(−)-Oleocanthal Combined with Lapatinib Treatment Synergized against HER-2 Positive Breast Cancer In Vitro and In Vivo
by
Abu Bakar Siddique 1
, Hassan Y. Ebrahim 1, Mohamed R. Akl 1, Nehad M. Ayoub 2, Amira A. Goda 1, Mohamed M. Mohyeldin 1, Suresh K. Nagumalli 1, Wael M. Hananeh 3, Yong-Yu Liu 1, Sharon A. Meyer 1 and Khalid A. El Sayed 1,*
, Hassan Y. Ebrahim 1, Mohamed R. Akl 1, Nehad M. Ayoub 2, Amira A. Goda 1, Mohamed M. Mohyeldin 1, Suresh K. Nagumalli 1, Wael M. Hananeh 3, Yong-Yu Liu 1, Sharon A. Meyer 1 and Khalid A. El Sayed 1,*
1
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA
2
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
3
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; https://doi.org/10.3390/nu11020412
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.
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Keywords:
breast cancer; combination; HER2/neu; lapatinib; c-Met; (−)-Oleocanthal
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MDPI and ACS Style
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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