Canadine Platinum(IV) Complexes Targeting Epithelial–Mesenchymal Transition as Antiproliferative and Antimetastatic Agents

Epithelial–mesenchymal
transition (EMT) is a critical process
for cancer progression, which is crucial in inhibiting the immunity
in tumors and further boosting tumor metastasis. The suppression of
EMT represents a promising strategy for inhibiting metastatic tumors.
Herein, a series of new canadine platinum(IV) conjugates with potent
antiproliferative and antimetastatic activities were developed, which
activated by suppressing EMT and provoking immune response in tumors
besides causing DNA injury. The complexes could covalently conjugate
to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3
signaling. The EMT process was remarkably inhibited by suppressing
the Wnt/β-catenin pathway, reversing the inflammatory tumor
microenvironment, and inhibiting the HIF-1α pathway, which further
resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor
immunity was elevated by blocking immune checkpoints PD-L1 and CD47
accompanied by the improvement of CD3+ and CD8+ T lymphocytes and the macrophage polarization from M2- toward M1-type
simultaneously in tumors.