陕西中医药大学 陕西 712046
司海龙,男,博士,副主任医师
#王惠玲,女,博士,副主任医师,主要研究方向:中医药防治内分泌疾病的临床与基础研究,E-mail:105586073@qq.com
纸质出版日期:2021-08-30,
收稿日期:2021-01-18,
移动端阅览
司海龙, 陈玉, 苟涛, 等. 培元抗癌汤通过PI3K-AKT-mTOR信号通路调节Lewis肺癌自噬抑制肿瘤生长和转移的实验研究[J]. 北京中医药大学学报, 2021,44(8):722-728.
Hailong Si, Yu Chen, Tao Gou, et al. Effect of
司海龙, 陈玉, 苟涛, 等. 培元抗癌汤通过PI3K-AKT-mTOR信号通路调节Lewis肺癌自噬抑制肿瘤生长和转移的实验研究[J]. 北京中医药大学学报, 2021,44(8):722-728. DOI: 10.3969/j.issn.1006-2157.2021.08.008.
Hailong Si, Yu Chen, Tao Gou, et al. Effect of
目的
2
观察培元抗癌汤对Lewis肺癌小鼠肿瘤生长及肿瘤肺转移的抑制作用,探讨培元抗癌汤对自噬及PI3K-AKT-mTOR信号通路的影响。
方法
2
Lewis肺癌细胞接种在C57BL/6小鼠右腋皮下,制成Lewis肺癌荷瘤小鼠模型。将荷瘤小鼠随机分为模型组、顺铂组、培元抗癌汤组、培元抗癌汤-顺铂组,分别给予中药灌胃、顺铂腹腔注射,进行药物干预后,观察各组小鼠生存质量;观察肺转移灶、计算肺转移抑制率;称取各组荷瘤小鼠肿瘤的质量、计算抑瘤率;透射电镜观察自噬泡的形成;Western blot法检测肿瘤组织中自噬因子LC3Ⅰ及LC3Ⅱ蛋白的表达,检测肿瘤组织中PI3K、p-PI3K、AKT、p-AKT、mTOR、p-mTOR表达。
结果
2
模型组、顺铂组小鼠生存质量差,小鼠有聚集、毛发脱落、反应迟缓等现象,培元抗癌汤组、培元抗癌汤-顺铂组小鼠生存质量较好。与模型组比较,培元抗癌汤组、培元抗癌汤-顺铂组能明显抑制肺转移(
P
<
0.05),顺铂组有抑制肺转移趋势,但差异无统计学意义(
P
>
0.05);培元抗癌汤-顺铂组肺转移抑制率则明显高于培元抗癌汤组。与模型组比较,顺铂组、培元抗癌汤组、培元抗癌汤-顺铂组能明显抑制肿瘤生长,差异有统计学意义(
P
<
0.05),顺铂组高于培元抗癌汤组(
P
<
0.05),培元抗癌汤-顺铂组明显高于培元抗癌汤组和顺铂组。与模型相比,顺铂组、培元抗癌汤组、培元抗癌汤-顺铂组自噬泡明显增多,提示自噬增强。各用药组肿瘤组织中LC3Ⅱ/LC3Ⅰ均明显高于模型组(
P
<
0.05);与培元抗癌汤组比较,顺铂组、培元抗癌汤-顺铂组的LC3Ⅱ/LC3Ⅰ表达更高(
P
<
0.05),而培元抗癌汤-顺铂组的LC3Ⅱ/LC3Ⅰ表达最高。与模型组比较,各用药组肿瘤组织中PI3K、AKT、mTOR的表达无明显差异(
P
>
0.05),各用药组肿瘤组织中p-PI3K、p-AKT、p-mTOR表达均明显低于模型组(
P
<
0.05);与培元抗癌汤组比较,顺铂组、培元抗癌汤-顺铂组的p-PI3K、p-AKT、p-mTOR表达更低(
P
<
0.05),而培元抗癌汤-顺铂组的p-PI3K、p-AKT、p-mTOR表达最低。
结论
2
培元抗癌汤能明显改善小鼠生存质量及抑制肿瘤生长及转移,其机制可能是抑制PI3K-AKT-mTOR信号通路,增强肿瘤自噬。
Objective
2
To observe the inhibitory effect of
Peiyuan Kang’ai
(Healthy qi-supplementing Anti-cancer) Decoction(PYKA Decoction) on tumor growth and lung metastasis of Lewis lung cancer mice
and to explore the effect of PKKA Decoction on autophagy and PI3K-AKT-mTOR pathway.
Methods
2
Lewis lung cancer cells were inoculated subcutaneously in the right armpit of C57BL/6 mice to establish Lewis lung cancer bearing mice model. The tumor bearing mice were randomly divided into model group
cisplatin group
PYKA Decoction group and PYKA Decoction-cisplatin group. After the interventions of traditional Chinese medicine decoction by gavage and intraperitoneal injection of cisplatin
the quality of life of mice was observed; the lung metastasis was observed and the inhibition rate of lung metastasis was calculated; the tumor mass and tumor inhibition rate were calculated; the formation of autophagic vesicles was observed by transmission electron microscope; Western blot was used to observe the expression of autophagy factors LC3Ⅱ/ LC3Ⅰ
as well as the expression levels of PI3K/p-PI3K
AKT/p-AKT and mTOR/p-mTOR in tumor tissues.
Results
2
The quality of life of mice in the model group and cisplatin group was poor
and there were aggregation
hair shedding and slow reaction in mice; while the quality of life of mice in PYKA Decoction group and PYKA Decoction-cisplatin group was better. Compared with those of the model group
in PYKA Decoction group and PYKA Decoction-cisplatin group
lung metastasis was significantly inhibited (
P
<
0.05)
and in the cisplatin group
there was a tendency to inhibit lung metastasis
but there was no statistical significance (
P
>
0.05). Compared with that of the model group
the growth rate of tumor was significantly inhibited in the PYKA Decoction group
PYKA Decoction-cisplatin group and cisplatin group (
P
<
0.05); specifically
the inhibition rate of tumor was higher in the cisplatin group than the PYKA Decoction group (
P
<
0.05)
and significantly higher in the PYKA Decoction-cisplatin group
compared with that of PYKA Decoction group or cisplatin group. Compared with the model group
the number of autophagic vesicles increased significantly in cisplatin group
PYKA Decoction group and PYKA Decoction-cisplatin group
suggesting that autophagy was enhanced. Compared with PYKA Decoction group
the expression of LC3Ⅱ/ LC3Ⅰ was higher in the cisplatin group and PYKA Decoction-cisplatin group (
P
<
0.05)
with that in the PYKA Decoction-cisplatin group being the highest(
P
<
0.05). Compared with the model group
there was no significant difference in the expression of PI3K/AKT /mTOR in the tumor tissues of the treatment groups (
P
>
0.05). The expression levels of p-PI3K/p-AKT/p-mTOR in the tumor tissues of the treatment groups were significantly lower than that of the model group (
P
<
0.05); compared with that of the PYKA Decoction group
the expression of p-PI3K/p-AKT/p-mTOR in cisplatin group and PYKA Decoction-cisplatin group was lower (
P
<
0.05)
with that in PYKA Decoction-cisplatin group being the lowest(
P
<
0.05).
Conclusion
2
PYKA Decoction could potentially improve the quality of life of mice and inhibit tumor growth and metastasis. The mechanism may be related to the inhibition of PI3K-AKT-mTOR signaling pathway and enhancement of tumor autophagy.
Lewis肺癌培元抗癌汤自噬PI3K-AKT-mTOR信号通路小鼠
Lewis lung carcinomaPeiyuan Kang’ai (Healthy qi-supplementing Anti-cancer) DecoctionautophagyPI3K-AKT-mTOR pathwaymice
JMM Levy,CG Towers, A Thorburn. Targeting autophagy in cancer[J].Nature Reviews Cancer, 2017,17(9):528–542. DOI:10.1038/nrc.2017.53http://doi.org/10.1038/nrc.2017.53.
B Levine, G Kroemer.Biological functions of autophagy genes:adisease perspective[J].Cell, 2019,176:11-42.
CM Dower, CA Wills, SM Frisch, et al. Mechanisms and context underlying the role of autophagy in cancer metastasis[J/OL].Autophagy,2018,14(7):1110-1128[2021-01-10].https://doi.org/10.1080/15548627.2018.1450020http://doi.org/10.1080/15548627.2018.1450020.
CG Towers,D Wodetzki,A Thorburn. Autophagy and cancer: modulation of cell death pathways and cancer cell adaptations[J/OL].The Journal of Cell Biology, 2019[2021-01-10].http://doi.org/10.1083/jcb.201909033http://doi.org/10.1083/jcb.201909033.
YH Wang, HX Xiong, DL Liu,et al. Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells[J/OL].Autophagy, 2019[2021-01-10].https://doi.org/10.1080/15548627.2019.1569912http://doi.org/10.1080/15548627.2019.1569912.
T Monkkonen, J Debnath. Inflammatory signaling cascades and autophagy in cancer[J/OL].Autophagy,2017[2021-01-10].http://dx.doi.org/10.1080/15548627.2017.1345412http://doi.org/10.1080/15548627.2017.1345412.
XL Gu, WY Guo, YJ Zhao, et al. Deoxynivalenol-induced cytotoxicity and apoptosis in IPEC-J2 cells through the activation of autophagy by inhibiting PI3K-AKT-mTOR signaling pathway[J].Acs Omega, 2019,4(19):18478-18486.DOI: 10.1021/acsomega.9b03208http://doi.org/10.1021/acsomega.9b03208.
S Li, YL Zhan, YW Xie, et al. The impact of icariside Ⅱ on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway[J].Drug Design, Development and Therapy, 2020(14):4169-4178.
郑荣寿,孙可欣,张思维,等.2015年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志,2019, 41(1): 19-28.
RS Zheng, KX Sun, SW Zhang, et al. Report of cancer epidemiology in China,2015[J].Chinese Journal of Oncology,2019,41(1):19-28.
千维娜,李治,李仁廷,等. 培元抗癌汤对人乳腺癌MDA-MB-231细胞裸鼠移植瘤生长及细胞凋亡的影响 [J].广西医学,2020, 42(15):1989-1994.
WN Qian, Z Li, RT Li, et al.Effect of peiyuan anticancer decoction on growth and apoptosis of human breast cancer MDA-MB-231 cell xenograft in nude mice[J].Guangxi Medical Journal, 2020,42(15):1989-1994.
李仁廷,范秋丽. 培元抗癌汤联合FOLFOX4方案化疗治疗中晚期肝癌临床研究 [J].辽宁中医杂志,2013, 40(1):92-93.
RT Li, QL Fan. Clinical research on peiyuan kang'ai decoction combined with FOLFOX4 scheme chemotherapy for advanced liver cancer[J].Liaoning Journal of Traditional Chinese Medicine, 2013,40(1):92-93.
LB Frankel, M Lubas, AH Lund. Emerging connections between RNA and autophagy[J/OL].Autophagy,2016,13(1)[2021-01-10].http://dx.doi.org/10.1080/15548627.2016.1222992http://doi.org/10.1080/15548627.2016.1222992.
SJ Chung, GJ Purnachandra Nagaraju, A Nagalingam, et al.ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis[J/OL].Autophagy, 2017,13(8)[2021-01-10].https://doi.org/10.1080/15548627.2017.1332565http://doi.org/10.1080/15548627.2017.1332565.
C Liang, J Xu, QC Meng, et al. TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status[J/OL].Autophagy,2020,16(3):486–500[2021-01-10].https://doi.org/10.1080/15548627.2019.1628540http://doi.org/10.1080/15548627.2019.1628540.
Y Sun, YH Huang, FY Huang, et al. 3′-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/AKT/mTOR axis in lung cancer cells[J].Theranostics, 2018,8(7):2044-2060.
王硕,廖文宇,程权,等. 香草扶正合剂对Lewis肺癌模型小鼠癌细胞自噬的影响 [J].浙江中医药大学学报,2020, 44(12): 1152-1159.
S Wang, WY Liao, Q Cheng,et al.Effect of xiangcao fuzheng mixture on autophagy of Lewis lung cancer mice[J].Journal of Zhejiang Chinese Medical University, 2020,44(12):1152-1159.
王程燕,焦丽静,赵蓓,等. 芪冬宁方通过调控自噬抑制肺癌细胞生长的分子机制研究 [J].上海中医药杂志,2020, 54(11): 64-70.
CY Wang, LJ Jiao, B Zhao, et al.Study on molecular mechanism of qidongning Formula ( QDF) suppressing lung cancer cells proliferation by regulating autophagy[J].Shanghai Journal of Traditional Chinese Medicine,2020,54(11):64-70.
张云珍,邵松军,余红,等. 白藜芦醇对非小细胞肺癌细胞自噬和凋亡的影响 [J].中国癌症防治杂志,2018, 10(6): 439-443.
YZ Zhang, SJ Shao, H Yu, et al.Effect of resveratrol on autophagy and apoptosis of non-small cell lung cancer cells[J].Chin J of Oncol Prev and Treat,2018,10(6):439-443.
E Taioli, R Yip, I Olkin, et al. Survival after sublobar resection for early-stage lung cancer: methodological obstacles in comparing the efficacy to lobectomy[J].Journal of Thoracic Oncology,2016,11(3):400-406.
B Yang, J Sun, Y Yuan, et al. Effects of atorvastatin on autophagy in skeletal muscles of diabetic rats[J].Journal of Diabetes Investigation, 2018,9(4):753–761.
YH Zhang, J Zhang, JN Song, et al. The PI3K-AKT-mTOR pathway activates recovery from general anesthesia[J].Oncotarget, 2016,7(27):40939-40952.
Q Shao, Z Zhang, R Cao, et al. CPA4 Promotes EMT in pancreatic cancer via stimulating PI3K-AKT-mTOR signaling[J].Onco Targets and Therapy,2020(13):8567-8580.
D Fan, Q Liu, F Wu, et al. Prognostic significance of PI3K/AKT/ mTOR signaling pathway members in clear cell renal cell carcinoma[J/OL].PeerJ,2020(8):e9261[2021-01-10].http://doi.org/10.7717/peerj.9261http://doi.org/10.7717/peerj.9261.
0
浏览量
17
下载量
4
CSCD
关联资源
相关文章
相关作者
相关机构