SCD1抑制剂抗肿瘤作用的研究进展
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摘要
硬脂酰辅酶A去饱和酶1(SCD1)是催化单不饱和脂肪酸合成的关键调控基因,在肿瘤脂代谢中发挥着重要作用。研究表明SCD1在多种恶性肿瘤中都存在过度表达现象,并牵涉肿瘤发生发展的多个方面,包括细胞增殖、细胞周期、凋亡、转移。SCD1已经成为肿瘤治疗的一个新靶点,其相关抑制剂在体内外实验中也表现出显著的抗肿瘤活性,该文就近年来SCD1及其抑制剂在肿瘤治疗中的研究现状作一综述。
SCD1(stearoyl-coenzyme A desaturase 1) gene is the key regulatory gene for the synthesis of monounsaturated fatty acids, and plays an important role in lipid metabolism of tumor. Studies have shown that SCD1 is overexpressed in many malignant tumors and involved in many aspects of tumor development, including cell proliferation, cell cycle, apoptosis and metastasis. SCD1 has become a new target for tumor therapy and its inhibitors have shown significant antitumor activity in in vivo and in vitro experiments. The function of SCD1 in tumor and the development of SCD-1 inhibitors as anti-cancer agents in recent years are reviewed in this article.
SCD1(stearoyl-coenzyme A desaturase 1) gene is the key regulatory gene for the synthesis of monounsaturated fatty acids, and plays an important role in lipid metabolism of tumor. Studies have shown that SCD1 is overexpressed in many malignant tumors and involved in many aspects of tumor development, including cell proliferation, cell cycle, apoptosis and metastasis. SCD1 has become a new target for tumor therapy and its inhibitors have shown significant antitumor activity in in vivo and in vitro experiments. The function of SCD1 in tumor and the development of SCD-1 inhibitors as anti-cancer agents in recent years are reviewed in this article.
引文
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[3]BOUGNOUX P,CHAJES V,LANSON M,et al.Prognostic significance of tumor phosphatidylcholine stearic acid level in breast carcinoma[J].Breast Cancer Research&Treatment,1992,20(3):185-194.
[4]HUANG J,FAN X X,HE J,et al.SCD1 is associated with tumor promotion,late stage and poor survival in lung adenocarcinoma[J].Oncotarget,2016,7(26):39970-39979.
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[6]PECK B,SCHUG Z T,ZHANG Q,et al.Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments[J].Cancer&Metabolism,2016,4(1):6.
[7]BANSAL S,BERK M,ALKHOURI N,et al.StearoylCo A desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma[J].Journal of Surgical Research,2014,186(1):29-38.
[8]LIU G.Stearoyl-Co A desaturase inhibitors:update on patented compounds[J].Expert Opinion on Therapeutic Patents,2009,19(9):1169-1191.
[9]POWELL D A.An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors(2009-2013)[J].Expert Opinion on Therapeutic Patents,2014,24(2):155-175.
[10]LIU G,LYNCH J K,FREEMAN J,et al.Discovery of potent,selective,orally bioavailable stearoyl-Co A desaturase 1inhibitors[J].Journal of Medicinal Chemistry,2007,50(13):3086-3100.
[11]HUANG G M,JIANG Q H,CAI C,et al.SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway[J].Cancer Letters,2015,358(2):180-190.
[12]MASON P,LIANG B,LI L,et al.SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids[J].PLo S One,2012,7(3):e33823.
[13]MOHAMMADZADEH F,MOSAYEBI G,MONTAZERI V,et al.Fatty acid composition of tissue cultured breast carcinoma and the effect of stearoyl-Co A desaturase 1 inhibition[J].Journal of Breast Cancer,2014,17(2):136-142.
[14]NANJAPPA V,RENUSE S,SATHE G J,et al.Chronic exposure to chewing tobacco selects for overexpression of stearoyl-Co A desaturase in normal oral keratinocytes[J].Cancer Biology&Therapy,2015,16(11):1593-1603.
[15]LI J,CONDELLO S,THOMES-PEPIN J,et al.Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells[J].Cell Stem Cell,2017,20(3):303-314.
[16]XIN Z,ZHAO H,SERBY M D,et al.Discovery of piperidine-aryl urea-based stearoyl-Co A desaturase 1 inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2008,18(15):4298-4302.
[17]ROONGTA U V,PABALAN J G,WANG X,et al.Cancer cell dependence on unsaturated fatty acids implicates stearoyl-Co A desaturase as a target for cancer therapy[J].Molecular Cancer Research,2011,9(11):1551-1561.
[18]VON ROEMELING C A,MARLOW L A,WEI J J,et al.Stearoyl-Co A desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma[J].Clinical Cancer Research An Official Journal of the American Association for Cancer Research,2013,19(9):2368-2380.
[19]VON ROEMELING C A,MARLOW L A,PINKERTON A B,et al.Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl Co A desaturase 1 as a novel therapeutic target[J].J Clin Endocrinol Metab,2015,100(5):697-709.
[20]MA M K F,LAU Y E T,LEUNG D H W,et al.Stearoyl-Co A desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation[J].Journal of Hepatology,2017,67(5):979-990.
[21]CHEN L,REN J,YANG L,et al.Stearoyl-Co A desaturase-1mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis[J].Scientific Reports,2016,6:19665.
[22]SCHLAEPFER I R,HITZ C A,GIJóN M A,et al.Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel[J].Molecular&Cellular Endocrinology,2012,363(1/2):111-121.
[23]KOLTUN D O,PARKHILL E Q,VASILEVICH N I,et al.Novel,potent,selective,and metabolically stable stearoyl-Co A desaturase(SCD)inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2009,19(7):2048-2052.
[24]SCAGLIA N,CHISHOLM J W,IGAL R A.Inhibition of stearoyl Co A desaturase-1 inactivates acetyl-Co A carboxylase and impairs proliferation in cancer cells:role of AMPK[J].PLo S One,2009,4(8):e6812.
[25]MINVILLEWALZ M,PIERRE A S,PICHON L,et al.Inhibition of stearoyl-Co A desaturase 1 expression induces CHOPdependent cell death in human cancer cells[J].PLo S One,2010,5(12):e14363.
[26]HESS D,CHISHOLM J W,IGAL R A.Inhibition of stearoyl Co A desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells[J].PLo S One,2010,5(6):e11394.
[27]NASHED M,CHISHOLM J W,IGAL R A.Stearoyl-Co A desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells[J].Experimental Biology&Medicine,2012,237(9):1007-1017.
[28]LéGER S,BLACK W C,DESCHENES D,et al.Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor(MF-438)[J].Bioorganic&Medicinal Chemistry Letters,2010,20(2):499-502.
[29]NOTO A,RAFFA S,VITIS C D,et al.Stearoyl-Co A desaturase-1is a key factor for lung cancer-initiating cells[J].Cell Death&Disease,2013,4(12):e947.
[30]PISANU M E,NOTO A,DE V C,et al.Blockade of StearoylCo A-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells[J].Cancer Letters,2017,406:93-104.
[31]IMAMURA K,TOMITA N,KAWAKITA Y,et al.Discovery of novel and potent stearoyl coenzyme A desaturase 1(SCD1)inhibitors as anticancer agents[J].Bioorganic&Medicinal Chemistry,2017,25(14):3768-3779.
[32]NISHIZAWA S,SUMI H,SATOH Y,et al.In vitro and in vivo antitumor activities of T-3764518,a novel and orally available small molecule stearoyl-Co A desaturase 1 inhibitor[J].European Journal of Pharmacology,2017,807:21-31.
[33]ONO A,SANO O,KAZETANI K,et al.Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition[J].PLo S One,2017,12(7):e0181243.
[34]BEN-DAVID U,GAN Q F,GOLAN-LEV T,et al.Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen[J].Cell Stem Cell,2013,12(2):167-179.
[35]ZHANG L,PAN Y,QIN G,et al.Inhibition of stearoyl-co A desaturase selectively eliminates tumorigenic nanog-positive cells:Improving the safety of i PS cell transplantation to myocardium[J].Cell Cycle,2014,13(5):762-771.
[36]FU J M,SUN S,KODOMURU V,et al.Nicotinamide derivatives and their use as therapeutic agents[P]:EP,EP2266566.2010,12.29.
[37]FRITZ V,BENFODDA Z,RODIER G,et al.Abrogation of de novo lipogenesis by stearoyl-Co A desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice[J].Molecular Cancer Therapeutics,2010,9(6):1740-1754.
[38]ZHAO H,SERBY M D,SMITH H T,et al.Discovery of 1-(4-phenoxypiperidin-1-yl)-2-arylaminoethanone stearoyl-Co A desaturase 1 inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2007,17(12):3388-3391.
[39]MASON P,LIANG B,LI L,et al.SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids[J].PLo S One,2012,7(3):e33823.
[40]MAUVOISIN D,CHARFI C,LOUNIS A M,et al.Decreasing stearoyl-Co A desaturase-1 expression inhibitsβ-catenin signaling in breast cancer cells[J].Cancer Science,2013,104(1):36-42.
[41]TAKADA R,SATOMI Y,KURATA T,et al.Monounsaturated fatty acid modification of Wnt protein:its role in Wnt secretion[J].Developmental Cell,2006,11(6):791-801.
[42]RIOS-ESTEVES J,RESH M.Stearoyl Co A desaturase is required to produce active,lipid-modified Wnt proteins[J].Cell Reports,2013,4(6):1072-1081.
[43]KIM H,RODRIGUEZNAVAS C,KOLLIPARA R K,et al.Unsaturated fatty acids stimulate tumor growth through stabilization ofβ-catenin[J].Cell Reports,2015,13(3):495-503.
[2]CHAJèS V,THIéBAUT A C,ROTIVAL M,et al.Association between serum trans-monounsaturated fatty acids and breast cancer risk in the E3N-EPIC Study[J].American Journal of Epidemiology,2008,167(11):1312-1320.
[3]BOUGNOUX P,CHAJES V,LANSON M,et al.Prognostic significance of tumor phosphatidylcholine stearic acid level in breast carcinoma[J].Breast Cancer Research&Treatment,1992,20(3):185-194.
[4]HUANG J,FAN X X,HE J,et al.SCD1 is associated with tumor promotion,late stage and poor survival in lung adenocarcinoma[J].Oncotarget,2016,7(26):39970-39979.
[5]KIM S J,CHOI H,PARK S S,et al.Stearoyl Co A desaturase(SCD)facilitates proliferation of prostate cancer cells through enhancement of androgen receptor transactivation[J].Molecules&Cells,2011,31(4):371-377.
[6]PECK B,SCHUG Z T,ZHANG Q,et al.Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments[J].Cancer&Metabolism,2016,4(1):6.
[7]BANSAL S,BERK M,ALKHOURI N,et al.StearoylCo A desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma[J].Journal of Surgical Research,2014,186(1):29-38.
[8]LIU G.Stearoyl-Co A desaturase inhibitors:update on patented compounds[J].Expert Opinion on Therapeutic Patents,2009,19(9):1169-1191.
[9]POWELL D A.An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors(2009-2013)[J].Expert Opinion on Therapeutic Patents,2014,24(2):155-175.
[10]LIU G,LYNCH J K,FREEMAN J,et al.Discovery of potent,selective,orally bioavailable stearoyl-Co A desaturase 1inhibitors[J].Journal of Medicinal Chemistry,2007,50(13):3086-3100.
[11]HUANG G M,JIANG Q H,CAI C,et al.SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway[J].Cancer Letters,2015,358(2):180-190.
[12]MASON P,LIANG B,LI L,et al.SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids[J].PLo S One,2012,7(3):e33823.
[13]MOHAMMADZADEH F,MOSAYEBI G,MONTAZERI V,et al.Fatty acid composition of tissue cultured breast carcinoma and the effect of stearoyl-Co A desaturase 1 inhibition[J].Journal of Breast Cancer,2014,17(2):136-142.
[14]NANJAPPA V,RENUSE S,SATHE G J,et al.Chronic exposure to chewing tobacco selects for overexpression of stearoyl-Co A desaturase in normal oral keratinocytes[J].Cancer Biology&Therapy,2015,16(11):1593-1603.
[15]LI J,CONDELLO S,THOMES-PEPIN J,et al.Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells[J].Cell Stem Cell,2017,20(3):303-314.
[16]XIN Z,ZHAO H,SERBY M D,et al.Discovery of piperidine-aryl urea-based stearoyl-Co A desaturase 1 inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2008,18(15):4298-4302.
[17]ROONGTA U V,PABALAN J G,WANG X,et al.Cancer cell dependence on unsaturated fatty acids implicates stearoyl-Co A desaturase as a target for cancer therapy[J].Molecular Cancer Research,2011,9(11):1551-1561.
[18]VON ROEMELING C A,MARLOW L A,WEI J J,et al.Stearoyl-Co A desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma[J].Clinical Cancer Research An Official Journal of the American Association for Cancer Research,2013,19(9):2368-2380.
[19]VON ROEMELING C A,MARLOW L A,PINKERTON A B,et al.Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl Co A desaturase 1 as a novel therapeutic target[J].J Clin Endocrinol Metab,2015,100(5):697-709.
[20]MA M K F,LAU Y E T,LEUNG D H W,et al.Stearoyl-Co A desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation[J].Journal of Hepatology,2017,67(5):979-990.
[21]CHEN L,REN J,YANG L,et al.Stearoyl-Co A desaturase-1mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis[J].Scientific Reports,2016,6:19665.
[22]SCHLAEPFER I R,HITZ C A,GIJóN M A,et al.Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel[J].Molecular&Cellular Endocrinology,2012,363(1/2):111-121.
[23]KOLTUN D O,PARKHILL E Q,VASILEVICH N I,et al.Novel,potent,selective,and metabolically stable stearoyl-Co A desaturase(SCD)inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2009,19(7):2048-2052.
[24]SCAGLIA N,CHISHOLM J W,IGAL R A.Inhibition of stearoyl Co A desaturase-1 inactivates acetyl-Co A carboxylase and impairs proliferation in cancer cells:role of AMPK[J].PLo S One,2009,4(8):e6812.
[25]MINVILLEWALZ M,PIERRE A S,PICHON L,et al.Inhibition of stearoyl-Co A desaturase 1 expression induces CHOPdependent cell death in human cancer cells[J].PLo S One,2010,5(12):e14363.
[26]HESS D,CHISHOLM J W,IGAL R A.Inhibition of stearoyl Co A desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells[J].PLo S One,2010,5(6):e11394.
[27]NASHED M,CHISHOLM J W,IGAL R A.Stearoyl-Co A desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells[J].Experimental Biology&Medicine,2012,237(9):1007-1017.
[28]LéGER S,BLACK W C,DESCHENES D,et al.Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor(MF-438)[J].Bioorganic&Medicinal Chemistry Letters,2010,20(2):499-502.
[29]NOTO A,RAFFA S,VITIS C D,et al.Stearoyl-Co A desaturase-1is a key factor for lung cancer-initiating cells[J].Cell Death&Disease,2013,4(12):e947.
[30]PISANU M E,NOTO A,DE V C,et al.Blockade of StearoylCo A-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells[J].Cancer Letters,2017,406:93-104.
[31]IMAMURA K,TOMITA N,KAWAKITA Y,et al.Discovery of novel and potent stearoyl coenzyme A desaturase 1(SCD1)inhibitors as anticancer agents[J].Bioorganic&Medicinal Chemistry,2017,25(14):3768-3779.
[32]NISHIZAWA S,SUMI H,SATOH Y,et al.In vitro and in vivo antitumor activities of T-3764518,a novel and orally available small molecule stearoyl-Co A desaturase 1 inhibitor[J].European Journal of Pharmacology,2017,807:21-31.
[33]ONO A,SANO O,KAZETANI K,et al.Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition[J].PLo S One,2017,12(7):e0181243.
[34]BEN-DAVID U,GAN Q F,GOLAN-LEV T,et al.Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen[J].Cell Stem Cell,2013,12(2):167-179.
[35]ZHANG L,PAN Y,QIN G,et al.Inhibition of stearoyl-co A desaturase selectively eliminates tumorigenic nanog-positive cells:Improving the safety of i PS cell transplantation to myocardium[J].Cell Cycle,2014,13(5):762-771.
[36]FU J M,SUN S,KODOMURU V,et al.Nicotinamide derivatives and their use as therapeutic agents[P]:EP,EP2266566.2010,12.29.
[37]FRITZ V,BENFODDA Z,RODIER G,et al.Abrogation of de novo lipogenesis by stearoyl-Co A desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice[J].Molecular Cancer Therapeutics,2010,9(6):1740-1754.
[38]ZHAO H,SERBY M D,SMITH H T,et al.Discovery of 1-(4-phenoxypiperidin-1-yl)-2-arylaminoethanone stearoyl-Co A desaturase 1 inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2007,17(12):3388-3391.
[39]MASON P,LIANG B,LI L,et al.SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids[J].PLo S One,2012,7(3):e33823.
[40]MAUVOISIN D,CHARFI C,LOUNIS A M,et al.Decreasing stearoyl-Co A desaturase-1 expression inhibitsβ-catenin signaling in breast cancer cells[J].Cancer Science,2013,104(1):36-42.
[41]TAKADA R,SATOMI Y,KURATA T,et al.Monounsaturated fatty acid modification of Wnt protein:its role in Wnt secretion[J].Developmental Cell,2006,11(6):791-801.
[42]RIOS-ESTEVES J,RESH M.Stearoyl Co A desaturase is required to produce active,lipid-modified Wnt proteins[J].Cell Reports,2013,4(6):1072-1081.
[43]KIM H,RODRIGUEZNAVAS C,KOLLIPARA R K,et al.Unsaturated fatty acids stimulate tumor growth through stabilization ofβ-catenin[J].Cell Reports,2015,13(3):495-503.
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