title: Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors.
abstract: Lymphangioleiomyomatosis (LAM) is a rare neoplastic metastatic disease affecting women of childbearing age. LAM is caused by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) as a consequence of tuberous sclerosis complex (TSC) 1/2 inactivation. Clinically, LAM results in cystic lung destruction. mTORC1 inhibition using rapamycin analogs (rapalogs) is partially effective in reducing disease progression and improving lung function. However, cessation of treatment results in continued progression of the disease. In the present study, we investigated the effectiveness of the combination of rapamycin treatment with resveratrol, an autophagy inhibitor, in the TSC2-null xenograft tumor model. We determined that this combination inhibits phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K/Akt/mTORC1 signaling and activates apoptosis. Therefore, the combination of rapamycin and resveratrol may be an effective clinical strategy for treatment of LAM and other diseases with mTORC1 hyperactivation.
authors.affiliation: 1 Department of Biology, Stern College for Women of Yeshiva University, New York, New York.
authors.forename: Anya
authors.initials: A
authors.lastname: Alayev
authors.affiliation: 1 Department of Biology, Stern College for Women of Yeshiva University, New York, New York.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Salamon
authors.affiliation: 2 Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 1 Department of Biology, Stern College for Women of Yeshiva University, New York, New York.
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Schwartz
authors.affiliation: 2 Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: 2 Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: 3 Department of Biology, Yeshiva University, New York, New York; and.|4 Department of Molecular Pharmacology and the Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Marina K
authors.initials: MK
authors.lastname: Holz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol; D020123:Sirolimus; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat
keywords: LAM; TSC2; mTORC1; rapamycin; resveratrol
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