木犀草素逆转宫颈癌细胞对阿霉素耐药性的机制研究

doi:10.3969/j.issn.2095-1264.2022.02.07

首页 > 过刊浏览>2022年第2期 >183-190. DOI:10.3969/j.issn.2095-1264.2022.02.07

木犀草素逆转宫颈癌细胞对阿霉素耐药性的机制研究
DOI:
                        10.3969/j.issn.2095-1264.2022.02.07
                    
作者:
                        
                        
                    
作者单位:1.湖南省妇幼保健院，妇产科，湖南 长沙，410008;2.湖南省妇幼保健院，急诊科，湖南 长沙，410008
作者简介:许一诺，女，硕士，住院医师，研究方向：妇科肿瘤。
通讯作者:易宇凌，女，硕士，副主任医师，研究方向：妇科肿瘤。
中图分类号:R737.3
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Luteolin reverses doxorubicin resistance in cervical cancer by regulating PI3K/Akt signaling pathway

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Affiliation:

1.Department of Obstetrics and Gynecology, Hunan Maternity and Child Health Hospital, Changsha, Hunan, 410008, China;2.Department of Emergency, Hunan Maternity and Child Health Hospital, Changsha, Hunan, 410008, China

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摘要:

目的探讨木犀草素（Lut）逆转宫颈癌对阿霉素（Dox）耐药性的效应及其机制。方法建立Dox耐药的宫颈癌HeLa/Dox细胞株，利用Dox、Lut单独或联合作用于细胞，分为control组、Dox组、Lut组、Dox＋Lut组，检测各组细胞存活率及凋亡率。构建小鼠移植瘤模型，经腹腔注射3 mg·kg^-1 Dox和/或5 mg·kg^-1 Lut，检测小鼠肿瘤生长情况及肿瘤中相关蛋白的表达。结果（1） CCK-8检测结果显示，Dox+Lut组细胞的生长活性明显受到抑制，存活率显著低于Dox组和Lut组（P<0.01）。细胞克隆形成实验显示出与CCK-8实验相似的细胞生长趋势。流式细胞术检测结果显示，Dox单药对HeLa/Dox细胞的凋亡无明显促进作用，而Lut单药可显著诱导HeLa/Dox细胞凋亡。（2） Dox单药对HeLa/Dox细胞迁移的影响较小（P<0.05），而Lut单药处理的HeLa/Dox细胞迁移数目明显减少，Dox与Lut联合应用对HeLa/Dox细胞迁移能力的抑制作用最强（P<0.01）。（3）与对照组相比，Dox组、Lut组、Dox+Lut组HeLa/Dox细胞中PI3K、Cleaved caspase-3蛋白表达均显著上调，p-Akt、p-mTOR、p70S6K蛋白表达显著下调（P<0.05），且Dox+Lut组蛋白表达水平变化最为显著。（4）对照组、Dox组、Lut组、Dox+Lut组小鼠肿瘤体积分别为（1265.8±123.3）mm³、（456.4±68.7）mm³、（479.9±57.2）mm³、（108.1±14.0）mm³，差异具有统计学意义（P＜0.05）。联合应用Dox和Lut后，肿瘤组织中PI3K和Cleaved caspase-3的表达显著上调（P<0.01），而p70S6K和Ki-67的表达显著下调（P<0.01）。结论 Lut可通过调节PI3K/Akt信号通路的活性逆转宫颈癌细胞对阿霉素的耐药性，从而抑制肿瘤细胞的增殖和转移，并促进其凋亡。

Abstract:

Objective To investigate the effects and mechanism of luteolin (Lut) in reversing doxorubicin (Dox) resistance of cervical cancer.Methods Dox-resistant HeLa/Dox cell line was established, and the HeLa/Dox cells were divided into control group, Dox group, Lut group, Dox＋Lut group after treated with Dox or/and Lut to detect the survival rate and apoptosis rate. The model of transplanted tumor in mice was established, and they were treated with 3 mg·kg^-1 Dox or/and 5 mg·kg^-1 Lut. Detect the growth of the tumor in mice and the changes of related proteins in tumor.Results (1) The results of CCK-8 assay showed that the cell growth of Dox+Lut group was significantly inhibited and its survival rate was lower than that of the Lut group and Dox group (P<0.01). Cell clone formation experiments showed a similar trend of cell growth as CCK-8 assay. Flow cytometry showed that Dox alone did not promote the apoptosis of HeLa/Dox cells, but Lut alone could significantly cause the apoptosis of HeLa/Dox cells. (2) Dox alone showed few effects on the migration of HeLa/Dox cells (P<0.05), while Lut alone significantly inhibited the migration of HeLa/Dox cells. Dox combined with Lut showed the strongest inhibitory effects on HeLa/Dox cell migration (P<0.01). (3) Compared with the control group, the expressions of PI3K and cleaved caspase-3 proteins in Dox group, Lut group and Dox+Lut group were up-regulated. The expression levels of PI3K and cleaved caspase-3 proteins in Dox+Lut group were the highest. The protein expressions of p-Akt, p-mTOR and p70S6K proteins was significantly decreased in Dox+Lut group (P<0.05). (4)The tumor volume of control group, Dox group, Lut group and Dox+Lut group were respectively (1265.8+123.3) mm³, (456.4+68.7) mm³, (479.9+57.2) mm³ and (108.1+14.0) mm³, with statistical differences (P<0.05). Immunohistochemistry showed that the expression of PI3K and cleaved caspase-3 increased significantly in Dox+Lut group (P<0.01), while the expression of P70S6K and Ki-67 decreased significantly (P<0.01).Conclusion Lut can reverse the drug resistance of cervical cancer cells to doxorubicin by regulating the activity of PI3K/Akt signaling pathway, and inhibit the proliferation and metastasis and promote the apoptosis of tumor cells.