Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity
Research on platinum-based anticancer drugs continuously strives to develop new non-classical platinum complexes. Pt(IV) prodrugs are the most promising, and their activation-by-reduction mechanism of action is being explored as a prospect for higher selectivity and efficiency. Herein, we present th...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/9/2310 |
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| author | Anife Ahmedova Rositsa Mihaylova Silviya Stoykova Veronika Mihaylova Nikola Burdzhiev Viktoria Elincheva Georgi Momekov Denitsa Momekova |
| author_facet | Anife Ahmedova Rositsa Mihaylova Silviya Stoykova Veronika Mihaylova Nikola Burdzhiev Viktoria Elincheva Georgi Momekov Denitsa Momekova |
| author_sort | Anife Ahmedova |
| collection | DOAJ |
| description | Research on platinum-based anticancer drugs continuously strives to develop new non-classical platinum complexes. Pt(IV) prodrugs are the most promising, and their activation-by-reduction mechanism of action is being explored as a prospect for higher selectivity and efficiency. Herein, we present the anticancer potency and chemical reactivity of Pt(IV) complexes formed by linking pyrene butyric acid with cisplatin. The results from cytotoxicity screening on 10 types of cancer cell lines and non-malignant cells (HEK-293) indicated IC<sub>50</sub> values as low as 50–70 nM for the monosubstituted Pt(IV) complex against leukemia cell lines (HL-60 and SKW3) and a cisplatin-resistant derivative (HL-60/CDDP). Interestingly, the bis-substituted complex is virtually non-toxic to both healthy and cancerous cells of adherent types. Nevertheless, it shows high cytotoxicity against multidrug-resistant derivatives HL-60/CDDP and HL-60/Dox. The reactivity of the complexes with biological reductants was monitored by the NMR method. Furthermore, the platinum uptake by the treated cells was examined on two types of cellular cultures: adherent and suspension growing, and proteome profiling was conducted to track expression changes of key apoptosis-related proteins in HL-60 cells. The general conclusion points to a possible cytoskeletal entrapment of the bulkier bis-pyrene complex that could be limiting its cytotoxicity to adherent cells, both cancerous and healthy ones. |
| first_indexed | 2024-03-10T22:14:55Z |
| format | Article |
| id | doaj.art-0337ffa9a33941b099cc117e50374d9b |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T22:14:55Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-0337ffa9a33941b099cc117e50374d9b2023-11-19T12:27:59ZengMDPI AGPharmaceutics1999-49232023-09-01159231010.3390/pharmaceutics15092310Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer ActivityAnife Ahmedova0Rositsa Mihaylova1Silviya Stoykova2Veronika Mihaylova3Nikola Burdzhiev4Viktoria Elincheva5Georgi Momekov6Denitsa Momekova7Faculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier Blvd., 1164 Sofia, BulgariaFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Street, 1000 Sofia, BulgariaFaculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier Blvd., 1164 Sofia, BulgariaFaculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier Blvd., 1164 Sofia, BulgariaFaculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier Blvd., 1164 Sofia, BulgariaFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Street, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Street, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Street, 1000 Sofia, BulgariaResearch on platinum-based anticancer drugs continuously strives to develop new non-classical platinum complexes. Pt(IV) prodrugs are the most promising, and their activation-by-reduction mechanism of action is being explored as a prospect for higher selectivity and efficiency. Herein, we present the anticancer potency and chemical reactivity of Pt(IV) complexes formed by linking pyrene butyric acid with cisplatin. The results from cytotoxicity screening on 10 types of cancer cell lines and non-malignant cells (HEK-293) indicated IC<sub>50</sub> values as low as 50–70 nM for the monosubstituted Pt(IV) complex against leukemia cell lines (HL-60 and SKW3) and a cisplatin-resistant derivative (HL-60/CDDP). Interestingly, the bis-substituted complex is virtually non-toxic to both healthy and cancerous cells of adherent types. Nevertheless, it shows high cytotoxicity against multidrug-resistant derivatives HL-60/CDDP and HL-60/Dox. The reactivity of the complexes with biological reductants was monitored by the NMR method. Furthermore, the platinum uptake by the treated cells was examined on two types of cellular cultures: adherent and suspension growing, and proteome profiling was conducted to track expression changes of key apoptosis-related proteins in HL-60 cells. The general conclusion points to a possible cytoskeletal entrapment of the bulkier bis-pyrene complex that could be limiting its cytotoxicity to adherent cells, both cancerous and healthy ones.https://www.mdpi.com/1999-4923/15/9/2310platinum(IV) prodrugsanticancer agentscytotoxicitycellular uptakeactivation by reduction |
| spellingShingle | Anife Ahmedova Rositsa Mihaylova Silviya Stoykova Veronika Mihaylova Nikola Burdzhiev Viktoria Elincheva Georgi Momekov Denitsa Momekova Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity Pharmaceutics platinum(IV) prodrugs anticancer agents cytotoxicity cellular uptake activation by reduction |
| title | Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity |
| title_full | Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity |
| title_fullStr | Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity |
| title_full_unstemmed | Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity |
| title_short | Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity |
| title_sort | pyrenebutyrate pt iv complexes with nanomolar anticancer activity |
| topic | platinum(IV) prodrugs anticancer agents cytotoxicity cellular uptake activation by reduction |
| url | https://www.mdpi.com/1999-4923/15/9/2310 |
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