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

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) is aggressive and chemotherapy-resistant.
• β-lapachone (β-LP) targets NQO1-expressing cancer cells.
• Hydroxytyrosol (HT) inhibits TNBC cancer stem cells (CSCs) and metastasis, and induces NQO1.

Purpose of the Study:

• To investigate the synergistic anticancer effects of β-LP and HT in TNBC.
• To explore the role of NQO1 in the combined treatment's efficacy.
• To elucidate the molecular mechanisms underlying the combined treatment's action.

Main Methods:

• Treatment of five TNBC cell lines with varying concentrations of β-LP and HT.
• Assessment of anti-proliferative, pro-apoptotic, and cell cycle arrest effects.
• Evaluation of CSC self-renewal and clonogenicity.
• RNA-sequencing (RNA-Seq) analysis to identify molecular pathways.

Main Results:

• The β-LP-HT combination demonstrated significant anti-proliferative and pro-apoptotic effects in TNBC cells, including docetaxel-resistant lines.
• Combined treatment inhibited CSC self-renewal and clonogenicity, reducing aggressive phenotypes.
• The efficacy was not solely dependent on NQO1 levels or ROS.
• RNA-Seq revealed that the combination strongly induces endoplasmic reticulum stress and apoptosis via the unfolded protein response.

Conclusions:

• The combination of β-lapachone and hydroxytyrosol shows significant synergistic anticancer activity against TNBC.
• This combination effectively targets cancer stem cells and overcomes docetaxel resistance.
• The anticancer effects are mediated by endoplasmic reticulum stress and apoptosis induction, not solely by NQO1.
• β-LP and HT represent a potentially safe, affordable, and effective therapeutic strategy for TNBC.