砷化合物抗肿瘤多药耐药性作用及作用机制研究进展

Research Progress of Anti-Tumor Multidrug Resistance and Mechanism of Arsenic Compounds

目的探讨砷化合物抗肿瘤多药耐药性(MDR)的作用及作用机制。方法查阅相关文献,分别从细胞、分子、基因水平,以及相关通路阐述砷化合物抗肿瘤MDR的作用及作用机制。结果三氧化二砷(ATO)联合维生素C、雄黄转化溶液(RST)均可抑制耐药性肿瘤细胞血管再生和转移;ATO、负载紫杉醇的亚砷酸钆纳米颗粒、ATO与阿霉素联用均可抑制耐药性肿瘤细胞侵袭和迁移;ATO、口服纳米硫化砷均可诱导肿瘤MDR细胞发生自噬。ATO,RTS,ATO-As_(4)O_(6)-顺铂的组合,白藜芦醇(RSV)和ATO联用,丁硫氨酸亚砜亚胺与ATO联用,As_(4)S_(4)均可抑制耐药相关蛋白的表达。ATO可抑制耐药酶谷胱甘肽S转移酶和DNA拓扑异构酶Ⅱ的表达;ATO与阿霉素联用可下调Stathmin表达。ATO,ATO联合RSV,As_(4)S_(4)均可抑制凋亡控制基因表达;ATO,ATO联合RSV均可抑制核因子κB;RST可下调MDR1基因;载有砷的双重药物(阿霉素和ATO)纳米药物系统协同DNA损伤和干预DNA修复。ATO、亚砷酸、亚砷酸钠、加马布他汀和p38丝裂原活化蛋白激酶抑制剂SB203580均可激活膜受体酪氨酸蛋白激酶信号传导途径(RAS/RAF/MAPK);As_(4)S_(4),As_(4)S_(4)和L-丁硫氨酸-(S,R)-亚磺酰亚胺联用,单用ATO或与磷脂酰肌醇激酶/蛋白激酶B(PI3K/AKT)信号通路抑制剂LY294002均可抑制PI3K-AKT信号通路;ATO可引发内质网应激反应;ATO可抑制Notch信号通路。结论砷化合物能有效逆转肿瘤细胞的MDR,是极具潜力的抗肿瘤药物。

Objective To investigate the anti-tumor multidrug resistance(MDR)of arsenic compounds and their mechanism.Methods The relevant literature was searched to explained the anti-tumor MDR of arsenic compounds and their mechanism from the cellular,molecu-lar,gene level and related pathways.Results The combination of arsenic trioxide(ATO),vitamin C and realgar transformation solution(RST)could inhibit the angiogenesis and metastasis of drug-resistant tumor cells.ATO,hybrid paclitaxel-loaded arsenite nanoparticle(HPAN)and the combination of ATO and azithromycin could inhibit the invasion and migration of drug-resistant tumor cells.ATO and oral nano-arsenic sulfide(ee-As_(4)S_(4))could induce autophagy in tumor MDR cells.The combination of ATO,RTs,ATO-As_(4)O6-cisplatin,the combination of resveratrol(RSV)and ATO,the combination of L-buthionine-sulfoximine and ATO,and As_(4)S_(4) could in-hibit the expression of drug resistance-related protein.ATO could inhibit the expression of drug-resistant enzyme glutathione S-trans-feraseπand DNA topoisomeraseⅡ.The combination of ATO and adriamycin could down-regulate the expression of Stathmin.ATO,the combination of ATO and RSV,and As_(4)S_(4) could inhibit the expression of apoptosis control apoptosis genes.ATO,the combination of ATO and RSV could inhibit nuclear factor-κB.RST could down-regulate MDR1 gene.Nano dual-drug(azithromycin and ATO)delivery system containing arsenic could synergistically aggravate DNA damage and intervene DNA repair.ATO,arsenite,sodium arsenite,gambu-tatin and p38 mitogen-activated protein kinase(MAPK)inhibitor SB203580 could activate RAS/RAF/MAPK signaling pathway.As_(4)S_(4),the combination of As_(4)S_(4) and L-butylthionine-(S,R)-sulfimide,ATO or the combination of ATO and phosphatidylinositol-3-ki-nase/protein kinase B(PI3K/AKT)inhibitor LY294002 could inhibit the PI3K/AKT signaling pathway.ATO could induce endoplasmic reticulum stress response,and inhibit the Notch signaling pathway.Conclusion Arsenic compounds can effectively reverse the MDR of tumor cells,and they are potential anti-tumor drugs.