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目的研究抑制聚腺苷酸二磷酸核糖转移酶-1[PARP-1]活性能否增加阿霉素(ADM)的细胞敏感性。方法以小鼠胚胎成纤维细胞为研究对象,将细胞按是否经PARP-1抑制剂4-氨基-1,8-萘二胺(4-AN)处理分为处理组和对照组,比较两组细胞经ADM染毒后细胞存活情况和DNA单链断裂及染色体损伤的差异。结果 4-AN处理组细胞的阿霉素半数抑制浓度(1.09±0.15μg/ml)低于对照组(2.19±0.22μg/ml),差异有显著性(P=0.002);在0.025～0.2μg/ml时,群体倍增时间较对照组长(P<0.05),0.05～0.2μg/ml时,集落形成率较对照组低(P<0.05)。单细胞凝胶电泳及微核实验结果显示,当ADM浓度范围为0.02～0.5μg/ml时,4-AN处理组细胞的拖尾率、尾长、Olive尾矩3个指标值均大于对照组(P<0.05),在ADM为0.01～0.2μg/ml时,4-AN处理组细胞的微核细胞率和细胞微核率均比对照组高(P<0.05)。结论抑制PARP-1活性能显著增加阿霉素的细胞敏感性,其机制与DNA损伤修复有关。
Objective To investigate whether inhibition of poly (ADP-ribose) transferase-1 (PARP-1) activity may increase cellular sensitivity to doxorubicin (ADM). Methods Mouse embryonic fibroblasts were divided into treatment group and control group according to whether PARP-1 inhibitor 4-amino-1,8-naphthalenediamine (4-AN) Cell viability after ADM exposure to DNA and DNA single strand breaks and chromosomal damage. Results The median inhibitory concentration of doxorubicin in 4-AN treatment group (1.09 ± 0.15μg / ml) was significantly lower than that in control group (2.19 ± 0.22μg / ml) (P = 0.002) The population doubling time was longer than that of the control group (P <0.05). When the concentration was 0.05-0.2μg / ml, the colony formation rate was lower than that of the control group (P <0.05). Single cell gel electrophoresis and micronucleus test results showed that when the ADM concentration range of 0.02 ~ 0.5μg / ml, 4-AN treatment group tailing rate, tail length, Olive tail moment three indicators were greater than the control group (P <0.05). When the concentration of ADM was 0.01-0.2 μg / ml, the rates of micronuclei and micronuclei in 4-AN treatment group were higher than those in control group (P <0.05). Conclusion Inhibition of PARP-1 activity can significantly increase the cell sensitivity of doxorubicin, and its mechanism is related to DNA damage repair.