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

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 [Pt (C^N^N)(NHC...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-04, Vol.118 (17), p.1
Main Authors: Wan, Pui-Ki, Tong, Ka-Chung, Lok, Chun-Nam, Zhang, Chunlei, Chang, Xiao-Yong, Sze, Kong-Hung, Wong, Alice Sze Tsai, Che, Chi-Ming
Format: Article
Language:English
Subjects:
Animal models
Anticancer properties
Antitumor activity
Binding
Biotransformation
Cancer
Chemotherapy
Cisplatin
Coils
Coordination compounds
Cytoskeleton
Hydrophobicity
Kidneys
Metastases
Metastasis
Physical Sciences
Platinum
Surface plasmon resonance
Tumors
Vimentin
Xenografts
Xenotransplantation
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Summary: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 [Pt (C^N^N)(NHC )]PF (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= -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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2025806118