DNA-PKcs抑制剂在肿瘤治疗中的研究现状
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摘要
细胞修复DNA损伤的能力与肿瘤的发生发展及治疗效果密切相关。肿瘤治疗中广泛使用的DNA损伤药物和放射治疗都会造成DNA双链断裂这种致命性的损伤,肿瘤细胞主要通过DNA依赖性蛋白激酶(DNA-PK)参与的一种非同源末端连接(NHEJ)方式来进行修复。DNA-PK全酶由催化亚单位DNA-PKcs和Ku70/Ku80异二聚体两部分组成,对它们活性的抑制能显著降低肿瘤细胞修复DNA双链断裂的能力,进而增强放化疗的敏感性。目前研究主要关注DNA-PKcs抑制剂,其中一些已进入临床研究阶段。本文对多种DNA-PKcs抑制剂在肿瘤治疗中的相关研究进行概括。
The capability of a cell to repair the DNA damage was tightly associated with the development and therapeutic effect of cancer. DNA damaging drugs and radiotherapy widely used in tumor treatment cause a lethal lesion-DNA double-strand break(DSBs),which are repaired mainly by non-homologous-end-joining(NHEJ). DNA-dependent protein kinase(DNA-PK) plays key roles in NHEJ and is composed of a catalytic subunit DNA-PKcs and a heterodimeric subunit Ku70/Ku80. Suppressing the activities of these two components can attenuate the repairmetn of DSBs and enhance the sensitivities of tumor cells against chemotherapy and radiotherapy. Nowadays,studies mainly focus on DNA-PKcs inhibitors,some of which have entered clinical trial. In this mini-review,progresses on DNA-PKcs inhibitors in tumor therapy have been summarized.
The capability of a cell to repair the DNA damage was tightly associated with the development and therapeutic effect of cancer. DNA damaging drugs and radiotherapy widely used in tumor treatment cause a lethal lesion-DNA double-strand break(DSBs),which are repaired mainly by non-homologous-end-joining(NHEJ). DNA-dependent protein kinase(DNA-PK) plays key roles in NHEJ and is composed of a catalytic subunit DNA-PKcs and a heterodimeric subunit Ku70/Ku80. Suppressing the activities of these two components can attenuate the repairmetn of DSBs and enhance the sensitivities of tumor cells against chemotherapy and radiotherapy. Nowadays,studies mainly focus on DNA-PKcs inhibitors,some of which have entered clinical trial. In this mini-review,progresses on DNA-PKcs inhibitors in tumor therapy have been summarized.
引文
[1]Jette N,Lees-Miller SP. The DNA-dependent protein kinase:A multifunctional protein kinase with roles in DNA double strand break repair and mitosis[J]. Prog Biophys Mol Biol,2015,117(2-3):194-205.
[2]Hsu FM,Zhang S,Chen BP. Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment[J]. Transl Cancer Res,2012,1(1):22–34.
[3] Zheng B,Mao JH,Li XQ,et al. Over-expression of DNA-PKcs in renal cell carcinoma regulates m TORC2 activation,HIF-2αexpression and cell proliferation[J]. Sci Rep,2016,6:29415.
[4]Cornell L,Munck JM,Alsinet C,et al. DNA-PK-A candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival[J]. Clin Cancer Res,2015,21(4):925-933.
[5]Chen MB,Zhou ZT,Yang L,et al. KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms[J].Oncotarget,2016,7(13):17047-17059.
[6]Hashimoto M,Rao S,Tokuno O,et al. DNA-PK:the major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway[J]. J Radiat Res,2003,44(2):151-159.
[7]Ortiz T,Burguillos MA,López-Lluch G,et al. Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin[J]. Radiat Environ Biophys,2008,47(4):445-452.
[8]Song W,Xiao X,Chen H,et al. Inhibitors of DNA-dependent protein kinase promote p53-independent apoptosis induced by 1,4-benzoquinone in HL60 cells[J].Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi,2015,33(1):20-23.
[9]Ryabaya OO,Inshakov AN,Egorova AV,et al. Autophagy inhibitors chloroquine and LY294002 enhance temozolomide cytotoxicity on cutaneous melanoma cell lines in vitro[J]. Anticancer Drugs,2017,28(3):307-315.
[10]Zhou Y,Zhu LB,Peng AF,et al. LY294002 inhibits the malignant phenotype of osteosarcoma cells by modulating the phosphatidylinositol 3kinase/Akt/fatty acid synthase signaling pathway in vitro[J]. Mol Med Rep,2015,11(2):1352-1357.
[11] Fuhrman CB,Kilgore J,La Coursiere YD,et al. Radiosensitization of cervical cancer cells via double-strand DNA break repair inhibition[J]. Gynecol Oncol,2008,110(1):93-98.
[12]Zhen YF,Li ST,Zhu YR,et al. Identification of DNAPKcs as a primary resistance factor of salinomycin in osteosarcoma cells[J]. Oncotarget, 2016, 7(48):79417-79427.
[13]Yang L,Liu Y,Sun C,et al. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation[J]. Oncol Lett,2015,10(5):2856-2864.
[14]Li Y,Li H,Peng W,et al. DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair[J]. Mol Med Rep,2015,12(1):1328-1334.
[15]Hu H,Gu Y,Qian Y,et al. DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1pancreatic cancer cells[J]. Biochem Biophys Res Commun,2014,452(1):106-111.
[16] Wu L,Zhang J,Wu H,et al. DNA-PKcs interference sensitizes colorectal cancer cells to a m TOR kinase inhibitor WAY-600[J]. Biochem Biophys Res Commun,2015,466(3):547-553.
[17]Cheng L,Liu YY,Lu PH,et al. Identification of DNAPKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells[J]. Oncotarget,2017,8(17):28385-28394.
[18]Tavecchio M,Munck JM,Cano C,et al. Further characterisation of the cellular activity of the DNA-PK inhibitor,NU7441,reveals potential cross-talk with homologous recombination[J]. Cancer Chemother Pharmacol,2012,69(1):155-164.
[19]Tichy A,Durisova K,Salovska B,et al. Radio-sensitization of human leukaemic MOLT-4 cells by DNA-dependent protein kinase inhibitor,NU7441[J]. Radiat Environ Biophys,2014,53(1):83-92.
[20]Ciszewski WM,Tavecchio M,Dastych J,et al. DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin[J]. Breast Cancer Res Treat,2014,143(1):47-55.
[21]Yang C,Wang Q,Liu X,et al. NU7441 Enhances the Radiosensitivity of Liver Cancer Cells[J]. Cell Physiol Biochem,2016,38(5):1897-1905.
[22]Sunada S,Kanai H,Lee Y,et al. Nontoxic concentration of DNA-PK inhibitor NU7441 radio-sensitizes lung tumor cells with little effect on double strand break repair[J]. Cancer Sci,2016,107(9):1250-1255.
[23]Yanai M,Makino H,Ping B,et al. DNA-PK Inhibition by NU7441 Enhances Chemosensitivity to Topoisomerase Inhibitor in Non-Small Cell Lung Carcinoma Cells by Blocking DNA Damage Repair[J]. Yonago Acta Med,2017,60(1):9-15.
[24]Dong J,Ren Y,Zhang T,et al. Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair[J]. Oncol Rep,2018,39(3):912-920.
[25]Robert F,Barbeau M,thier S,et al. Pharmacological inhibition of DNA-PK stimulates Cas9-mediated genome editing[J]. Genome Med,2015,7:93.
[26]Mamo T,Mladek AC,Shogren KL,et al. Inhibiting DNAPKcs radiosensitizes human osteosarcoma cells[J]. Biochem Biophys Res Commun,2017,486(2):307-313.
[27]Mao M,Liu Y,Gao X. Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells[J]. Biochem Biophys Res Commun,2017,490(4):1244-1249.
[28]Munck JM,Batey MA,Zhao Y,et al. Chemosensitization of cancer cells by KU-0060648,a dual inhibitor of DNA-PK and PI-3K[J]. Mol Cancer Ther,2012,11(8):1789-1798.
[29] Davidson D,Grenier J,Martinez-Marignac V,et al.Effects of the novel DNA dependent protein kinase inhibitor,IC486241,on the DNA damage response to doxorubicin and cisplatin in breast cancer cells[J]. Invest New Drugs,2012,30(4):1736-1742.
[30]Davidson D,Coulombe Y,Martinez-Marignac VL,et al.Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells[J]. Invest New Drugs,2012,30(3):1248-1256.
[31]Boucher D,Hoover R,Wang Y,et al. Proceedings of the107th Annual Meeting of the American Association for Cancer Research[C]. New Orleans, LA,(USA),AACR,2016,Abstract No. 3716.
[32]Khan AJ,Misenko SM,Thandoni A,et al. VX-984 is a selective inhibitor of non-homologous end joining,with possible preferential activity in transformed cells[J]. Oncotarget,2018,9(40):25833-25841.
[33]Lees-Miller SP,Godbout R,Chan DW,et al. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line[J]. Science,1995,267(5201):1183-1185.
[34]Davidson D,Amrein L,Panasci L,et al. Small Molecules,Inhibitors of DNA-PK,Targeting DNA Repair,and Beyond[J]. Front Pharmacol,2013,4:5.
[35]Timme CR,Rath BH,O'Neill JW,et al. The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitroand as Orthotopic Xenografts[J]. Mol Cancer Ther,2018,17(6):1207-1216.
[36]Zenke FT,Zimmermann A,Sirrenberg C,et al. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research[C]. New Orleans, LA,(USA),AACR,Cancer Res,2016,76(Suppl. 14),Abstract No. 1658.
[37]Damstrup L,Zimmerman A,Sirrenberg C,et al. M3814,a DNA-dependent Protein Kinase Inhibitor(DNAPKi),Potentiates the Effect of Ionizing Radiation(IR)in Xenotransplanted Tumors in Nude Mice[J]. Int J Radiat Oncol,2016,94(4):940-941.
[38]Fuchss T,Mederski WWKR,Emde U,et al. Proceedings of the 108th Annual Meeting of the American Association for Cancer Research[C],Washington,DC,(USA),AACR,2017,Abstract No. 4198.
[39] McKeown SR. Defining normoxia,physoxia and hypoxia in tumors-implications for treatment response[J]. Br J Radiol,2014,87(1035):20130676.
[40]Antonovic L,Brahme A,Furusawa Y,et al. Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions[J]. J Radiat Res,2013,54(1):18-26.
[41]Klein C,Dokic I,Mairani A,et al. Overcoming hypoxiainduced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation[J]. Radiat Oncol,2017,12(1):208.
[42] Mortensen DS,Perrin-Ninkovic SM,Shevlin G,et al.Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin(m TOR)Kinase Inhibitors and the Discovery of CC-115[J]. J Med Chem,2015,58(14):5599-5608.
[43] Thijssen R,Ter Burg J,Garrick B,et al. Dual TORK/DNA-PK inhibition blocks critical signaling pathways inchronic lymphocytic leukemia[J]. Blood,2016,128(4):574-583.
[2]Hsu FM,Zhang S,Chen BP. Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment[J]. Transl Cancer Res,2012,1(1):22–34.
[3] Zheng B,Mao JH,Li XQ,et al. Over-expression of DNA-PKcs in renal cell carcinoma regulates m TORC2 activation,HIF-2αexpression and cell proliferation[J]. Sci Rep,2016,6:29415.
[4]Cornell L,Munck JM,Alsinet C,et al. DNA-PK-A candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival[J]. Clin Cancer Res,2015,21(4):925-933.
[5]Chen MB,Zhou ZT,Yang L,et al. KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms[J].Oncotarget,2016,7(13):17047-17059.
[6]Hashimoto M,Rao S,Tokuno O,et al. DNA-PK:the major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway[J]. J Radiat Res,2003,44(2):151-159.
[7]Ortiz T,Burguillos MA,López-Lluch G,et al. Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin[J]. Radiat Environ Biophys,2008,47(4):445-452.
[8]Song W,Xiao X,Chen H,et al. Inhibitors of DNA-dependent protein kinase promote p53-independent apoptosis induced by 1,4-benzoquinone in HL60 cells[J].Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi,2015,33(1):20-23.
[9]Ryabaya OO,Inshakov AN,Egorova AV,et al. Autophagy inhibitors chloroquine and LY294002 enhance temozolomide cytotoxicity on cutaneous melanoma cell lines in vitro[J]. Anticancer Drugs,2017,28(3):307-315.
[10]Zhou Y,Zhu LB,Peng AF,et al. LY294002 inhibits the malignant phenotype of osteosarcoma cells by modulating the phosphatidylinositol 3kinase/Akt/fatty acid synthase signaling pathway in vitro[J]. Mol Med Rep,2015,11(2):1352-1357.
[11] Fuhrman CB,Kilgore J,La Coursiere YD,et al. Radiosensitization of cervical cancer cells via double-strand DNA break repair inhibition[J]. Gynecol Oncol,2008,110(1):93-98.
[12]Zhen YF,Li ST,Zhu YR,et al. Identification of DNAPKcs as a primary resistance factor of salinomycin in osteosarcoma cells[J]. Oncotarget, 2016, 7(48):79417-79427.
[13]Yang L,Liu Y,Sun C,et al. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation[J]. Oncol Lett,2015,10(5):2856-2864.
[14]Li Y,Li H,Peng W,et al. DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair[J]. Mol Med Rep,2015,12(1):1328-1334.
[15]Hu H,Gu Y,Qian Y,et al. DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1pancreatic cancer cells[J]. Biochem Biophys Res Commun,2014,452(1):106-111.
[16] Wu L,Zhang J,Wu H,et al. DNA-PKcs interference sensitizes colorectal cancer cells to a m TOR kinase inhibitor WAY-600[J]. Biochem Biophys Res Commun,2015,466(3):547-553.
[17]Cheng L,Liu YY,Lu PH,et al. Identification of DNAPKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells[J]. Oncotarget,2017,8(17):28385-28394.
[18]Tavecchio M,Munck JM,Cano C,et al. Further characterisation of the cellular activity of the DNA-PK inhibitor,NU7441,reveals potential cross-talk with homologous recombination[J]. Cancer Chemother Pharmacol,2012,69(1):155-164.
[19]Tichy A,Durisova K,Salovska B,et al. Radio-sensitization of human leukaemic MOLT-4 cells by DNA-dependent protein kinase inhibitor,NU7441[J]. Radiat Environ Biophys,2014,53(1):83-92.
[20]Ciszewski WM,Tavecchio M,Dastych J,et al. DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin[J]. Breast Cancer Res Treat,2014,143(1):47-55.
[21]Yang C,Wang Q,Liu X,et al. NU7441 Enhances the Radiosensitivity of Liver Cancer Cells[J]. Cell Physiol Biochem,2016,38(5):1897-1905.
[22]Sunada S,Kanai H,Lee Y,et al. Nontoxic concentration of DNA-PK inhibitor NU7441 radio-sensitizes lung tumor cells with little effect on double strand break repair[J]. Cancer Sci,2016,107(9):1250-1255.
[23]Yanai M,Makino H,Ping B,et al. DNA-PK Inhibition by NU7441 Enhances Chemosensitivity to Topoisomerase Inhibitor in Non-Small Cell Lung Carcinoma Cells by Blocking DNA Damage Repair[J]. Yonago Acta Med,2017,60(1):9-15.
[24]Dong J,Ren Y,Zhang T,et al. Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair[J]. Oncol Rep,2018,39(3):912-920.
[25]Robert F,Barbeau M,thier S,et al. Pharmacological inhibition of DNA-PK stimulates Cas9-mediated genome editing[J]. Genome Med,2015,7:93.
[26]Mamo T,Mladek AC,Shogren KL,et al. Inhibiting DNAPKcs radiosensitizes human osteosarcoma cells[J]. Biochem Biophys Res Commun,2017,486(2):307-313.
[27]Mao M,Liu Y,Gao X. Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells[J]. Biochem Biophys Res Commun,2017,490(4):1244-1249.
[28]Munck JM,Batey MA,Zhao Y,et al. Chemosensitization of cancer cells by KU-0060648,a dual inhibitor of DNA-PK and PI-3K[J]. Mol Cancer Ther,2012,11(8):1789-1798.
[29] Davidson D,Grenier J,Martinez-Marignac V,et al.Effects of the novel DNA dependent protein kinase inhibitor,IC486241,on the DNA damage response to doxorubicin and cisplatin in breast cancer cells[J]. Invest New Drugs,2012,30(4):1736-1742.
[30]Davidson D,Coulombe Y,Martinez-Marignac VL,et al.Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells[J]. Invest New Drugs,2012,30(3):1248-1256.
[31]Boucher D,Hoover R,Wang Y,et al. Proceedings of the107th Annual Meeting of the American Association for Cancer Research[C]. New Orleans, LA,(USA),AACR,2016,Abstract No. 3716.
[32]Khan AJ,Misenko SM,Thandoni A,et al. VX-984 is a selective inhibitor of non-homologous end joining,with possible preferential activity in transformed cells[J]. Oncotarget,2018,9(40):25833-25841.
[33]Lees-Miller SP,Godbout R,Chan DW,et al. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line[J]. Science,1995,267(5201):1183-1185.
[34]Davidson D,Amrein L,Panasci L,et al. Small Molecules,Inhibitors of DNA-PK,Targeting DNA Repair,and Beyond[J]. Front Pharmacol,2013,4:5.
[35]Timme CR,Rath BH,O'Neill JW,et al. The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitroand as Orthotopic Xenografts[J]. Mol Cancer Ther,2018,17(6):1207-1216.
[36]Zenke FT,Zimmermann A,Sirrenberg C,et al. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research[C]. New Orleans, LA,(USA),AACR,Cancer Res,2016,76(Suppl. 14),Abstract No. 1658.
[37]Damstrup L,Zimmerman A,Sirrenberg C,et al. M3814,a DNA-dependent Protein Kinase Inhibitor(DNAPKi),Potentiates the Effect of Ionizing Radiation(IR)in Xenotransplanted Tumors in Nude Mice[J]. Int J Radiat Oncol,2016,94(4):940-941.
[38]Fuchss T,Mederski WWKR,Emde U,et al. Proceedings of the 108th Annual Meeting of the American Association for Cancer Research[C],Washington,DC,(USA),AACR,2017,Abstract No. 4198.
[39] McKeown SR. Defining normoxia,physoxia and hypoxia in tumors-implications for treatment response[J]. Br J Radiol,2014,87(1035):20130676.
[40]Antonovic L,Brahme A,Furusawa Y,et al. Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions[J]. J Radiat Res,2013,54(1):18-26.
[41]Klein C,Dokic I,Mairani A,et al. Overcoming hypoxiainduced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation[J]. Radiat Oncol,2017,12(1):208.
[42] Mortensen DS,Perrin-Ninkovic SM,Shevlin G,et al.Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin(m TOR)Kinase Inhibitors and the Discovery of CC-115[J]. J Med Chem,2015,58(14):5599-5608.
[43] Thijssen R,Ter Burg J,Garrick B,et al. Dual TORK/DNA-PK inhibition blocks critical signaling pathways inchronic lymphocytic leukemia[J]. Blood,2016,128(4):574-583.