title: Oridonin inhibits mTOR signaling and the growth of lung cancer tumors.
abstract: Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been widely used for treatment of various types of cancer. It has been shown that oridonin produced an antiproliferative effect in a lung cancer cell line in vitro. However, the antitumor effects of oridonin in lung cancer cells xenograft mice were poorly understood. The aim of the current study was to investigate the antitumor activity of oridonin in vivo and the molecular mechanisms mediating this antitumor efficacy. The human A549 and NCI-H292 non-small cell lung cancer cell lines were transferred to nude mice for the establishment of xenograft models. The results showed that oridonin (10, 20, 40 mg/kg, intraperitoneally) treatment for 28 days significantly decreased tumor volume and induced tumor growth inhibition in both A549 and NCI-H292 xenograft mice. Furthermore, oridonin promoted apoptosis by increasing terminal dUTP nick end labeling-positive cells as well as the ratio of Bax/Bcl-2 in xenograft mice. In addition, chronic oridonin administration inhibited mammalian target of rapamycin (mTORC1) activity by reduction of p-mTOR and p-p70s6k levels, suggesting that the increased apoptosis triggered by oridonin administration was associated with the downregulation of mTORC1 activity. Moreover, inhibition of mTORC1 by rapamycin (2 mg/kg, intraperitoneally) enhanced the anticancer activity of oridonin in mice xenograft models. These findings indicate that treatment with oridonin exhibited antitumor actions through induction of apoptotic response by inhibition of mTORC1 function. Our results also proposed the potential that inhibition of mTORC1 might be an effective target for increasing the therapeutic outcome in lung cancer patients treated with oridonin.
authors: aDepartment of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University bDepartment of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin cDepartment of Medical Oncology, Daqing Oilfield General Hospital dVIP ward, Daqing Longnan Hospital, Daqing, China.
authors: Yan-Yan
authors: YY
authors: Wang
authors: Yan-Fang
authors: YF
authors: Lv
authors: Lu
authors: L
authors: Lu
authors: Li
authors: L
authors: Cai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; C481505:BCL2L15 protein, human; D045786:Diterpenes, Kaurane; D046912:Multiprotein Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C011959:oridonin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus