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Article

Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells

by
Mikhail G. Akimov
1,*,
Natalia M. Gretskaya
1,
Evgenia I. Gorbacheva
1,
Nisreen Khadour
1,2,
Galina D. Sherstyanykh
1 and
Vladimir V. Bezuglov
1
1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russia
2
Moscow Center for Advanced Studies, Kulakova Str. 20, 123592 Moscow, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(2), 820; https://doi.org/10.3390/ijms26020820
Submission received: 14 December 2024 / Revised: 15 January 2025 / Accepted: 16 January 2025 / Published: 19 January 2025
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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Abstract

2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types of tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, ceramide is counterbalanced by the sphingosine-1-phosphate, and thus the mechanisms of 2-AG influence on proliferation are poorly understood. We evaluated the mechanism of the anti-proliferative action by 2-AG and the influence of lysophaosphatidylinositol (LPI) on it in six human breast cancer cell lines of different tumor degree (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, and MDA-MB-231) using resazurin test, inhibitor, blocker, and anti-oxidant analysis, and siRNA interference. To avoid acyl migration in 2-AG, we replaced it with the analog 2-arachidonoyl-1,3-difluoropropanol (2-ADFP) newly synthesized by us. Using a molecular docking approach, we showed that at the CB2 receptor, 2-ADFP and 2-AG were very close to each other. However, 2-ADFP demonstrated a stronger affinity towards CB1 in the antagonist-bound conformation. 2-ADFP was anti-proliferative in all the cell lines tested. The toxicity of 2-ADFP was enhanced by LPI. 2-ADFP activity was reduced or prevented by the CB2 and vanilloid receptor 1 (TRPV1) blockers, inositol triphosphate receptor, CREB, and cyclooxygenase 2 inhibitor, and by anti-oxidant addition. Together with the literature data, these results indicate CB2- and TRPV1-dependent COX-2 induction with concomitant cell death induction by the oxidized molecule’s metabolites.
Keywords: CB1; CB2; TRPV1; LPI; 2-arachidonoylglycerol; COX-2; breast cancer CB1; CB2; TRPV1; LPI; 2-arachidonoylglycerol; COX-2; breast cancer

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MDPI and ACS Style

Akimov, M.G.; Gretskaya, N.M.; Gorbacheva, E.I.; Khadour, N.; Sherstyanykh, G.D.; Bezuglov, V.V. Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells. Int. J. Mol. Sci. 2025, 26, 820. https://doi.org/10.3390/ijms26020820

AMA Style

Akimov MG, Gretskaya NM, Gorbacheva EI, Khadour N, Sherstyanykh GD, Bezuglov VV. Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells. International Journal of Molecular Sciences. 2025; 26(2):820. https://doi.org/10.3390/ijms26020820

Chicago/Turabian Style

Akimov, Mikhail G., Natalia M. Gretskaya, Evgenia I. Gorbacheva, Nisreen Khadour, Galina D. Sherstyanykh, and Vladimir V. Bezuglov. 2025. "Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells" International Journal of Molecular Sciences 26, no. 2: 820. https://doi.org/10.3390/ijms26020820

APA Style

Akimov, M. G., Gretskaya, N. M., Gorbacheva, E. I., Khadour, N., Sherstyanykh, G. D., & Bezuglov, V. V. (2025). Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells. International Journal of Molecular Sciences, 26(2), 820. https://doi.org/10.3390/ijms26020820

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