{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:26:38Z","timestamp":1793129198922,"version":"4.5.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1165\/rcmb.2015-0022oc","type":"journal-article","created":{"date-parts":[[2015,4,6]],"date-time":"2015-04-06T10:16:37Z","timestamp":1428315397000},"page":"637-646","source":"Crossref","is-referenced-by-count":30,"title":["Effects of Combining Rapamycin and Resveratrol on Apoptosis and Growth of TSC2-Deficient Xenograft Tumors"],"prefix":"10.1093","volume":"53","author":[{"given":"Anya","family":"Alayev","sequence":"first","affiliation":[{"name":"Department of Biology, Stern College for Women of Yeshiva University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel S.","family":"Salamon","sequence":"additional","affiliation":[{"name":"Department of Biology, Stern College for Women of Yeshiva University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi S.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Biology, Stern College for Women of Yeshiva University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenggang","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane J.","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina K.","family":"Holz","sequence":"additional","affiliation":[{"name":"Department of Biology, Yeshiva University, New York, New York; and"},{"name":"Department of Molecular Pharmacology and the Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,11,1]]},"reference":[{"key":"2026021122350745900_bib1","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1172\/JCI58709","article-title":"Lymphangioleiomyomatosis: a wolf in sheep's clothing","volume":"122","author":"Henske","year":"2012","journal-title":"J Clin Invest"},{"key":"2026021122350745900_bib2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s12672-012-0128-4","article-title":"Targeted approaches toward understanding and treating pulmonary lymphangioleiomyomatosis (LAM)","volume":"4","author":"Hammes","year":"2013","journal-title":"Horm Cancer"},{"key":"2026021122350745900_bib3","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1378\/chest.07-0898","article-title":"Lymphangioleiomyomatosis: a clinical update","volume":"133","author":"McCormack","year":"2008","journal-title":"Chest"},{"key":"2026021122350745900_bib4","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1177\/107327480601300405","article-title":"Lymphangioleiomyomatosis","volume":"13","author":"Taveira-DaSilva","year":"2006","journal-title":"Cancer Control"},{"key":"2026021122350745900_bib5","doi-asserted-by":"crossref","first-page":"30958","DOI":"10.1074\/jbc.M202678200","article-title":"Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM)","volume":"277","author":"Goncharova","year":"2002","journal-title":"J Biol Chem"},{"key":"2026021122350745900_bib6","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1165\/rcmb.2005-0300OC","article-title":"Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: role for tumor suppressor TSC2","volume":"34","author":"Goncharova","year":"2006","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122350745900_bib7","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/S1097-2765(03)00220-X","article-title":"Insulin activation of Rheb, a mediator of mTOR\/S6K\/4E-BP signaling, is inhibited by TSC1 and 2","volume":"11","author":"Garami","year":"2003","journal-title":"Mol Cell"},{"key":"2026021122350745900_bib8","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/ncb999","article-title":"Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins","volume":"5","author":"Zhang","year":"2003","journal-title":"Nat Cell Biol"},{"key":"2026021122350745900_bib9","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.cub.2005.02.053","article-title":"Rheb binds and regulates the mTOR kinase","volume":"15","author":"Long","year":"2005","journal-title":"Curr Biol"},{"key":"2026021122350745900_bib10","doi-asserted-by":"crossref","first-page":"721","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic: I. Taxonomy of the producing streptomycete and isolation of the active principle","volume":"28","author":"Vezina","year":"1975","journal-title":"J Antibiot (Tokyo)"},{"key":"2026021122350745900_bib11","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1002\/jcp.24351","article-title":"mTOR signaling for biological control and cancer","volume":"228","author":"Alayev","year":"2013","journal-title":"J Cell Physiol"},{"key":"2026021122350745900_bib12","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb839","article-title":"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling","volume":"4","author":"Inoki","year":"2002","journal-title":"Nat Cell Biol"},{"key":"2026021122350745900_bib13","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/ncb840","article-title":"Akt regulates growth by directly phosphorylating Tsc2","volume":"4","author":"Potter","year":"2002","journal-title":"Nat Cell Biol"},{"key":"2026021122350745900_bib14","doi-asserted-by":"crossref","first-page":"37288","DOI":"10.1074\/jbc.M303257200","article-title":"Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase\/Akt-dependent and -independent phosphorylation of tuberin","volume":"278","author":"Tee","year":"2003","journal-title":"J Biol Chem"},{"key":"2026021122350745900_bib15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/Akt pathway","volume":"10","author":"Manning","year":"2002","journal-title":"Mol Cell"},{"key":"2026021122350745900_bib16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2005.02.031","article-title":"Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis","volume":"121","author":"Ma","year":"2005","journal-title":"Cell"},{"key":"2026021122350745900_bib17","doi-asserted-by":"crossref","first-page":"13489","DOI":"10.1073\/pnas.0405659101","article-title":"Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase","volume":"101","author":"Roux","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122350745900_bib18","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"Crino","year":"2006","journal-title":"N Engl J Med"},{"key":"2026021122350745900_bib19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1056\/NEJMoa063564","article-title":"Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis","volume":"358","author":"Bissler","year":"2008","journal-title":"N Engl J Med"},{"key":"2026021122350745900_bib20","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1056\/NEJMoa1100391","article-title":"Efficacy and safety of sirolimus in lymphangioleiomyomatosis","volume":"364","author":"McCormack","year":"2011","journal-title":"N Engl J Med"},{"key":"2026021122350745900_bib21","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1073\/pnas.1104361108","article-title":"Tumorigenesis in tuberous sclerosis complex is autophagy and p62\/sequestosome 1 (SQSTM1)-dependent","volume":"108","author":"Parkhitko","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122350745900_bib22","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/jcb.24997","article-title":"The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells.","volume":"116","author":"Alayev","year":"2015","journal-title":"J Cell Biochem"},{"key":"2026021122350745900_bib23","doi-asserted-by":"crossref","first-page":"371","DOI":"10.4161\/cc.27355","article-title":"Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells","volume":"13","author":"Alayev","year":"2014","journal-title":"Cell Cycle"},{"key":"2026021122350745900_bib24","first-page":"1568","article-title":"Rodent model of reproductive tract leiomyomata: establishment and characterization of tumor-derived cell lines","volume":"146","author":"Howe","year":"1995","journal-title":"Am J Pathol"},{"key":"2026021122350745900_bib25","doi-asserted-by":"crossref","first-page":"4996","DOI":"10.1210\/endo.136.11.7588234","article-title":"Estrogen stimulation and tamoxifen inhibition of leiomyoma cell growth in vitro and in vivo","volume":"136","author":"Howe","year":"1995","journal-title":"Endocrinology"},{"key":"2026021122350745900_bib26","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1073\/pnas.0810790106","article-title":"Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells","volume":"106","author":"Yu","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122350745900_bib27","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1172\/JCI119038","article-title":"Rapamycin inhibits vascular smooth muscle cell migration","volume":"98","author":"Poon","year":"1996","journal-title":"J Clin Invest"},{"key":"2026021122350745900_bib28","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0304-3835(01)00443-8","article-title":"Resveratrol and quercetin inhibit angiogenesis in vitro","volume":"171","author":"Igura","year":"2001","journal-title":"Cancer Lett"},{"key":"2026021122350745900_bib29","doi-asserted-by":"crossref","first-page":"14056","DOI":"10.1074\/jbc.M700906200","article-title":"RAS\/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation","volume":"282","author":"Roux","year":"2007","journal-title":"J Biol Chem"},{"key":"2026021122350745900_bib30","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.4161\/cc.21194","article-title":"The role of S6K1 in ER-positive breast cancer","volume":"11","author":"Holz","year":"2012","journal-title":"Cell Cycle"},{"key":"2026021122350745900_bib31","doi-asserted-by":"crossref","first-page":"5734","DOI":"10.1021\/pr500714a","article-title":"Phosphoproteomics reveals resveratrol-dependent inhibition of Akt\/mTORC1\/S6K1 signaling","volume":"13","author":"Alayev","year":"2014","journal-title":"J Proteome Res"},{"key":"2026021122350745900_bib32","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.1158\/1078-0432.CCR-11-0445","article-title":"Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial","volume":"17","author":"Davies","year":"2011","journal-title":"Clin Cancer Res"},{"key":"2026021122350745900_bib33","doi-asserted-by":"crossref","first-page":"797","DOI":"10.7326\/0003-4819-154-12-201106210-00007","article-title":"Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus","volume":"154","author":"Taveira-DaSilva","year":"2011","journal-title":"Ann Intern Med"},{"key":"2026021122350745900_bib34","doi-asserted-by":"crossref","first-page":"e23379","DOI":"10.1371\/journal.pone.0023379","article-title":"Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease","volume":"6","author":"Dabora","year":"2011","journal-title":"PLoS One"},{"key":"2026021122350745900_bib35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1183\/09059180.00008813","article-title":"Towards personalised therapy for lymphangioleiomyomatosis: lessons from cancer","volume":"23","author":"El-Chemaly","year":"2014","journal-title":"Eur Respir Rev"},{"key":"2026021122350745900_bib36","doi-asserted-by":"crossref","first-page":"166","DOI":"10.2119\/2006-00091.Carelli","article-title":"Survivin expression in tuberous sclerosis complex cells","volume":"13","author":"Carelli","year":"2007","journal-title":"Mol Med"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/53\/5\/637\/66833406\/ajrcmb_53_5_637.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/53\/5\/637\/66833406\/ajrcmb_53_5_637.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:37:44Z","timestamp":1770867464000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/53\/5\/637\/8467930"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,1]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2015,11,1]]},"published-print":{"date-parts":[[2015,11,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2015-0022oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,11]]},"published":{"date-parts":[[2015,11,1]]}}}