POL Scientific / JBM / Volume 11 / Issue 4 / DOI: 10.14440/jbm.2024.0055
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RESEARCH ARTICLE

Reappraisal of the fundamental mechanisms of the sHA14-1 molecule as a Bcl-2/Bcl-XL ligand in the context of anticancer therapy: A cell biological study

Aoula Moustapha1,2† ,  Pauline Andreu2† ,  François Gonzalvez2† ,  Delphine Fradin2 ,  Jean-Pierre Tissier3 ,  Phillippe Diolez4,5 ,  Patrice Xavier Petit1,2*
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1 National Center for Scientific Research UMR 8003, Paris City University, SSPIN Neuroscience Institute, Saint-Germain Campus, Paris, Île de France 75006, France
2 Department of Genetic and Development, INSERM U567/National Center for Scientific Research UMR 8104, Cochin Institut, Paris 750014, France
3 Laboratory of Process Engineering and Food Technologies, INRA Lille Research Center, Villeneuve D’Ascq Cedex, Hauts-de-France 59591, France
4 IHU Liryc, Bordeaux University Foundation, Pessac, Bordeaux, Nouvelle-Aquitaine 33000, France
5 National Institute of Health and Medical Research, Cardio-Thoracic Research Center, Bordeaux, Nouvelle-Aquitaine 33000, France
JBM 2024 , 11(4), e99010040; https://doi.org/10.14440/jbm.2024.0055
Submitted: 12 August 2024 | Revised: 26 August 2024 | Accepted: 5 November 2024 | Published: 30 December 2024
© 2024 by the Journal of Biological Methods published by POL Scientific. Licensee POL Scientific, USA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Background: HA14-1 is a small-molecule, stable B-cell lymphoma 2 (Bcl-2) antagonist that promotes apoptosis in malignant cells through an incompletely-defined mechanism of action. Bcl-2 and related anti-apoptotic proteins, such as B-cell lymphoma-extra-large [Bcl-XL]), are predominantly localized to the outer mitochondrial membrane, where they regulate cell death pathways. However, the notably short half-life of HA14-1 in vitro limits its potential therapeutic application. To address this limitation, a more stable analog, ethyl-2-amino-6-phenyl-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (sHA14-1), was developed. Objective: This study investigated the relationship between sHA14-1 and Bcl-2/Bcl-XL. The sHA14-1 molecule acts as a hormetic substance. Therefore, it is crucial to determine whether the hormetic zone corresponds to a putative therapeutic window, that is, the optimal concentration at which sHA14-1 selectively kills cancer cells overexpressing Bcl-2 or Bcl-XL while causing minimal damage to normal cells. Methods: Using classical cell biology and flow cytometry, we examined the main signaling pathways involving Bcl-2 or Bcl-XL, and their modification in the presence of sHA14-1. Results: We showed that sHA14-1 exerted a dual effect on mitochondria: (i) it sensitized cells to increased permeability, and (ii) it inhibited adenosine diphosphate-stimulated respiration and uncoupled respiration. At relatively low concentrations, sHA14-1 induced mitochondrial swelling, reminiscent of “pore opening” but with distinct characteristics. Over 30 μM, sHA14-1 caused mitochondrial transition depolarization independent of permeability transition and cell death that resembled secondary necrosis (i.e., occurring after maximal mitochondrial permeability) rather than apoptosis. The balance between apoptotic and necrotic cell death induced by sHA14-1 was also evaluated. Conclusion: Our results suggested that sHA14-1 plays a multifunctional role, involving both mitochondria and the endoplasmic reticulum. Its actions are more complex than its originally intended role in targeting anti-apoptotic Bcl-2 family members, which may complicate its potential application as an anticancer therapy.

Keywords
Apoptosis
Bcl-2/Bcl-XL ligand
Bioenergetic
Calcium
Cancer therapy
Mitochondria
PTP pore mitochondria
sHA14-1
Funding
This work was supported by funding dedicated to fundamental research from the National Center for Scientific Research (CNRS) and the National Institute of Health and Medical Research (INSERM).
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The authors declare no conflicts of interest.
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