Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth.

Abstract

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.

• Authors: Pui-Ki Wan, Ka-Chung Tong, Chun-Nam Lok, Chunlei Zhang, Xiao-Yong Chang, Kong-Hung Sze, Alice Sze Tsai Wong, Chi-Ming Che
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 17 (04 27 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33883283 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Pt-NHC complex
• Vimentin

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Female
• HCT116 Cells
• Humans
• Lung Neoplasms (drug therapy, secondary)
• Mice
• Mice, Nude
• Molecular Dynamics Simulation
• Organoplatinum Compounds (metabolism, pharmacology, therapeutic use)
• Rats
• Vimentin (drug effects, metabolism)
• Xenograft Model Antitumor Assays