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

School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
Department of Pathology and Public Health, Faculty of Veterinary Medicine, Jordan University of Science and Technology (JUST), Irbid 22110, Jordan
Author to whom correspondence should be addressed.
Nutrients 2019, 11(2), 412;
Received: 28 December 2018 / Revised: 30 January 2019 / Accepted: 11 February 2019 / Published: 15 February 2019
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. View Full-Text
Keywords: breast cancer; combination; HER2/neu; lapatinib; c-Met; (−)-Oleocanthal breast cancer; combination; HER2/neu; lapatinib; c-Met; (−)-Oleocanthal
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Siddique, A.B.; Ebrahim, H.Y.; Akl, M.R.; Ayoub, N.M.; Goda, A.A.; Mohyeldin, M.M.; Nagumalli, S.K.; Hananeh, W.M.; Liu, Y.-Y.; Meyer, S.A.; El Sayed, K.A. (−)-Oleocanthal Combined with Lapatinib Treatment Synergized against HER-2 Positive Breast Cancer In Vitro and In Vivo. Nutrients 2019, 11, 412.

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