Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer.
We recently reported that a combination of dietary grape polyphenols resveratrol, quercetin, and catechin (RQC), at low concentrations, was effective at inhibiting metastatic cancer progression. Herein, we investigate the molecular mechanisms of RQC in breast cancer and explore the potential of RQC as a potentiation agent for the epidermal growth factor receptor (EGFR) therapeutic gefitinib. Our in vitro experiments showed RQC induced apoptosis in gefitinib-resistant breast cancer cells via regulation of a myriad of proapoptotic proteins. Because the Akt/mammalian target of rapamycin (mTOR) signaling pathway is often elevated during development of anti-EGFR therapy resistance, the effect of RQC on the mTOR upstream effector Akt and the negative regulator AMP kinase (AMPK) was investigated. RQC was found to reduce Akt activity, induce the activation of AMPK, and inhibit mTOR signaling in breast cancer cells. Combined RQC and gefitinib decreased gefitinib resistant breast cancer cell viability to a greater extent than RQC or gefitinib alone. Moreover, RQC inhibited Akt and mTOR and activated AMPK even in the presence of gefitinib. Our in vivo experiments showed combined RQC and gefitinib was more effective than the individual treatments at inhibiting mammary tumor growth and metastasis in nude mice. Therefore, RQC treatment inhibits breast cancer progression and may potentiate anti-EGFR therapy by inhibition of Akt/mTOR signaling.
Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
Linette
L
Castillo-Pichardo
Suranganie F
SF
Dharmawardhane
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D059808:Polyphenols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D000077185:Resveratrol; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D027843:Vitis / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D059808:Polyphenols; D011799:Quinazolines; D013267:Stilbenes; D002392:Catechin; D011794:Quercetin; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; C505407:CASP3 protein, human; D053148:Caspase 3; D000077185:Resveratrol; D000077156:Gefitinib; D020123:Sirolimus