2. Academic Validation
  3. Unlocking the effective alliance of β-lapachone and hydroxytyrosol against triple-negative breast cancer cells

Unlocking the effective alliance of β-lapachone and hydroxytyrosol against triple-negative breast cancer cells

  • Biomed Pharmacother. 2024 Mar 21:174:116439. doi: 10.1016/j.biopha.2024.116439.
Jesús Calahorra 1,  José L Blaya-Cánovas 2,  Olivia Castellini-Pérez 3,  Ernesto Aparicio-Puerta 4,  Candela Cives-Losada 5,  Jose J G Marin 5,  Markel Rementeria 3,  Francisca E Cara 6,  Araceli López-Tejada 7,  Carmen Griñán-Lisón 7,  Francesco Aulicino 8,  Imre Berger 9,  Juan A Marchal 6,  Violeta Delgado-Almenta 3,  Sergio Granados-Principal 10
Affiliations

Affiliations

  • 1 UGC de Oncología Médica, Hospital Universitario de Jaén, Jaén 23007, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada-University of Granada, Granada 18100, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain. Electronic address: [email protected].
  • 2 UGC de Oncología Médica, Hospital Universitario de Jaén, Jaén 23007, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada-University of Granada, Granada 18100, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain.
  • 3 GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain.
  • 4 Clinical Bioinformatics, Center for Bioinformatics, Saarland University, Saarbrücken 66123, Germany.
  • 5 Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca 37007, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid 28029, Spain.
  • 6 Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada-University of Granada, Granada 18100, Spain.
  • 7 Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada-University of Granada, Granada 18100, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Department of Biochemistry and Molecular Biology 2, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada 18071, Spain.
  • 8 BrisSynBio Bristol Synthetic Biology Centre, Biomedical Sciences, School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK.
  • 9 BrisSynBio Bristol Synthetic Biology Centre, Biomedical Sciences, School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK; Max Planck Bristol Centre for Minimal Biology, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
  • 10 Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada-University of Granada, Granada 18100, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Department of Biochemistry and Molecular Biology 2, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada 18071, Spain. Electronic address: [email protected].
PMID: 38518601 DOI: 10.1016/j.biopha.2024.116439
Abstract

Triple-negative breast Cancer (TNBC) is characterised by its aggressiveness and resistance to chemotherapy, demanding the development of effective strategies against its unique characteristics. Derived from lapacho tree bark, β-lapachone (β-LP) selectively targets Cancer cells with elevated levels of the detoxifying Enzyme NQO1. Hydroxytyrosol (HT) is a phenolic compound derived from olive trees with important Anticancer properties that include the inhibition of Cancer Stem Cells (CSCs) and metastatic features in TNBC, as well as relevant antioxidant activities by mechanisms such as the induction of NQO1. We aimed to study whether these compounds could have synergistic Anticancer activity in TNBC cells and the possible role of NQO1. For this pourpose, we assessed the impact of β-LP (0.5 or 1.5 μM) and HT (50 and 100 μM) on five TNBC cell lines. We demonstrated that the combination of β-LP and HT exhibits anti-proliferative, pro-apoptotic, and cell cycle arrest effects in several TNBC cells, including docetaxel-resistant TNBC cells. Additionally, it effectively inhibits the self-renewal and clonogenicity of CSCs, modifying their aggressive phenotype. However, the notable impact of the β-LP-HT combination does not appear to be solely associated with the levels of the NQO1 protein and ROS. RNA-Seq analysis revealed that the combination's Anticancer activity is linked to a strong induction of endoplasmic reticulum stress and Apoptosis through the unfolded protein response. In conclusion, in this study, we demonstrated how the combination of β-LP and HT could offer an affordable, safe, and effective approach against TNBC.

Keywords

Hydroxytyrosol; NQO1; Triple-negative breast cancer; Unfolded protein response; β-lapachone.

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