Mechanisms of S-phase arrest and mitochondrial dysfunction in complex III by DHODH inhibitors in tumorigenic TNBC cells.

Autor: Shahhiran MAA; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.; Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia., Abdul Kadir MF; Aurigene Discovery Technology (M) Sdn Bhd, Level 2 Research Management and Innovation Complex, University of Malaya, 50603, Kuala Lumpur, Malaysia., Nor Rashid N; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.; Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia., Abdul-Rahman PS; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia., Othman S; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. shatraho@um.edu.my.; Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia. shatraho@um.edu.my.
Jazyk: angličtina
Zdroj: Histochemistry and cell biology [Histochem Cell Biol] 2024 Nov 18; Vol. 163 (1), pp. 3. Date of Electronic Publication: 2024 Nov 18.
DOI: 10.1007/s00418-024-02339-0
Abstrakt: Dihydroorotate dehydrogenase (DHODH) inhibitors have recently gained increasing research interest owing to their potential for treating breast cancers. We explored their effects in different breast cancer subtypes, focusing on mitochondrial dysfunction. The sensitivity of different subtypes to the inhibitors was investigated with respect to DHODH expression, tumorigenic, and receptor status. Analysis of respiratory complexes, cell cycle, reactive oxygen species (ROS), and cell differentiation were performed. Four cell lines with different receptor status were included, namely MCF-7, MDAMB-231, SKBR-3, and MCF-10A. We showed that MCF-7 and MDAMB-231 cells of the subtypes (ER + /PR + /HER2 - ) and (ER - /PR - /HER2 - ), respectively, were responsive to brequinar. Brequinar (BQR) caused cell cycle arrest in the S-phase in sensitive subtypes of breast cells but induced cell differentiation only in poorly differentiated breast cells. All cell subtypes showed increased generation of ROS, both intracellular and mitochondrial ROS with a greater increase seen in mitochondrial ROS in response to DHODH inhibitor, subsequently contributing to mitochondrial dysfunction. BQR also disrupts the function of complex III in ER + /PR + and triple negative breast cancer (TNBC) subtypes. Collectively, we have found that MDAMB-231 TNBC cell was the most affected by DHODH inhibition in terms of sensitivity, cell cycle arrest, induction of cell differentiation, production of ROS, and mitochondrial complexes disruption. In conclusion, these findings suggest that DHODH inhibitors can potentially become a valuable targeted therapy for TNBC subtype and further consolidates its therapeutic potential as part of the combinatorial therapy against this resilient breast cancer subtype.
Competing Interests: Declarations Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. The authors have no relevant financial and non-financial interests to disclose. Ethical approval Not applicable. Informed consent Not applicable. Consent for publication Not applicable.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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