%). The underlying molecular mechanism indicates
that in addition to targeting nuclear DNA, 4a can modulate
polyamine metabolism and function in a manner different from that
of cisplatin. By upregulating SSAT and PAO, 4a downregulates
the concentrations of Put, Spd, and Spm, which favors the suppression
of fast-growing tumor cells. Moreover, the p53/SSAT/β-catenin
and PAO/ROS/GSH/GSH-Px pathways are involved in the inhibition of 4a-induced tumor metastasis. Our study implies a promising
strategy for the design of platinum drugs for the treatment of terminal
cancer.