Abstract:Autophagy capacity may correlate with malignant transformation and differentiation of cancer cells. The mammalian target of rapamycin (mTOR) has close relationship with autophagy, which can play an important role through regulating the autophagic activity on cancer genesis and progression. So far mTOR inhibitors (inhibiting targets of signaling pathways) have potential in the future for cancer therapy, the development of mTOR inhibitors represents an important field in anticancer research. This article summarizes the relationship between mTOR signaling pathway and tumor in autophagy pathways, and the current status of the development of mTOR inhibitors, it hopes to provide information for studies on cancer research and targets for tumor therapy.
[1] 王大伟,张斌,吕斌,等.自噬受体介导的非自噬降解功能研究进展[J].药学学报,2016,51(1):1-8.
[2] Klionsky DJ. The autophagy connection [J]. Dev Cell,2010,19(1):11-12.
[3] Prieto-Dominguez N,Ordonez R,Fernandez A,et al. Modulation of autophagy by sorafenib:effects on treatment response [J]. Front Pharmacol,2016,7:151.
[4] Puissant A,Robert G,Auberger P. Targeting autophagy to fight hematopoietic malignancies [J]. Cell Cycle,2010,9(17):3470-3478.
[5] Farrow JM,Yang JC,Evans CP. Autophagy as a modulator and target in prostate cancer [J]. Nat Rve Urol,2014,11(9): 508-516.
[6] 梁冰,刘晓冬,刘欣,等.分割剂量电离辐射对卵巢癌耐药细胞自噬性死亡的影响[J].吉林大学学报,2011,37(6):971-975.
[7] Yang Z,Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation [J]. Curr Opin Cell Biol,2010,22(2):124-131.
[8] Zhao Y,Huang Q,Yang J,et al. Autophagy impairment inhibits differentiation of glioma stem/progenitor cells [J]. Brain Res,2010,1313:250-258.
[9] Colosetti P,Puissant A,Robert G,et al. Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line [J]. Autophagy,2009,5(8):1092-1098.
[10] Rodon J,Dienstmann R,Serra V,et al. Development of PI3K inhibitors:lessons learned from early clinical trials [J]. Nat Rev Clin Oncol,2013,10(3):143-153.
[11] Vander Hoar E,Lee SI,Bandhakavi S,et al. Insulin signalling to mTOR mediated by the Akt /PKB substrate PRAS40 [J]. Nature Cell Biology,2007,9(3):316-323.
[12] Efeyan A,Sabatini DM. mTOR and cancer: many loops in one pathway [J]. Curr Opin Cell Biol,2010,22(2):169-176.
[13] Hay N,Sonenberg N. Upstream and downstream of mT-OR [J]. Genes Dev,2004,18(16):1926-1945.
[14] Scott RC,Juhász G,Neufeld TP. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death [J]. Curr Biol,2007,17(1):1-11.
[15] Arsham AM,Neufeld TP. Thinking globally and acting locally with TOR [J]. Curr Opin Cell Biol,2006,18(6):589-597.
[16] Kim KW,Hwang M,Moretti L,et al. Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer [J]. Autophagy,2008,4(5):659-668.
[17] Niehr F,Weichert W,Stenzinger A,et al. CCI-779 (Temsirolimus) exhibits increased anti-tumor activity in low EGFR expressing HNSCC cell lines and is effective in cells with acquired resistance to cisplatin or cetuximab [J]. J Transl Med,2015,13:106.
[18] Alp E,Yilmaz A,Onen HI,et al. Effects of EF-24,RAD001,and paclitaxel on the expression profiles of apoptotic and anti-apoptotic genes [J]. J Cancer Res Ther, 2017,13(2):346-350.
[19] Alshaker H,Wang Q,Böhler T,et al. Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1 [J]. Sci Rep,2017,7(1):3493.
[20] Lin JF,Lin YC,Yang SC,et al. Autophagy inhibition enhances RAD001-induced cytotoxicity in human bladder cancer cells [J]. Drug Des Devel Ther,2016,10:1501-1513.
[21] Yokoyama T,Iwado E,Kondo Y,et al. Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells [J]. Gene Ther,2008,15(17):1233-1239.
[22] Sun SY,Rosenberg LM,Wang X,et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition [J]. Cancer Res,2005,65(16):7052-7058.
[23] 林辰初,袁胜涛.雷帕霉素靶蛋白信号通路与靶向雷帕霉素靶蛋白抗肿瘤药物研究进展[J].中国新药杂志,2013,22(14):1656-1666.
[24] Kim A,Park S,Lee JE,et al. The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells [J]. Leuk Res,2012,36(7):912-920.
[25] Torki S,Soltani A,Shirzad H,et al. Synergistic antitumor effect of NVP-BEZ235 and CAPE on MDA-MB-231 breast cancer cells [J]. Biomed Pharmacother, 2017,92:39-45.
[26] Zhang LD,Liu Z,Liu H,et al. Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy [J]. Int J Oncol,2016,49(2):657-665.
[27] Schult C,Dahlhaus M,Glass A,et al. The Dual Kinase Inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells [J]. Anticancer Res,2012,32(2): 463-474.
[28] Risberg K,Redalen KR,Sønstevold L,et al. Pro-survival responses to the dual inhibition of anti-apoptotic Bcl-2 family proteins and mTOR-mediated signaling in hypoxic colorectal carcinoma cells [J]. BMC Cancer,2016,16:531.
[29] Chresta CM,Davies BR,Hickson I,et al. AZD8055 is a potent,selective,and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity [J]. Cancer Res,2010,70(1):288-298.
[30] Simmons BH,Lee JH,Lalwani K,et al. Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras (G12D-LSL) mice [J]. Cancer Chemother Pharmacol,2012,70(2): 213-220.
[31] Arval P,Kim K,Park PH,et al. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells [J]. FEBS J,2014,281(20):4644-4658.
[32] Ruan Y,Hu K,Chen H. Autophagy inhibition enhances isorhamnetininduced mitochondriadependent apoptosis in nonsmall cell lung cancer cells [J]. Mol Med Rep,2015, 12(4):5796-5806.
[33] Yang X,Niu B,Wang L,et al. Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 [J]. Oncol Lett,2016,12(1):102-106.