Development of Synergetic Combinations of a Novel Apoptosis Inducer with AKT and Hsp90 Selective Inhibitors Targeting Hormone-Sensitive and Hormone-Resistant Breast Cancer Cells †
by
, , , , and
Diana I. Salnikova
1,*
,
Stepan K. Krymov
2
,
Danila V. Sorokin
1,3,
Fedor B. Bogdanov
1,4,
Olga E. Andreeva
1,
Alvina I. Khamidullina
5,
Andrey E. Shchekotikhin
2 and
Alexander M. Scherbakov
1,3
1
Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115522 Moscow, Russia
2
Gause Institute of New Antibiotics, B. Pirogovskaya Street 11, 119021 Moscow, Russia
3
Molecular Genetics Laboratory, Institute of Clinical Medicine, National Research Lobachevsky State University of Nizhny Novgorod, Gagarina Prospect 23, 603950 Nizhny Novgorod, Russia
4
Faculty of Medicine, Moscow State University, Lomonosovsky Prospect 27 bldg. 1, 119991 Moscow, Russia
5
Laboratory of Molecular Oncobiology, Institute of Gene Biology, Russian Academy of Sciences, Vavilova Street 34/5, 119334 Moscow, Russia
*
Author to whom correspondence should be addressed.
†
Presented at the 4th International Electronic Conference on Cancers, 6–8 March 2024; Available online: https://sciforum.net/event/IECC2024.
Proceedings 2024, 100(1), 4; https://doi.org/10.3390/proceedings2024100004
Published: 27 March 2024
Introduction: The design and development of antitumor compounds based on an isatin core led to the synthesis of 1-substituted isatin-5-sulfonamides with potent antiproliferative activity. This investigation is aimed at new 1-substituted isatin-5-sulfonamides with pro-apoptotic properties alone and in combination with AKT and Hsp90 inhibitors on hormone-sensitive and hormone-resistant breast cancer cells.
Methods: The synthesis of target 1-substituted isatin-5-sulfonamides involved 3 stages. The alkylation of isatin-5-sulfonamide via various benzyl chlorides allowed us to synthesize previously unknown series of 1-substituted isatin-5-sulfonamides. 4-Hydroxytamoxifen (HT) was used to develop a MCF7-resistant subline (MCF7/HT) via the long-term incubation of MCF7 cells with HT. MCF7 cells were transfected with the p53 luciferase reporter plasmid to obtain MCF7/p53-LUC cells.
Results: 1-(4-((trifluoromethyl)thio)benzyl)isatin-5-sulfonamide (LCTA-3344) exhibited the highest antiproliferative activity, suppressing tumor cells at low micromolar concentrations. After the development of the resistant subline, the IC50 values of HT were 5.1 ± 0.3 μМ (MCF7) and 10.2 ± 0.4 μМ (MCF7/HT), and a resistance index (RI) of 2 was found. Compound LCTA-3344 showed higher antiproliferative activity in MCF7/HT (IC50 = 1.4 ± 0.1 μМ), than in MCF7 (2.6 ± 0.3 μМ). A search for effective combinations with AKT Inhibitor IV (6-(2-benzothiazolyl)-1-ethyl-2-[2-(methylphenylamino)ethenyl]-3-phenyl-1H-benzimidazolium, monoiodide), AKT Inhibitor X (10-DEBC; 2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine), and Hsp90 Inhibitor (luminespib, NVP-AUY922; 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide) was performed. The combinations of LCTA-3344 and AKT Inhibitor IV on MCF7 and MCF7/HT were synergetic with combination index (CI) values equal to 0.8 and 0.4 (a higher effect), correspondingly. For comparison, combinations of LCTA-3344 with 10-DEBC and luminespib did not demonstrate such a high effect with a minimal value of CI 0.9. MCF7/p53-LUC cells were used to assess p53 activity. LCTA-3344 did not increase luciferase activity in MCF7/p53-LUC cells, whereas doxorubicin has been identified as its strong inducer.
Conclusions: A leading 1-substituted isatin-5-sulfonamide LCTA-3344 was 1.9 times more effective against MCF7/HT, than parental cells. The most effective drug combination was LCTA-3344 with AKT Inhibitor IV on the MCF7/HT subline, CI 0.4. The isatin-5-sulfonamide LCTA-3344 induced apoptosis with the p53-independent mechanism, which may provide a basis for novel therapeutic strategies in the treatment of hormone-resistant breast cancers.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/proceedings2024100004/s1, Conference poster.
Author Contributions
Conceptualization, A.M.S. and A.E.S.; methodology, S.K.K., D.V.S., O.E.A. and A.M.S.; validation, D.I.S., S.K.K., D.V.S., F.B.B., A.I.K. and O.E.A.; formal analysis, D.I.S., S.K.K., D.V.S., F.B.B., O.E.A. and A.I.K.; investigation, D.I.S., S.K.K., D.V.S., F.B.B., A.I.K. and O.E.A.; resources, A.M.S. and A.E.S.; data curation, A.M.S. and S.K.K.; writing—original draft preparation, D.I.S.; writing—review and editing, A.M.S. and A.E.S.; visualization, D.I.S., S.K.K., D.V.S. and O.E.A.; supervision, A.M.S. and A.E.S.; project administration, A.E.S. and A.M.S.; funding acquisition, A.E.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research was partly funded by the Russian Science Foundation (agreement 20-13-00402, https://rscf.ru/project/23-13-45035/, accessed on 24 November 2023).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
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MDPI and ACS Style
Salnikova, D.I.; Krymov, S.K.; Sorokin, D.V.; Bogdanov, F.B.; Andreeva, O.E.; Khamidullina, A.I.; Shchekotikhin, A.E.; Scherbakov, A.M. Development of Synergetic Combinations of a Novel Apoptosis Inducer with AKT and Hsp90 Selective Inhibitors Targeting Hormone-Sensitive and Hormone-Resistant Breast Cancer Cells. Proceedings 2024, 100, 4. https://doi.org/10.3390/proceedings2024100004
AMA Style
Salnikova DI, Krymov SK, Sorokin DV, Bogdanov FB, Andreeva OE, Khamidullina AI, Shchekotikhin AE, Scherbakov AM. Development of Synergetic Combinations of a Novel Apoptosis Inducer with AKT and Hsp90 Selective Inhibitors Targeting Hormone-Sensitive and Hormone-Resistant Breast Cancer Cells. Proceedings. 2024; 100(1):4. https://doi.org/10.3390/proceedings2024100004
Chicago/Turabian StyleSalnikova, Diana I., Stepan K. Krymov, Danila V. Sorokin, Fedor B. Bogdanov, Olga E. Andreeva, Alvina I. Khamidullina, Andrey E. Shchekotikhin, and Alexander M. Scherbakov. 2024. "Development of Synergetic Combinations of a Novel Apoptosis Inducer with AKT and Hsp90 Selective Inhibitors Targeting Hormone-Sensitive and Hormone-Resistant Breast Cancer Cells" Proceedings 100, no. 1: 4. https://doi.org/10.3390/proceedings2024100004
