(-)-Oleocanthal Combined with Lapatinib Treatment Synergized against HER-2 Positive Breast Cancer In Vitro and In Vivo

Nutrients. 2019 Feb 15;11(2):412. doi: 10.3390/nu11020412.

Abstract

Dysregulation of epidermal growth factor receptor (EGFR)/human epidermal growth factor-2 (HER2) family is a hallmark of aggressive breast cancer. Small-molecule tyrosine kinase inhibitors are among the most effective cancer targeted treatments. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid lead from extra-virgin olive oil with documented anti-cancer activities via targeting mesenchymal epithelial transition factor (c-Met). Dysregulation of c-Met promotes aggressiveness to breast cancer-targeted therapies. Lapatinib (LP) is an FDA-approved dual EGFR/HER2 inhibitor for HER2-amplified breast cancer. HER2-Positive tumor cells can escape targeted therapies like LP effects by overexpressing c-Met. Combined OC-LP treatment is hypothesized to be mechanistically synergistic against HER2-overexpressing breast cancer. Combined sub-effective treatments of OC-LP resulted in synergistic anti-proliferative effects against the HER2-positive BT-474 and SK-BR-3 breast cancer cell lines, compared to OC or LP monotherapy. Antibody array and Western blot analysis showed that combined OC-LP treatment significantly inhibited EGFR, HER2, and c-Met receptor activation, as well as multiple downstream signaling proteins, compared to individual OC or LP treatment. OC-LP Combination significantly inhibited invasion and migration of breast cancer cells through reduced activation of focal adhesion kinase (FAK) and paxillin. Combined treatment of OC-10 mg/kg with LP-12.5 mg/kg suppressed more than 90% of BT-474 tumor cells growth in a nude mouse xenograft model, compared to individual OC or LP treatment. Activated c-Met, EGFR, HER2, and protein kinase B (AKT) were significantly suppressed in combination-treated mice tumors, compared to OC or LP monotherapy. This study reveals the OC future potential as combination therapy to sensitize HER2-overexpressing breast cancers and significantly reduce required doses of targeted HER family therapeutics.

Keywords: (−)-Oleocanthal; HER2/neu; breast cancer; c-Met; combination; lapatinib.

MeSH terms

  • Aldehydes / administration & dosage*
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cyclopentane Monoterpenes
  • Drug Therapy, Combination
  • Epithelial-Mesenchymal Transition / drug effects
  • ErbB Receptors / drug effects
  • Female
  • Humans
  • Lapatinib / administration & dosage*
  • Mice
  • Phenols / administration & dosage*
  • Receptor, ErbB-2 / drug effects*
  • Receptor, ErbB-2 / metabolism

Substances

  • Aldehydes
  • Antineoplastic Agents
  • Cyclopentane Monoterpenes
  • Phenols
  • Lapatinib
  • oleocanthal
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2