Multiaction Pt(IV) Prodrugs Releasing Cisplatin and Dasatinib Are Potent Anticancer and Anti-Invasive Agents Displaying Synergism between the Two Drugs

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt­(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tu...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2024-06, Vol.67 (11), p.9745-9758
Main Authors: Markova, Lenka, Maji, Moumita, Kostrhunova, Hana, Novohradsky, Vojtech, Kasparkova, Jana, Gibson, Dan, Brabec, Viktor
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Cisplatin - pharmacology
Dasatinib - chemical synthesis
Dasatinib - chemistry
Dasatinib - pharmacology
Drug Screening Assays, Antitumor
Drug Synergism
Humans
MCF-7 Cells
Organoplatinum Compounds - chemical synthesis
Organoplatinum Compounds - chemistry
Organoplatinum Compounds - pharmacology
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt­(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt­(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt­(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial–mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00888