EYES2023 ESE Young Endocrinologists and Scientists (EYES) 2023 Oral communication 8: Interdisciplinary Endocrinology and Environment, Society and Governance (4 abstracts)
Identifying and characterizing novel HSP90 inhibitors with senolytic activity in a hormone-induced breast cancer-senescence model
Luca Cis 1 , Sandra Atlante 2 , Sara De Martino 3 , Chiara Cencioni 3 , Aurora Aiello 3 , Davide Pirolli 4 , Marco Malavolta 5 , Simona Nanni 6 , Maria Cristina De Rosa 4 , Carlo Gaetano 2 & Antonella Farsetti 3
1Università Cattolica del Sacro Cuore, Medicina e Chirurgia Traslazionale, Roma, Italy; 2Istituti Clinici Scientifici Maugeri-Irccs, Pavia, Italy; 3National Research Council Cnr-Iasi, Roma, Italy; 4National Research Council Cnr-Scitec, Roma, Italy; 5Irccs Inrca – Istituto Nazionale Riposo e Cura Anziani, Ancona, Italy; 6Università Cattolica del Sacro Cuore, Roma, Italy.
Background: Cell senescence is characterized by halted cell proliferation and the acquisition of a pro-inflammatory profile. Cancer cells can enter into senescent state following treatments that inflict DNA damage. Intriguingly, these cells can evade the senescent state, gaining enhanced proliferative capabilities and resistance to further treatment, thereby prompting tumor recurrence. Senolytics offer the potential to eradicate selectively senescent cells, preventing tumor recurrence and catalyzing tumor regression. Several senolytics with varying targets have been recognized. Nevertheless, these drugs, pose safety and specificity challenges.
Objectives: Our research, therefore, strives to identify and characterize innovative HSP90 inhibitors with senolytic features for application in hormone-driven cancers.
Methods: and resultsWe utilized in silico strategy to pinpoint several new, optimized HSP90-inhibiting compounds with minimal cytotoxicity, exploiting a structure- and ligand-based virtual screening approach. Among them, two HSP90α inhibitors, K4 and K5, exhibited senolytic activity in vitro without any observable cytotoxicity in non-senescent cells (patent pending). We selected the MCF7 cell line as our in vitro model. Senescence was induced via treatment with 4-Hydroxytamoxifen (Tam, 10uM 96h). Growth curve and beta-galactosidase (β-gal) assays confirmed that Tam effectively blocked MCF7 cell proliferation and triggered senescence up to 35–40% of cells compared to control. To assess the potential senolytic activity of K4 and K5, we treated senescence-induced cells with both drugs (10 μM, 96 h). β-gal staining was notably reduced, with only 10% of senescent cells remaining with K4 or K5 compared to DMSO. Interestingly, compared to control, the mortality rate rose significantly with K5 but not with K4. Western blot confirmed that p21 and γH2AX were stabilized by Tam, corroborating the induction of DNA damage.
Conclusions: Our findings suggest that the two newly identified HSP90 inhibitors, particularly K5, display senolytic properties and may be leveraged with tamoxifen to inhibit proliferation and stimulate cell death in breast cancer cells.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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