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.
- MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- cisplatina * farmakologie MeSH
- dasatinib * farmakologie chemie chemická syntéza MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny farmakologie chemie chemická syntéza MeSH
- prekurzory léčiv * farmakologie chemie chemická syntéza MeSH
- proliferace buněk účinky léků MeSH
- synergismus léků * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky * MeSH
- cisplatina * MeSH
- dasatinib * MeSH
- organoplatinové sloučeniny MeSH
- prekurzory léčiv * MeSH
A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s ; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non-treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed slightly better tumor free survival than doxorubicin.
- Klíčová slova
- Doxorubicin, Gemcitabine, Immunogenic Cell Death, Multi-Targeting Prodrugs, Oxaliplatin,
- MeSH
- antitumorózní látky * farmakologie terapeutické užití MeSH
- doxorubicin farmakologie terapeutické užití MeSH
- gemcitabin MeSH
- imunogenní buněčná smrt MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory * MeSH
- oxaliplatin farmakologie MeSH
- prekurzory léčiv * farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky * MeSH
- doxorubicin MeSH
- gemcitabin MeSH
- oxaliplatin MeSH
- prekurzory léčiv * MeSH
