{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:29:39Z","timestamp":1793363379232,"version":"4.5.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2012,5,4]],"date-time":"2012-05-04T00:00:00Z","timestamp":1336089600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the chemotherapy efficacy against HCC is still unsatisfactory. The mammalian target of rapamycin (mTOR) has been emerged as an important cancer therapeutic target. However, HCC cells often resistant to rapamycin because of the paradoxical activation of Akt by rapamycin. In this study, we investigated whether bortezomib could enhance the antitumor effects of rapamycin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The effects of rapamycin and bortezomib on HCC proliferation, apoptosis, migration, and invasiveness <jats:italic>in vitro<\/jats:italic> were assessed by CCK-8 analysis, flow cytometry, Hoechst 33342 staining and transwell assays, respectively. Total and phosphorylated protein levels of Akt were detected by Western blotting. The effects of rapamycin and\/or bortezomib on the mRNA expression levels of p53, p27, p21 and Bcl-2 family in HCCLM3 cells were evaluated by RT-PCR. The roles of rapamycin and bortezomib on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. The effects of rapamycin and bortezomib on cell proliferation and apoptosis <jats:italic>in vivo<\/jats:italic> were test by PCNA and TUNEL staining.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Bortezomib synergized with rapamycin to reduce cell growth, induce apoptosis, and inhibit cell mobility <jats:italic>in vitro<\/jats:italic>. Further mechanistic studies showed that bortezomib inhibited rapamycin-induced phosphorylated Akt, which in turn enhanced apoptosis of HCC cell lines. The alteration of the mRNA expression of cell cycle inhibitors p53, p27, p21 and apoptosis associated genes Bcl-2, Bax were also involved in the synergistic antitumor effects of rapamycin and bortezomib. P53 inhibitor PFT-\u03b1 significantly attenuate the effect of rapamycin and bortezomib on cell apoptosis, which indicated that the pro-apoptotic effect of rapamycin and bortezomib may be p53-dependent. Treatment of HCCLM3-R bearing nude mice with rapamycin and bortezomib significantly enhanced tumor growth inhibition (72.4%), comparing with either rapamycin- (54.7%) or bortezomib-treated mice (22.4%). In addition, the lung metastasis was significantly suppressed in mice received the combination treatment (16.6%). The combination treatment of rapamycin and bortezomib significantly inhibited tumor cell proliferation and tumor angiogenesis <jats:italic>in vivo<\/jats:italic>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The combination of rapamycin with bortezomib could be a novel and promising therapeutic approach to the treatment of HCC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2407-12-166","type":"journal-article","created":{"date-parts":[[2012,10,11]],"date-time":"2012-10-11T14:27:24Z","timestamp":1349965644000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model"],"prefix":"10.1186","volume":"12","author":[{"given":"Cun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaonan","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangzhi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinkun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,5,4]]},"reference":[{"issue":"2","key":"3273_CR1","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3322\/canjclin.55.2.74","volume":"55","author":"DM Parkin","year":"2005","unstructured":"Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55 (2): 74-108. 10.3322\/canjclin.55.2.74.","journal-title":"CA Cancer J Clin"},{"issue":"5 Suppl 1","key":"3273_CR2","doi-asserted-by":"publisher","first-page":"S218","DOI":"10.1053\/j.gastro.2004.09.036","volume":"127","author":"BI Carr","year":"2004","unstructured":"Carr BI: Hepatocellular carcinoma: current management and future trends. Gastroenterology. 2004, 127 (5 Suppl 1): S218-S224.","journal-title":"Gastroenterology"},{"issue":"5 Suppl 1","key":"3273_CR3","doi-asserted-by":"publisher","first-page":"S248","DOI":"10.1053\/j.gastro.2004.09.039","volume":"127","author":"TJ Song","year":"2004","unstructured":"Song TJ, Ip EW, Fong Y: Hepatocellular carcinoma: current surgical management. Gastroenterology. 2004, 127 (5 Suppl 1): S248-S260.","journal-title":"Gastroenterology"},{"issue":"7","key":"3273_CR4","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1634\/theoncologist.11-7-790","volume":"11","author":"AX Zhu","year":"2006","unstructured":"Zhu AX: Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be?. Oncologist. 2006, 11 (7): 790-800. 10.1634\/theoncologist.11-7-790.","journal-title":"Oncologist"},{"issue":"4","key":"3273_CR5","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","volume":"359","author":"JM Llovet","year":"2008","unstructured":"Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008, 359 (4): 378-390. 10.1056\/NEJMoa0708857.","journal-title":"N Engl J Med"},{"issue":"2","key":"3273_CR6","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1002\/cncr.24029","volume":"115","author":"T Yau","year":"2009","unstructured":"Yau T, Chan P, Ng KK, Chok SH, Cheung TT, Fan ST, Poon RT: Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer. 2009, 115 (2): 428-436. 10.1002\/cncr.24029.","journal-title":"Cancer"},{"issue":"1","key":"3273_CR7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ccr.2007.05.008","volume":"12","author":"DA Guertin","year":"2007","unstructured":"Guertin DA, Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 2007, 12 (1): 9-22. 10.1016\/j.ccr.2007.05.008.","journal-title":"Cancer Cell"},{"issue":"5","key":"3273_CR8","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1007\/s00432-008-0506-z","volume":"135","author":"Z Wang","year":"2009","unstructured":"Wang Z, Zhou J, Fan J, Tan CJ, Qiu SJ, Yu Y, Huang XW, Tang ZY: Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2009, 135 (5): 715-722. 10.1007\/s00432-008-0506-z.","journal-title":"J Cancer Res Clin Oncol"},{"issue":"16","key":"3273_CR9","doi-asserted-by":"publisher","first-page":"5124","DOI":"10.1158\/1078-0432.CCR-07-4774","volume":"14","author":"Z Wang","year":"2008","unstructured":"Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, Tang ZY: Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res. 2008, 14 (16): 5124-5130. 10.1158\/1078-0432.CCR-07-4774.","journal-title":"Clin Cancer Res"},{"issue":"2","key":"3273_CR10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.canlet.2009.09.015","volume":"290","author":"G Hou","year":"2010","unstructured":"Hou G, Zhang Q, Wang L, Liu M, Wang J, Xue L: mTOR inhibitor rapamycin alone or combined with cisplatin inhibits growth of esophageal squamous cell carcinoma in nude mice. Cancer Lett. 2010, 290 (2): 248-254. 10.1016\/j.canlet.2009.09.015.","journal-title":"Cancer Lett"},{"issue":"1 Pt 1","key":"3273_CR11","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1158\/1078-0432.CCR-0629-3","volume":"10","author":"DJ Boffa","year":"2004","unstructured":"Boffa DJ, Luan F, Thomas D, Yang H, Sharma VK, Lagman M, Suthanthiran M: Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res. 2004, 10 (1 Pt 1): 293-300.","journal-title":"Clin Cancer Res"},{"issue":"6","key":"3273_CR12","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1586\/14737140.5.6.1031","volume":"5","author":"WK Rathmell","year":"2005","unstructured":"Rathmell WK, Wright TM, Rini BI: Molecularly targeted therapy in renal cell carcinoma. Expert Rev Anticancer Ther. 2005, 5 (6): 1031-1040. 10.1586\/14737140.5.6.1031.","journal-title":"Expert Rev Anticancer Ther"},{"issue":"1","key":"3273_CR13","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.canlet.2010.11.003","volume":"301","author":"S Wedel","year":"2011","unstructured":"Wedel S, Hudak L, Seibel JM, Juengel E, Tsaur I, Haferkamp A, Blaheta RA: Combined targeting of the VEGFr\/EGFr and the mammalian target of rapamycin (mTOR) signaling pathway delays cell cycle progression and alters adhesion behavior of prostate carcinoma cells. Cancer Lett. 2011, 301 (1): 17-28. 10.1016\/j.canlet.2010.11.003.","journal-title":"Cancer Lett"},{"issue":"16","key":"3273_CR14","doi-asserted-by":"publisher","first-page":"7052","DOI":"10.1158\/0008-5472.CAN-05-0917","volume":"65","author":"SY Sun","year":"2005","unstructured":"Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005, 65 (16): 7052-7058. 10.1158\/0008-5472.CAN-05-0917.","journal-title":"Cancer Res"},{"issue":"3","key":"3273_CR15","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1158\/0008-5472.CAN-05-2925","volume":"66","author":"KE O'Reilly","year":"2006","unstructured":"O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006, 66 (3): 1500-1508. 10.1158\/0008-5472.CAN-05-2925.","journal-title":"Cancer Res"},{"issue":"5712","key":"3273_CR16","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1126\/science.1106148","volume":"307","author":"DD Sarbassov","year":"2005","unstructured":"Sarbassov DD, Guertin DA, Ali SM, Sabatini DM: Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex. Science. 2005, 307 (5712): 1098-1101. 10.1126\/science.1106148.","journal-title":"Science"},{"issue":"6","key":"3273_CR17","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/S1368-7646(02)00120-6","volume":"5","author":"KA West","year":"2002","unstructured":"West KA, Castillo SS, Dennis PA: Activation of the PI3K\/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002, 5 (6): 234-248. 10.1016\/S1368-7646(02)00120-6.","journal-title":"Drug Resist Updat"},{"issue":"9","key":"3273_CR18","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1056\/NEJMoa0801479","volume":"359","author":"MJ San","year":"2008","unstructured":"San MJ, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008, 359 (9): 906-917. 10.1056\/NEJMoa0801479.","journal-title":"N Engl J Med"},{"issue":"16","key":"3273_CR19","doi-asserted-by":"publisher","first-page":"6698","DOI":"10.1158\/0008-5472.CAN-08-0257","volume":"68","author":"KF Chen","year":"2008","unstructured":"Chen KF, Yeh PY, Yeh KH, Lu YS, Huang SY, Cheng AL: Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 2008, 68 (16): 6698-6707. 10.1158\/0008-5472.CAN-08-0257.","journal-title":"Cancer Res"},{"issue":"10","key":"3273_CR20","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1136\/gut.2009.196519","volume":"59","author":"B Boozari","year":"2010","unstructured":"Boozari B, Mundt B, Woller N, Struver N, Gurlevik E, Schache P, Kloos A, Knocke S, Manns MP, Wirth TC, et al: Antitumoural immunity by virus-mediated immunogenic apoptosis inhibits metastatic growth of hepatocellular carcinoma. Gut. 2010, 59 (10): 1416-1426. 10.1136\/gut.2009.196519.","journal-title":"Gut"},{"issue":"1","key":"3273_CR21","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1007\/s10637-010-9532-1","volume":"30","author":"GP Kim","year":"2010","unstructured":"Kim GP, Mahoney MR, Szydlo D, Mok TS, Marshke R, Holen K, Picus J, Boyer M, Pitot HC, Rubin J, et al: An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. Invest New Drugs. 2010, 30 (1): 387-394.","journal-title":"Invest New Drugs"},{"key":"3273_CR22","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1146\/annurev.pharmtox.46.120604.141300","volume":"46","author":"PM Voorhees","year":"2006","unstructured":"Voorhees PM, Orlowski RZ: The proteasome and proteasome inhibitors in cancer therapy. Annu Rev Pharmacol Toxicol. 2006, 46: 189-213. 10.1146\/annurev.pharmtox.46.120604.141300.","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"47","key":"3273_CR23","doi-asserted-by":"publisher","first-page":"6257","DOI":"10.1038\/onc.2010.357","volume":"29","author":"KF Chen","year":"2010","unstructured":"Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, Chen PJ, Cheng AL: CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene. 2010, 29 (47): 6257-6266. 10.1038\/onc.2010.357.","journal-title":"Oncogene"},{"issue":"17","key":"3273_CR24","doi-asserted-by":"publisher","first-page":"11121","DOI":"10.1074\/jbc.M806268200","volume":"284","author":"KF Chen","year":"2009","unstructured":"Chen KF, Yeh PY, Hsu C, Hsu CH, Lu YS, Hsieh HP, Chen PJ, Cheng AL: Bortezomib overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells in part through the inhibition of the phosphatidylinositol 3-kinase\/Akt pathway. J Biol Chem. 2009, 284 (17): 11121-11133.","journal-title":"J Biol Chem"},{"issue":"1","key":"3273_CR25","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.jhep.2009.10.011","volume":"52","author":"KF Chen","year":"2010","unstructured":"Chen KF, Yu HC, Liu TH, Lee SS, Chen PJ, Cheng AL: Synergistic interactions between sorafenib and bortezomib in hepatocellular carcinoma involve PP2A-dependent Akt inactivation. J Hepatol. 2010, 52 (1): 88-95. 10.1016\/j.jhep.2009.10.011.","journal-title":"J Hepatol"},{"issue":"3","key":"3273_CR26","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/S1470-2045(11)70028-6","volume":"12","author":"IM Ghobrial","year":"2011","unstructured":"Ghobrial IM, Weller E, Vij R, Munshi NC, Banwait R, Bagshaw M, Schlossman R, Leduc R, Chuma S, Kunsman J, et al: Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1\/2, open-label, dose-escalation study. Lancet Oncol. 2011, 12 (3): 263-272. 10.1016\/S1470-2045(11)70028-6.","journal-title":"Lancet Oncol"},{"issue":"5","key":"3273_CR27","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1038\/sj.bjc.6690769","volume":"81","author":"J Tian","year":"1999","unstructured":"Tian J, Tang ZY, Ye SL, Liu YK, Lin ZY, Chen J, Xue Q: New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer. 1999, 81 (5): 814-821. 10.1038\/sj.bjc.6690769.","journal-title":"Br J Cancer"},{"issue":"11","key":"3273_CR28","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1097\/MEG.0b013e3283050a67","volume":"20","author":"BW Yang","year":"2008","unstructured":"Yang BW, Liang Y, Xia JL, Sun HC, Wang L, Zhang JB, Tang ZY, Liu KD, Chen J, Xue Q, et al: Biological characteristics of fluorescent protein-expressing human hepatocellular carcinoma xenograft model in nude mice. Eur J Gastroenterol Hepatol. 2008, 20 (11): 1077-1084. 10.1097\/MEG.0b013e3283050a67.","journal-title":"Eur J Gastroenterol Hepatol"},{"issue":"2","key":"3273_CR29","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1002\/(SICI)1097-0215(19960410)66:2<239::AID-IJC17>3.0.CO;2-7","volume":"66","author":"FX Sun","year":"1996","unstructured":"Sun FX, Tang ZY, Lui KD, Ye SL, Xue Q, Gao DM, Ma ZC: Establishment of a metastatic model of human hepatocellular carcinoma in nude mice via orthotopic implantation of histologically intact tissues. Int J Cancer. 1996, 66 (2): 239-243. 10.1002\/(SICI)1097-0215(19960410)66:2<239::AID-IJC17>3.0.CO;2-7.","journal-title":"Int J Cancer"},{"key":"3273_CR30","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1186\/1471-2407-11-150","volume":"11","author":"CL Xiao","year":"2011","unstructured":"Xiao CL, Tao ZH, Guo L, Li WW, Wan JL, Sun HC, Wang L, Tang ZY, Fan J, Wu WZ: Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice. BMC Cancer. 2011, 11: 150-10.1186\/1471-2407-11-150.","journal-title":"BMC Cancer"},{"issue":"2","key":"3273_CR31","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.canlet.2011.08.031","volume":"313","author":"C Wang","year":"2011","unstructured":"Wang C, Guo K, Gao D, Kang X, Jiang K, Li Y, Sun L, Zhang S, Sun C, Liu X, et al: Identification of transaldolase as a novel serum biomarker for hepatocellular carcinoma metastasis using xenografted mouse model and clinic samples. Cancer Lett. 2011, 313 (2): 154-166. 10.1016\/j.canlet.2011.08.031.","journal-title":"Cancer Lett"},{"issue":"2","key":"3273_CR32","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1002\/hep.22685","volume":"49","author":"SA Lang","year":"2009","unstructured":"Lang SA, Moser C, Fichnter-Feigl S, Schachtschneider P, Hellerbrand C, Schmitz V, Schlitt HJ, Geissler EK, Stoeltzing O: Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice. Hepatology. 2009, 49 (2): 523-532. 10.1002\/hep.22685.","journal-title":"Hepatology"},{"issue":"4","key":"3273_CR33","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1158\/1535-7163.MCT-09-0763","volume":"9","author":"D Cirstea","year":"2010","unstructured":"Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, Ikeda H, Perrone G, Gorgun G, Patel K, et al: Dual inhibition of akt\/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010, 9 (4): 963-975. 10.1158\/1535-7163.MCT-09-0763.","journal-title":"Mol Cancer Ther"},{"issue":"2","key":"3273_CR34","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.canlet.2010.11.012","volume":"301","author":"X He","year":"2011","unstructured":"He X, Wang Y, Zhu J, Orloff M, Eng C: Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett. 2011, 301 (2): 168-176. 10.1016\/j.canlet.2010.11.012.","journal-title":"Cancer Lett"},{"issue":"2","key":"3273_CR35","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1111\/j.1349-7006.2009.01412.x","volume":"101","author":"Z Yang","year":"2010","unstructured":"Yang Z, Lei Z, Li B, Zhou Y, Zhang GM, Feng ZH, Zhang B, Shen GX, Huang B: Rapamycin inhibits lung metastasis of B16 melanoma cells through down-regulating alphav integrin expression and up-regulating apoptosis signaling. Cancer Sci. 2010, 101 (2): 494-500. 10.1111\/j.1349-7006.2009.01412.x.","journal-title":"Cancer Sci"},{"issue":"8","key":"3273_CR36","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1038\/sj.onc.1205181","volume":"21","author":"TM Gottlieb","year":"2002","unstructured":"Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M: Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene. 2002, 21 (8): 1299-1303. 10.1038\/sj.onc.1205181.","journal-title":"Oncogene"},{"issue":"44","key":"3273_CR37","doi-asserted-by":"publisher","first-page":"6719","DOI":"10.1038\/sj.onc.1208825","volume":"24","author":"SJ Jeong","year":"2005","unstructured":"Jeong SJ, Pise-Masison CA, Radonovich MF, Park HU, Brady JN: Activated AKT regulates NF-kappaB activation, p53 inhibition and cell survival in HTLV-1-transformed cells. Oncogene. 2005, 24 (44): 6719-6728. 10.1038\/sj.onc.1208825.","journal-title":"Oncogene"},{"issue":"8","key":"3273_CR38","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nrc864","volume":"2","author":"KH Vousden","year":"2002","unstructured":"Vousden KH, Lu X: Live or let die: the cell's response to p53. Nat Rev Cancer. 2002, 2 (8): 594-604. 10.1038\/nrc864.","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"3273_CR39","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.bbrc.2005.03.211","volume":"331","author":"SE Artandi","year":"2005","unstructured":"Artandi SE, Attardi LD: Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer. Biochem Biophys Res Commun. 2005, 331 (3): 881-890. 10.1016\/j.bbrc.2005.03.211.","journal-title":"Biochem Biophys Res Commun"},{"issue":"16","key":"3273_CR40","doi-asserted-by":"publisher","first-page":"11991","DOI":"10.1074\/jbc.M109.066621","volume":"285","author":"SC Moss","year":"2010","unstructured":"Moss SC, Lightell DJ, Marx SO, Marks AR, Woods TC: Rapamycin regulates endothelial cell migration through regulation of the cyclin-dependent kinase inhibitor p27Kip1. J Biol Chem. 2010, 285 (16): 11991-11997. 10.1074\/jbc.M109.066621.","journal-title":"J Biol Chem"},{"issue":"5","key":"3273_CR41","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1053\/jlts.2003.50079","volume":"9","author":"JC Dunkelberg","year":"2003","unstructured":"Dunkelberg JC, Trotter JF, Wachs M, Bak T, Kugelmas M, Steinberg T, Everson GT, Kam I: Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl. 2003, 9 (5): 463-468. 10.1053\/jlts.2003.50079.","journal-title":"Liver Transpl"},{"issue":"16","key":"3273_CR42","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1093\/jnci\/djj309","volume":"98","author":"C Brignole","year":"2006","unstructured":"Brignole C, Marimpietri D, Pastorino F, Nico B, Di Paolo D, Cioni M, Piccardi F, Cilli M, Pezzolo A, Corrias MV, et al: Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J Natl Cancer Inst. 2006, 98 (16): 1142-1157. 10.1093\/jnci\/djj309.","journal-title":"J Natl Cancer Inst"}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-12-166.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/1471-2407-12-166\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-12-166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-12-166.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T20:42:51Z","timestamp":1630615371000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccancer.biomedcentral.com\/articles\/10.1186\/1471-2407-12-166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,4]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["3273"],"URL":"https:\/\/doi.org\/10.1186\/1471-2407-12-166","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,4]]},"assertion":[{"value":"8 February 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"166"}}