Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer

Porcel-Pastrana, Francisco; Montero-Hidalgo, Antonio J.; G-García, Miguel E.; Gil-Duque, Ignacio; Prats-Escribano, Antonio; Gahete, Manuel D.; Sarmento-Cabral, André; Luque, Raúl M.; León-González, Antonio J.

doi:10.3390/ijms26031341

Open AccessArticle

Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer

by

Francisco Porcel-Pastrana

^1,2,3

,

Antonio J. Montero-Hidalgo

^1,2,3

,

Miguel E. G-García

^1,2,3

,

Ignacio Gil-Duque

^1,2,3

,

Antonio Prats-Escribano

^1,2,3

,

Manuel D. Gahete

^1,2,3,4

,

André Sarmento-Cabral

^1,2,3

,

Raúl M. Luque

^1,2,3,4,*

and

Antonio J. León-González

^1,2,3,5,*

¹

Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Córdoba, Spain

²

Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14014 Córdoba, Spain

³

Hospital Universitario Reina Sofía (HURS), 14004 Córdoba, Spain

⁴

Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28019 Madrid, Spain

⁵

Department of Pharmacology, School of Pharmacy, University of Seville, 41012 Seville, Spain

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(3), 1341; https://doi.org/10.3390/ijms26031341

Submission received: 28 December 2024 / Revised: 30 January 2025 / Accepted: 31 January 2025 / Published: 5 February 2025

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

Download

Browse Figures

Review Reports Versions Notes

Abstract

Prostate cancer (PCa) is the tumour pathology with the second highest incidence among men worldwide. PCa is strongly influenced by obesity (OB), which increases its aggressiveness. Hence, some metabolic drugs like metformin have emerged as potential anti-tumour agents against several endocrine-related cancers. Likewise, a high adherence to the Mediterranean diet has been associated with lower rates of OB and a reduction in PCa aggressiveness since this diet contains phenolic bioactive compounds such as hydroxytyrosol (HT) that is mainly present in extra virgin olive oil. Thus, we decided to analyse the therapeutic potential of the combination of HT + metformin in different PCa cell models. Specifically, combinations of different doses of HT and metformin were evaluated by analysing the proliferation rate of LNCaP, 22Rv1, DU-145, and PC−3 cells using the SynergicFinder method. The results revealed a synergistic effect of HT + metformin in significantly reducing proliferation, especially in LNCaP cells. This anti-tumour effect of HT + metformin was also confirmed in migration and tumoursphere formation assays in LNCaP. The effects on the cell cycle and apoptosis were also assessed by flow-cytometry, and a cycle arrest in the G1 phase and an increase in late apoptosis were observed with the combination of HT + metformin. The phosphorylation levels of critical components of different oncogenic pathways were measured which revealed that the combination of HT + metformin significantly reduced the activity of multiple components of the MAPK, AKT, and TGF-β pathways. Overall, the combination of HT + metformin might represent a new therapeutic avenue for the management of PCa patients, an observation that certainly warrants further investigation through a well-designed clinical trial.

Keywords: prostate cancer; metformin; hydroxytyrosol; anti-tumour actions

Share and Cite

MDPI and ACS Style

Porcel-Pastrana, F.; Montero-Hidalgo, A.J.; G-García, M.E.; Gil-Duque, I.; Prats-Escribano, A.; Gahete, M.D.; Sarmento-Cabral, A.; Luque, R.M.; León-González, A.J. Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer. Int. J. Mol. Sci. 2025, 26, 1341. https://doi.org/10.3390/ijms26031341

AMA Style

Porcel-Pastrana F, Montero-Hidalgo AJ, G-García ME, Gil-Duque I, Prats-Escribano A, Gahete MD, Sarmento-Cabral A, Luque RM, León-González AJ. Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer. International Journal of Molecular Sciences. 2025; 26(3):1341. https://doi.org/10.3390/ijms26031341

Chicago/Turabian Style

Porcel-Pastrana, Francisco, Antonio J. Montero-Hidalgo, Miguel E. G-García, Ignacio Gil-Duque, Antonio Prats-Escribano, Manuel D. Gahete, André Sarmento-Cabral, Raúl M. Luque, and Antonio J. León-González. 2025. "Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer" International Journal of Molecular Sciences 26, no. 3: 1341. https://doi.org/10.3390/ijms26031341

APA Style

Porcel-Pastrana, F., Montero-Hidalgo, A. J., G-García, M. E., Gil-Duque, I., Prats-Escribano, A., Gahete, M. D., Sarmento-Cabral, A., Luque, R. M., & León-González, A. J. (2025). Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer. International Journal of Molecular Sciences, 26(3), 1341. https://doi.org/10.3390/ijms26031341

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI