奥沙利铂抗肿瘤及其耐药机制的研究进展(3)

自噬是一种在健康以及病理状态下维持细胞稳态重要的代谢过程，一般出现在细胞处于应激、缺氧、DNA损伤以及内质网压力时。自噬在多种肿瘤中被激活，抑制这一过程有助于增加细胞死亡或者延长生存从而影响肿瘤耐药，其在化疗耐药中的作用也存在着争议，如可还原的HMGB1诱导Beclin1依赖的自噬并且促进肿瘤对于奥沙利铂的抵抗。大量研究表明，奥沙利铂处理肝癌以及结肠癌细胞或者裸鼠移植瘤模型后活化了自噬，进而降低了活性氧簇（ROS）的表达，从而使肿瘤对奥沙利铂耐药[36,39]。另外，有报道Beclin1或者ATG5的下调增强了奥沙利铂的敏感性，说明自噬在奥沙利铂耐药中起正向调节作用[39]。Gines等[40]报道奥沙利铂处理结肠癌细胞系HT29后，PKM2依赖的转录水平的Bcl-2调节因子（BMF）升高，诱导了凋亡、坏死性凋亡以及自噬，但在其对应的奥沙利铂耐药株中并不存在这一现象。最近，有研究表明胃癌多药耐药细胞系中ARHGAP5-AS1表达升高，抑制耐药细胞的自噬可以提高ARHGAP5-AS1水平，ARHGAP5-AS1可以在核内与ARHGAP5的启动子区域结合促进ARHGAP5的转录，并且在细胞质中ARHGAP5-AS1通过招募METTL3促进m6A，从而稳定ARHGAP5的m RNA,ARHGAP5的升高可以导致细胞的化疗耐药[41]。然而，也有报道circ HIPK3在奥沙利铂耐药的结直肠癌组织中高表达，通过吸附mi R-637促进STAT3表达，从而活化下游的Bcl-2/beclin1通路，进一步抑制细胞自噬水平从而促进细胞对奥沙利铂的耐药[42]。因此，对于自噬在肿瘤耐药中的研究仍存在诸多争议，自噬在不同肿瘤的不同阶段所起的作用可能有所差异，临床上缺乏有效的肿瘤自噬水平检测标志物，导致这一重要生理过程的评估难以转化到临床应用。

目前，奥沙利铂是结直肠癌及其他肿瘤患者的最主要的化疗药物，而耐药是导致治疗失败以及肿瘤进展的关键一环，因此，研究其化疗耐药的分子机制对于提高此类肿瘤的治愈率至关重要。尽管已取得了一些进展，已掌握的一些分子机制及相关标识物不仅有助于识别耐药患者，而且对发明新的能够克服耐药的药物意义重大，但是对于目前奥沙利铂耐药的主要机制及通路尚未完全阐明，有待全世界的研究者们进一步探索。

参考文献

[1]Jiang Z,Sun Y,Zhang W,et al.Comparison of S-1 plus oxaliplatin(SOX) and capecitabine plus oxaliplatin(XELOX)as adjuvant chemotherapies for stage II and III gastric cancer after D2 resection:A single-center retrospective study[J].Asia Pac J Clin Oncol,2020,16(3):180-186.

[2]Terazawa T,Matsuyama J,Goto M,et al.A phase II study of perioperative Capecitabine plus Oxaliplatin therapy for clinical SS/SE N1-3 M0 gastric cancer (OGSG 1601)[J].Oncologist,2020,25(2):119-e208.

[3]Sawasaki M,Tsubamoto H,Nakamoto Y,et al.S-1,Oxaliplatin,Nab-paclitaxel and Itraconazole for conversion surgery for advanced or recurrent gastric cancer[J].Anticancer Res,2020,40(2):991-997.

[4]Perego P,Robert J.Oxaliplatin in the era of personalized medicine:from mechanistic studies to clinical efficacy[J].Cancer Chemother Pharmacol,2016,77(1):5-18.

[5]Sprowl J A,Ness RA,Sparreboom A.Polymorphic transporters and platinum pharmacodynamics[J].Drug Metab Pharmacokinet,2013,28(1):19-27.

[6]Yonezawa A,Masuda S,Yokoo S,et al.Cisplatin and oxaliplatin,but not carboplatin and nedaplatin,are substrates for human organic cation transporters (slc22a1-3 and multidrug and toxin extrusion family)[J].J Pharmacol Exp Ther,2006,319(2):879-886.

[7]Yokoo S,Yonezawa A,Masuda S,et al.Differential contribution of organic cation transporters,oct2 and mate1,in platinum agent-induced nephrotoxicity[J].Biochem Pharmacol,2007,74(3):477-487.

[8]Zhang S,Lovejoy KS,Shima JE,et al.Organic cation transporters are determinants of oxaliplatin cytotoxicity[J].Cancer Res,2006,66(17):8847-8857.

[9]Li S,Chen Y,Zhang S,et al.Role of organic cation transporter 1,oct1 in the pharmacokinetics and toxicity of cis-diammine(pyridine)chloroplatinum(ii) and oxaliplatin in mice[J].Pharm Res,2011,28(3):610-625.

[10]Burger H,Zoumaro-Djayoon A,Boersma AW,et al.Differential transport of platinum compounds by the human organic cation transporter hoct2 (hslc22a2)[J].Br JPharmacol,2010,159(4):898-908.

[11]Larson CA,Blair BG,Safaei R,et al.The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs[J].Mol Pharmacol,2009,75(2):324-330.

[12]Liu JJ,Jamieson SM,Subramaniam J,et al.Neuronal expression of copper transporter 1 in rat dorsal root ganglia:Association with platinum neurotoxicity[J].Cancer Chemother Pharmacol,2009,64(4):847-856.

[13]Blair BG,Larson CA,Safaei R,et al.Copper transporter2 regulates the cellular accumulation and cytotoxicity of cisplatin and carboplatin[J].Clin Cancer Res,2009,15(13):4312-4321.

[14]Martinez-Balibrea E,Martinez-Cardus A,Musulen E,et al.Increased levels of copper efflux transporter atp7b are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy[J].Int J Cancer,2009,124(12):2905-2910.

[15]Ip V,Liu JJ,Mercer JF,et al.Differential expression of atp7a,atp7b and ctr1 in adult rat dorsal root ganglion tissue[J].Mol Pain,2010,6:53.

[16]Beretta GL,Benedetti V,Cossa G,et al.Increased levels and defective glycosylation of mrps in ovarian carcinoma cells resistant to oxaliplatin[J].Biochem Pharmacol,2010,79(8):1108-1117.

[17]Ekblad L,Kjellstrom J,Johnsson A.Reduced drug accumulation is more important in acquired resistance against oxaliplatin than against cisplatin in isogenic colon cancer cells[J].Anticancer Drugs,2010,21(5):523-531.

百度搜索“77cn”或“免费范文网”即可找到本站免费阅读全部范文。收藏本站方便下次阅读，免费范文网，提供经典小说医药类奥沙利铂抗肿瘤及其耐药机制的研究进展(3)在线全文阅读。