骨肉瘤耐受顺铂的机制研究进展
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摘要
<正>骨肉瘤是临床最常见的原发恶性骨肿瘤,好发于儿童及青少年。过去以手术为主的治疗手段只能使患者5年生存率维持在20%左右,从20世纪70年代开始,化疗联合手术的治疗方案使患者的5年生存率达到60%～70%~([1])。然而,近30年来,骨肉瘤的治疗效果没有进一步的提高,这其中一个重要原因是化疗耐受的普遍发生~([2])。因此明确化疗耐受机制并寻找逆转耐受的新策略成为改善骨肉瘤预后的当务之急。自1978年被批准使用,顺铂已经广泛用于多种实体瘤如睾丸癌、卵巢癌、宫颈癌、头颈癌及肺癌等的治
Osteosarcoma is the most common primary malignant bone tumor that is presently treated with surgery combined with multidrug chemotherapy. However, the five-year survival rate of osteosarcoma patients remains stagnant in the last three decades, which is partly attributed to cisplatin resistance. In this paper, we reviewed the resistance mechanisms of osteosarcoma to cisplatin, including cisplatin accumulation, detoxification, DNA damage repair or tolerance, apoptosis-related signaling pathway, autophagy, non-coding RNAs, tumor microenvironment and tumor stem cells. From understanding these mechanisms, we hope to offer a broader perspective to the exploration of new targets and new strategies to overcome cisplatin resistance.
Osteosarcoma is the most common primary malignant bone tumor that is presently treated with surgery combined with multidrug chemotherapy. However, the five-year survival rate of osteosarcoma patients remains stagnant in the last three decades, which is partly attributed to cisplatin resistance. In this paper, we reviewed the resistance mechanisms of osteosarcoma to cisplatin, including cisplatin accumulation, detoxification, DNA damage repair or tolerance, apoptosis-related signaling pathway, autophagy, non-coding RNAs, tumor microenvironment and tumor stem cells. From understanding these mechanisms, we hope to offer a broader perspective to the exploration of new targets and new strategies to overcome cisplatin resistance.
引文
[1]Gianferante DM,Mirabello L,Savage SA.Germline and somatic genetics of osteosarcoma-connecting aetiology,biology and therapy[J].Nat Rev Endocrinol,2017,13(8):480-491.
[2]Luetke A,Meyers PA,Lewis I,et al.Osteosarcoma treatmentwhere do we stand?A state of the art review[J].Cancer Treat Rev,2014,40(4):523-532.
[3]Dasari S,Tchounwou PB.Cisplatin in cancer therapy:molecular mechanisms of action[J].Eur J Pharmacol,2014,740:364-378.
[4]Chou AJ,Gorlick R.Chemotherapy resistance in osteosarcoma:current challenges and future directions[J].Expert Rev Anticancer Ther,2006,6(7):1075-1085.
[5]To KK,Tong WS,Fu LW.Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat[J].Lung Cancer,2017,103:58-65.
[6]Sun S,Zhao S,Yang Q,et al.Enhancer of zeste homolog 2promotes cisplatin resistance by reducing cellular platinum accumulation[J].Cancer Sci,2018,109(6):1853-1864.
[7]Beretta GL,Gatti L,Tinelli S,et al.Cellular pharmacology of cisplatin in relation to the expression of human copper transporter CTR1 in different pairs of cisplatin-sensitive andresistant cells[J].Biochem Pharmacol,2004,68(2):283-291.
[8]Martelli L,Di Mario F,Botti P,et al.Accumulation,platinumDNA adduct formation and cytotoxicity of cisplatin,oxaliplatin and satraplatin in sensitive and resistant human osteosarcoma cell lines,characterized by p53 wild-type status[J].Biochem Pharmacol,2007,74(1):20-27.
[9]Chen HH,Chen WC,Liang ZD,et al.Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy[J].Expert Opin Ther Targets,2015,19(10):1307-1317.
[10]Ishida S,Lee J,Thiele DJ,et al.Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals[J].Proc Natl Acad Sci USA,2002,99(22):14298-14302.
[11]Ishida S,Mccormick F,Smith-Mccune K,et al.Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator[J].Cancer Cell,2010,17(6):574-583.
[12]Kim ES,Tang X,Peterson DR,et al.Copper transporter CTR1expression and tissue platinum concentration in non-small cell lung cancer[J].Lung Cancer,2014,85(1):88-93.
[13]Fanelli M,Hattinger CM,Vella S,et al.Targeting ABCB1 and ABCC1 with their specific inhibitor CBT-1(R)can overcome drug resistance in osteosarcoma[J].Curr Cancer Drug Targets,2016,16(3):261-274.
[14]Ye S,Zhang J,Shen J,et al.NVP-TAE684 reverses multidrug resistance(MDR)in human osteosarcoma by inhibiting P-glycoprotein(PGP1)function[J].Br J Pharmacol,2016,173(3):613-626.
[15]Inesi G,Pilankatta R,Tadini-Buoninsegni F.Biochemical characterization of P-type copper ATPases[J].Biochem J,2014,463(2):167-176.
[16]Li ZH,Zheng R,Chen JT,et al.The role of copper transporter ATP7A in platinum-resistance of esophageal squamous cell cancer(ESCC)[J].J Cancer,2016,7(14):2085-2092.
[17]Xiao F,Li Y,Wan Y,et al.MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B[J].Cancer Chemother Pharmacol,2018,81(5):935-947.
[18]Komiya S,Gebhardt MC,Mangham DC,et al.Role of glutathione in cisplatin resistance in osteosarcoma cell lines[J].J Orthop Res,1998,16(1):15-22.
[19]Huang G,Mills L,Worth LL.Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells[J].Mol Cancer Ther,2007,6(5):1610-1619.
[20]Goricar K,Kovac V,Jazbec J,et al.Genetic variability of DNA repair mechanisms and glutathione-S-transferase genes influences treatment outcome in osteosarcoma[J].Cancer Epidemiol,2015,39(2):182-188.
[21]Pasello M,Michelacci F,Scionti I,et al.Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma[J].Cancer Res,2008,68(16):6661-6668.
[22]Obiedat H,Alrabadi N,Sultan E,et al.The effect of ERCC1and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients[J].BMC Med Genet,2018,19(1):112.
[23]Hattinger CM,Michelacci F,Sella F,et al.Excision repair cross-complementation group 1 protein expression predicts survival in patients with high-grade,non-metastatic osteosarcoma treated with neoadjuvant chemotherapy[J].Histopathology,2015,67(3):338-347.
[24]Graf N,Ang WH,Zhu G,et al.Role of endonucleases XPFand XPG in nucleotide excision repair of platinated DNA and cisplatin/oxaliplatin cytotoxicity[J].Chem Bio Chem,2011,12(7):1115-1123.
[25]Biason P,Hattinger CM,Innocenti F,et al.Nucleotide excision repair gene variants and association with survival i n o s t e o s a r c o m a p a t i e n t s t r e a t e d w i t h n e o a d j u v a n t chemotherapy[J].Pharmacogenomics J,2012,12(6):476-483.
[26]Jentzsch T,Robl B,Husmann M,et al.Expression of MSH2 and MSH6 on a tissue microarray in patients with osteosarcoma[J].Anticancer Res,2014,34(12):6961-6972.
[27]Huang JW,Wang Y,Dhillon KK,et al.Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity[J].Mol Cancer Res,2013,11(12):1564-1573.
[28]Liang Q,Dexheimer TS,Zhang P,et al.A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses[J].Nat Chem Biol,2014,10(4):298-304.
[29]Moriarity BS,Otto GM,Rahrmann EP,et al.A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis[J].Nat Genet,2015,47(6):615-624.
[30]Duan L,Perez RE,Hansen M,et al.Increasing cisplatin sensitivity by schedule-dependent inhibition of AKT and Chk1[J].Cancer Biol Ther,2014,15(12):1600-1612.
[31]Han X G,Du L,Qiao H,et al.CXCR1 knockdown improves the sensitivity of osteosarcoma to cisplatin[J].Cancer Lett,2015,369(2):405-415.
[32]Brozovic A,Fritz G,Christmann M,et al.Long-term activation of SAPK/JNK,p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance[J].Int J Cancer,2004,112(6):974-985.
[33]Yong L,Ma Y,Zhu B,et al.Oleandrin synergizes with cisplatin in human osteosarcoma cells by enhancing cell apoptosis through activation of the p38 MAPK signaling pathway[J].Cancer Chemother Pharmacol,2018,82(6):1009-1020.
[34]Ye S,Shen J,Choy E,et al.p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines[J].Cancer Chemother Pharmacol,2016,77(2):349-356.
[35]Gay CM,Tong P,Cardnell RJ,et al.Differential sensitivity analysis for resistant malignancies(DISARM)identifies common candidate therapies across platinum-resistant cancers[J].Clin Cancer Res,2019,25(1):346-357.
[36]Fellenberg J,Kunz P,Sahr H,et al.Overexpression of inosine 5’-monophosphate dehydrogenase type II mediates chemoresistance to human osteosarcoma cells[J].PLoS One,2010,5(8):e12179.
[37]Tsai HC,Huang CY,Su HL,et al.CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma[J].PLoS One,2014,9(3):e90159.
[38]Levy JMM,Towers CG,Thorburn A.Targeting autophagy in cancer[J].Nat Rev Cancer,2017,17(9):528-542.
[39]Jiang K,Zhang C,Yu B,et al.Autophagic degradation of FOXO3a represses the expression of PUMA to block cell apoptosis in cisplatin-resistant osteosarcoma cells[J].Am JCancer Res,2017,7(7):1407-1422.
[40]Kim M,Jung JY,Choi S,et al.GFRA1 promotes cisplatininduced chemoresistance in osteosarcoma by inducing autophagy[J].Autophagy,2017,13(1):149-168.
[41]Huang J,Ni J,Liu K,et al.HMGB1 promotes drug resistance in osteosarcoma[J].Cancer Res,2012,72(1):230-238.
[42]Zhao G,Cai C,Yang T,et al.MicroRNA-221 induces cell survival and cisplatin resistance through PI3K/Akt pathway in human osteosarcoma[J].PLoS One,2013,8(1):e53906.
[43]Zhou Y,Huang Z,Wu S,et al.miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST[J].J Exp Clin Cancer Res,2014,33:12.
[44]Shao XJ,Miao MH,Xue J,et al.The down-regulation of microRNA-497 contributes to cell growth and cisplatin resistance through PI3K/Akt pathway in osteosarcoma[J].Cell Physiol Biochem,2015,36(5):2051-2062.
[45]Zhu Z,Tang J,Wang J,et al.MiR-138 acts as a tumor suppressor by targeting EZH2 and enhances cisplatininduced apoptosis in osteosarcoma cells[J].PLoS One,2016,11(3):e0150026.
[46]Keremu A,Aini A,Maimaitirexiati Y,et al.Overcoming cisplatin resistance in osteosarcoma through the miR-199amodulated inhibition of HIF-1alpha[J].Biosci Rep,2017.
[47]Tang Q,Yuan Q,Li H,et al.miR-223/Hsp70/JNK/JUN/miR-223 feedback loop modulates the chemoresistance of osteosarcoma to cisplatin[J].Biochem Biophys Res Commun,2018,497(3):827-834.
[48]Yuan G,Zhao Y,Wu D,et al.miRNA-20a upregulates TAK1and increases proliferation in osteosarcoma cells[J].Future Oncol,2018,14(5):461-469.
[49]Zhou X,Natino D,Zhai X,et al.MicroRNA-22 inhibits the proliferation and migration,and increases the cisplatin sensitivity,of osteosarcoma cells[J].Molecular Medicine Reports,2018,17(5):7209-7217.
[50]Xu M,Jin H,Xu CX,et al.MiR-34c inhibits osteosarcoma metastasis and chemoresistance[J].Med Oncol,2014,31(6):972.
[51]Wang SN,Luo S,Liu C,et al.miR-491 Inhibits osteosarcoma lung metastasis and chemoresistance by targeting alphaB-crystallin[J].Mol Ther,2017,25(9):2140-2149.
[52]Song L,Duan P,Gan Y,et al.MicroRNA-340-5p modulates cisplatin resistance by targeting LPAATbeta in osteosarcoma[J].Braz J Med Biol Res,2017,50(5):e6359.
[53]Li Z,Zhao L,Wang Q.Overexpression of long non-coding RNA HOTTIP increases chemoresistance of osteosarcoma cell by activating the Wnt/beta-catenin pathway[J].Am J Transl Res,2016,8(5):2385-2393.
[54]Hu Y,Yang Q,Wang L,et al.Knockdown of the oncogene lncRNA NEAT1 restores the availability of miR-34c and improves the sensitivity to cisplatin in osteosarcoma[J].Biosci Rep,2018,38(3).
[55]Wang Y,Zhang L,Zheng X,et al.Long non-coding RNALINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR-645-IFIT2 axis[J].Cancer Lett,2016,382(2):137-146.
[56]Kun-Peng Z,Xiao-Long M,Chun-Lin Z.Overexpressed circPVT1,a potential new circular RNA biomarker,contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1[J].Int J Biol Sci,2018,14(3):321-330.
[57]Zhang H,Yan J,Lang X,et al.Expression of circ_001569 is upregulated in osteosarcoma and promotes cell proliferation and cisplatin resistance by activating the Wnt/β-catenin signaling pathway[J].Oncology Letters,2018,16(5)5856-5862.
[58]Debes A,Willers R,Gobel U,et al.Role of heat treatment in childhood cancers:distinct resistance profiles of solid tumor cell lines towards combined thermochemotherapy[J].Pediatr Blood Cancer,2005,45(5):663-669.
[59]Nathan SS,Diresta GR,Casas-Ganem JE,et al.Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma[J].Clin Cancer Res,2005,11(6):2389-2397.
[60]Avnet S,Lemma S,Cortini M,et al.Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance[J].Oncotarget,2016,7(39):63408-63423.
[61]Graham K,Unger E.Overcoming tumor hypoxia as a barrier to radiotherapy,chemotherapy and immunotherapy in cancer treatment[J].Int J Nanomedicine,2018,13:6049-6058.
[62]Zhao W,Xia SQ,Zhuang JP,et al.Hypoxia-induced resistance to cisplatin-mediated apoptosis in osteosarcoma cells is reversed by gambogic acid independently of HIF-1alpha[J].Mol Cell Biochem,2016,420(1-2):1-8.
[63]Zheng D,Wu W,Dong N,et al.Mxd1 mediates hypoxiainduced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene[J].Mol Carcinog,2017,56(10):2234-2244.
[64]Takebe N,Miele L,Harris PJ,et al.Targeting Notch,Hedgehog,and Wnt pathways in cancer stem cells:clinical update[J].Nat Rev Clin Oncol,2015,12(8):445-464.
[65]Fujii H,Honoki K,Tsujiuchi T,et al.Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines[J].Int J Oncol,2009,34(5):1381-1386.
[66]Dai G,Deng S,Guo W,et al.Notch pathway inhibition using DAPT,a gamma-secretase inhibitor(GSI),Enhances the antitumor effect of cisplatin in resistant osteosarcoma[J].Mol Carcinog,2018,58(1):3-18.
[67]Shang D,Wu J,Guo L,et al.Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2[J].Int J Oncol,2017,50(5):1848-1856.
[68]Foley JM,Scholten Ii DJ,Monks NR,et al.Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling[J].J Transl Med,2015,13(1):110.
[69]Challagundla KB,Wise PM,Neviani P,et al.Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy[J].J Natl Cancer Inst,2015,107(7).
[70]Qin X,Yu S,Zhou L,et al.Cisplatin-resistant lung cancer cellderived exosomes increase cisplatin resistance of recipientcells in exosomal miR-100-5p-dependent manner[J].Int JNanomedicine,2017,12:3721-3733.
[71]Zheng P,Chen L,Yuan X,et al.Exosomal transfer of tumorassociated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells[J].J Exp Clin Cancer Res,2017,36(1):53.
[72]Merchant MS,Wright M,Baird K,et al.Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors[J].Clin Cancer Res,2016,22(6):1364-1370.
[73]Tawbi HA,Burgess M,Bolejack V,et al.Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma(SARC028):a multicentre,two-cohort,single-arm,open-label,phase 2 trial[J].Lancet Oncol,2017,18(11):1493-1501.
[2]Luetke A,Meyers PA,Lewis I,et al.Osteosarcoma treatmentwhere do we stand?A state of the art review[J].Cancer Treat Rev,2014,40(4):523-532.
[3]Dasari S,Tchounwou PB.Cisplatin in cancer therapy:molecular mechanisms of action[J].Eur J Pharmacol,2014,740:364-378.
[4]Chou AJ,Gorlick R.Chemotherapy resistance in osteosarcoma:current challenges and future directions[J].Expert Rev Anticancer Ther,2006,6(7):1075-1085.
[5]To KK,Tong WS,Fu LW.Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat[J].Lung Cancer,2017,103:58-65.
[6]Sun S,Zhao S,Yang Q,et al.Enhancer of zeste homolog 2promotes cisplatin resistance by reducing cellular platinum accumulation[J].Cancer Sci,2018,109(6):1853-1864.
[7]Beretta GL,Gatti L,Tinelli S,et al.Cellular pharmacology of cisplatin in relation to the expression of human copper transporter CTR1 in different pairs of cisplatin-sensitive andresistant cells[J].Biochem Pharmacol,2004,68(2):283-291.
[8]Martelli L,Di Mario F,Botti P,et al.Accumulation,platinumDNA adduct formation and cytotoxicity of cisplatin,oxaliplatin and satraplatin in sensitive and resistant human osteosarcoma cell lines,characterized by p53 wild-type status[J].Biochem Pharmacol,2007,74(1):20-27.
[9]Chen HH,Chen WC,Liang ZD,et al.Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy[J].Expert Opin Ther Targets,2015,19(10):1307-1317.
[10]Ishida S,Lee J,Thiele DJ,et al.Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals[J].Proc Natl Acad Sci USA,2002,99(22):14298-14302.
[11]Ishida S,Mccormick F,Smith-Mccune K,et al.Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator[J].Cancer Cell,2010,17(6):574-583.
[12]Kim ES,Tang X,Peterson DR,et al.Copper transporter CTR1expression and tissue platinum concentration in non-small cell lung cancer[J].Lung Cancer,2014,85(1):88-93.
[13]Fanelli M,Hattinger CM,Vella S,et al.Targeting ABCB1 and ABCC1 with their specific inhibitor CBT-1(R)can overcome drug resistance in osteosarcoma[J].Curr Cancer Drug Targets,2016,16(3):261-274.
[14]Ye S,Zhang J,Shen J,et al.NVP-TAE684 reverses multidrug resistance(MDR)in human osteosarcoma by inhibiting P-glycoprotein(PGP1)function[J].Br J Pharmacol,2016,173(3):613-626.
[15]Inesi G,Pilankatta R,Tadini-Buoninsegni F.Biochemical characterization of P-type copper ATPases[J].Biochem J,2014,463(2):167-176.
[16]Li ZH,Zheng R,Chen JT,et al.The role of copper transporter ATP7A in platinum-resistance of esophageal squamous cell cancer(ESCC)[J].J Cancer,2016,7(14):2085-2092.
[17]Xiao F,Li Y,Wan Y,et al.MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B[J].Cancer Chemother Pharmacol,2018,81(5):935-947.
[18]Komiya S,Gebhardt MC,Mangham DC,et al.Role of glutathione in cisplatin resistance in osteosarcoma cell lines[J].J Orthop Res,1998,16(1):15-22.
[19]Huang G,Mills L,Worth LL.Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells[J].Mol Cancer Ther,2007,6(5):1610-1619.
[20]Goricar K,Kovac V,Jazbec J,et al.Genetic variability of DNA repair mechanisms and glutathione-S-transferase genes influences treatment outcome in osteosarcoma[J].Cancer Epidemiol,2015,39(2):182-188.
[21]Pasello M,Michelacci F,Scionti I,et al.Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma[J].Cancer Res,2008,68(16):6661-6668.
[22]Obiedat H,Alrabadi N,Sultan E,et al.The effect of ERCC1and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients[J].BMC Med Genet,2018,19(1):112.
[23]Hattinger CM,Michelacci F,Sella F,et al.Excision repair cross-complementation group 1 protein expression predicts survival in patients with high-grade,non-metastatic osteosarcoma treated with neoadjuvant chemotherapy[J].Histopathology,2015,67(3):338-347.
[24]Graf N,Ang WH,Zhu G,et al.Role of endonucleases XPFand XPG in nucleotide excision repair of platinated DNA and cisplatin/oxaliplatin cytotoxicity[J].Chem Bio Chem,2011,12(7):1115-1123.
[25]Biason P,Hattinger CM,Innocenti F,et al.Nucleotide excision repair gene variants and association with survival i n o s t e o s a r c o m a p a t i e n t s t r e a t e d w i t h n e o a d j u v a n t chemotherapy[J].Pharmacogenomics J,2012,12(6):476-483.
[26]Jentzsch T,Robl B,Husmann M,et al.Expression of MSH2 and MSH6 on a tissue microarray in patients with osteosarcoma[J].Anticancer Res,2014,34(12):6961-6972.
[27]Huang JW,Wang Y,Dhillon KK,et al.Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity[J].Mol Cancer Res,2013,11(12):1564-1573.
[28]Liang Q,Dexheimer TS,Zhang P,et al.A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses[J].Nat Chem Biol,2014,10(4):298-304.
[29]Moriarity BS,Otto GM,Rahrmann EP,et al.A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis[J].Nat Genet,2015,47(6):615-624.
[30]Duan L,Perez RE,Hansen M,et al.Increasing cisplatin sensitivity by schedule-dependent inhibition of AKT and Chk1[J].Cancer Biol Ther,2014,15(12):1600-1612.
[31]Han X G,Du L,Qiao H,et al.CXCR1 knockdown improves the sensitivity of osteosarcoma to cisplatin[J].Cancer Lett,2015,369(2):405-415.
[32]Brozovic A,Fritz G,Christmann M,et al.Long-term activation of SAPK/JNK,p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance[J].Int J Cancer,2004,112(6):974-985.
[33]Yong L,Ma Y,Zhu B,et al.Oleandrin synergizes with cisplatin in human osteosarcoma cells by enhancing cell apoptosis through activation of the p38 MAPK signaling pathway[J].Cancer Chemother Pharmacol,2018,82(6):1009-1020.
[34]Ye S,Shen J,Choy E,et al.p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines[J].Cancer Chemother Pharmacol,2016,77(2):349-356.
[35]Gay CM,Tong P,Cardnell RJ,et al.Differential sensitivity analysis for resistant malignancies(DISARM)identifies common candidate therapies across platinum-resistant cancers[J].Clin Cancer Res,2019,25(1):346-357.
[36]Fellenberg J,Kunz P,Sahr H,et al.Overexpression of inosine 5’-monophosphate dehydrogenase type II mediates chemoresistance to human osteosarcoma cells[J].PLoS One,2010,5(8):e12179.
[37]Tsai HC,Huang CY,Su HL,et al.CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma[J].PLoS One,2014,9(3):e90159.
[38]Levy JMM,Towers CG,Thorburn A.Targeting autophagy in cancer[J].Nat Rev Cancer,2017,17(9):528-542.
[39]Jiang K,Zhang C,Yu B,et al.Autophagic degradation of FOXO3a represses the expression of PUMA to block cell apoptosis in cisplatin-resistant osteosarcoma cells[J].Am JCancer Res,2017,7(7):1407-1422.
[40]Kim M,Jung JY,Choi S,et al.GFRA1 promotes cisplatininduced chemoresistance in osteosarcoma by inducing autophagy[J].Autophagy,2017,13(1):149-168.
[41]Huang J,Ni J,Liu K,et al.HMGB1 promotes drug resistance in osteosarcoma[J].Cancer Res,2012,72(1):230-238.
[42]Zhao G,Cai C,Yang T,et al.MicroRNA-221 induces cell survival and cisplatin resistance through PI3K/Akt pathway in human osteosarcoma[J].PLoS One,2013,8(1):e53906.
[43]Zhou Y,Huang Z,Wu S,et al.miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST[J].J Exp Clin Cancer Res,2014,33:12.
[44]Shao XJ,Miao MH,Xue J,et al.The down-regulation of microRNA-497 contributes to cell growth and cisplatin resistance through PI3K/Akt pathway in osteosarcoma[J].Cell Physiol Biochem,2015,36(5):2051-2062.
[45]Zhu Z,Tang J,Wang J,et al.MiR-138 acts as a tumor suppressor by targeting EZH2 and enhances cisplatininduced apoptosis in osteosarcoma cells[J].PLoS One,2016,11(3):e0150026.
[46]Keremu A,Aini A,Maimaitirexiati Y,et al.Overcoming cisplatin resistance in osteosarcoma through the miR-199amodulated inhibition of HIF-1alpha[J].Biosci Rep,2017.
[47]Tang Q,Yuan Q,Li H,et al.miR-223/Hsp70/JNK/JUN/miR-223 feedback loop modulates the chemoresistance of osteosarcoma to cisplatin[J].Biochem Biophys Res Commun,2018,497(3):827-834.
[48]Yuan G,Zhao Y,Wu D,et al.miRNA-20a upregulates TAK1and increases proliferation in osteosarcoma cells[J].Future Oncol,2018,14(5):461-469.
[49]Zhou X,Natino D,Zhai X,et al.MicroRNA-22 inhibits the proliferation and migration,and increases the cisplatin sensitivity,of osteosarcoma cells[J].Molecular Medicine Reports,2018,17(5):7209-7217.
[50]Xu M,Jin H,Xu CX,et al.MiR-34c inhibits osteosarcoma metastasis and chemoresistance[J].Med Oncol,2014,31(6):972.
[51]Wang SN,Luo S,Liu C,et al.miR-491 Inhibits osteosarcoma lung metastasis and chemoresistance by targeting alphaB-crystallin[J].Mol Ther,2017,25(9):2140-2149.
[52]Song L,Duan P,Gan Y,et al.MicroRNA-340-5p modulates cisplatin resistance by targeting LPAATbeta in osteosarcoma[J].Braz J Med Biol Res,2017,50(5):e6359.
[53]Li Z,Zhao L,Wang Q.Overexpression of long non-coding RNA HOTTIP increases chemoresistance of osteosarcoma cell by activating the Wnt/beta-catenin pathway[J].Am J Transl Res,2016,8(5):2385-2393.
[54]Hu Y,Yang Q,Wang L,et al.Knockdown of the oncogene lncRNA NEAT1 restores the availability of miR-34c and improves the sensitivity to cisplatin in osteosarcoma[J].Biosci Rep,2018,38(3).
[55]Wang Y,Zhang L,Zheng X,et al.Long non-coding RNALINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR-645-IFIT2 axis[J].Cancer Lett,2016,382(2):137-146.
[56]Kun-Peng Z,Xiao-Long M,Chun-Lin Z.Overexpressed circPVT1,a potential new circular RNA biomarker,contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1[J].Int J Biol Sci,2018,14(3):321-330.
[57]Zhang H,Yan J,Lang X,et al.Expression of circ_001569 is upregulated in osteosarcoma and promotes cell proliferation and cisplatin resistance by activating the Wnt/β-catenin signaling pathway[J].Oncology Letters,2018,16(5)5856-5862.
[58]Debes A,Willers R,Gobel U,et al.Role of heat treatment in childhood cancers:distinct resistance profiles of solid tumor cell lines towards combined thermochemotherapy[J].Pediatr Blood Cancer,2005,45(5):663-669.
[59]Nathan SS,Diresta GR,Casas-Ganem JE,et al.Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma[J].Clin Cancer Res,2005,11(6):2389-2397.
[60]Avnet S,Lemma S,Cortini M,et al.Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance[J].Oncotarget,2016,7(39):63408-63423.
[61]Graham K,Unger E.Overcoming tumor hypoxia as a barrier to radiotherapy,chemotherapy and immunotherapy in cancer treatment[J].Int J Nanomedicine,2018,13:6049-6058.
[62]Zhao W,Xia SQ,Zhuang JP,et al.Hypoxia-induced resistance to cisplatin-mediated apoptosis in osteosarcoma cells is reversed by gambogic acid independently of HIF-1alpha[J].Mol Cell Biochem,2016,420(1-2):1-8.
[63]Zheng D,Wu W,Dong N,et al.Mxd1 mediates hypoxiainduced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene[J].Mol Carcinog,2017,56(10):2234-2244.
[64]Takebe N,Miele L,Harris PJ,et al.Targeting Notch,Hedgehog,and Wnt pathways in cancer stem cells:clinical update[J].Nat Rev Clin Oncol,2015,12(8):445-464.
[65]Fujii H,Honoki K,Tsujiuchi T,et al.Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines[J].Int J Oncol,2009,34(5):1381-1386.
[66]Dai G,Deng S,Guo W,et al.Notch pathway inhibition using DAPT,a gamma-secretase inhibitor(GSI),Enhances the antitumor effect of cisplatin in resistant osteosarcoma[J].Mol Carcinog,2018,58(1):3-18.
[67]Shang D,Wu J,Guo L,et al.Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2[J].Int J Oncol,2017,50(5):1848-1856.
[68]Foley JM,Scholten Ii DJ,Monks NR,et al.Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling[J].J Transl Med,2015,13(1):110.
[69]Challagundla KB,Wise PM,Neviani P,et al.Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy[J].J Natl Cancer Inst,2015,107(7).
[70]Qin X,Yu S,Zhou L,et al.Cisplatin-resistant lung cancer cellderived exosomes increase cisplatin resistance of recipientcells in exosomal miR-100-5p-dependent manner[J].Int JNanomedicine,2017,12:3721-3733.
[71]Zheng P,Chen L,Yuan X,et al.Exosomal transfer of tumorassociated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells[J].J Exp Clin Cancer Res,2017,36(1):53.
[72]Merchant MS,Wright M,Baird K,et al.Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors[J].Clin Cancer Res,2016,22(6):1364-1370.
[73]Tawbi HA,Burgess M,Bolejack V,et al.Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma(SARC028):a multicentre,two-cohort,single-arm,open-label,phase 2 trial[J].Lancet Oncol,2017,18(11):1493-1501.