Role mechanism of Metformin combined with Paclitaxel in inducing apoptosis of human breast cancer cell MCF-7
LIANG Junwei1 FANG Zhihua2 LI Qingshan1 LYU Xiying1
1.Department of Oncology, Affiliated Hospital of Chengde Medical College, Hebei Province, Chengde 067000, China;
2.Department of Thoracic and Abdominal Surgery, Chengde Third Hospital, Hebei Province, Chengde 067000, China
Abstract：Objective To explore the role mechanism of Metformin combined with Paclitaxel in inducing apoptosis of human breast cancer cell MCF-7. Methods CCK-8 kit was used to detect the 50% inhibitory concentration (IC50 value) of cell proliferation after 48 h of single action of different concentrations of Metformin (0.25, 0.50, 1.00, 2.00, 4.00 mmol/L) or Paclitaxel (0.025, 0.050, 0.100, 0.200, 0.400 μmol/L) or two combined action on MCF-7 cell. And the flow cytometry was used to detect the cell cycle distribution after 48 h action of Metformin or Paclitaxel on MCF-7 cell. And Western blot method was used to detect the expression levels of MAPK pathway protein and Bcl-2, Bax proteins after 48 h of single action of Paclitaxel or Metformin or two combined action on MCF-7 cell. Results Low concentration of Metformin (0.25-4.00 mmol/L) combined with Paclitaxel (0.025-0.400 μmol/L) had a synergistic effect (CI<1). sp600125 could significantly inhibite MCF-7 cell proliferation, and the inhibitory effect of MCF-7 cell proliferation by Metformin combined with Paclitaxel was stronger than that by single action of the two. The number of G2/M phase cells by combined action of Metformin and Paclitaxel were less than by single action of Paclitaxel, but more than by single action of Metformin. The expression levels of p-JNK/SAPK and p-p38 proteins after 48 h of Metformin combined with Paclitaxel on MCF-7 cell were significantly higher than those by single action of the two, and the expression levels of p-ERK and Bcl-2 proteins were decreased (P < 0.05). Conclusion Metformin combined with Paclitaxel has a synergistic effect on human breast cancer cell MCF-7, and its inhibitory effect on cells is significantly enhanced when combined with sp600125. Metformin combined with Paclitaxel can inhibit cell aggregation and ERK pathway in G2/M phase, activate JNK and p38 pathway, and reduce the ratio of Bcl-2 and Bax proteins.
梁君伟1 方志华2 李青山1 吕喜英1. 二甲双胍联合紫杉醇诱导人乳腺癌细胞MCF-7凋亡的作用机制研究[J]. 中国医药导报, 2018, 15(35): 17-21,25.
LIANG Junwei1 FANG Zhihua2 LI Qingshan1 LYU Xiying1. Role mechanism of Metformin combined with Paclitaxel in inducing apoptosis of human breast cancer cell MCF-7. 中国医药导报, 2018, 15(35): 17-21,25.
[1] 陈万青，郑荣寿．中国女性乳腺癌发病死亡和生存状况[J].中国肿瘤临床，2015，42（13）：668-674．
[2] 石建伟，唐智柳，蔡美玉，等．2008~2012年我国女性乳腺癌流行状况的系统性综述[J].中国妇幼保健，2014，29（10）：1622-1626．
[3] 张龙，王凤玮.紫杉醇用于乳腺癌治疗的应用进展[J].中国医药导报，2014，11（31）：167-168．
[4] 周寒丽，耿健雄，张华.二甲双胍抗肿瘤机制的研究进展[J].现代肿瘤医学，2015，23（12）：1760-1763．
[5] 郑亚，孙红.二甲双胍联合化疗药对妇科肿瘤的作用[J].现代妇产科进展，2016，25（11）：856-858.
[6] 吴婧，王宁菊，马吉光.MAPK蛋白在乳腺癌中的表达及其意义[J].宁夏医科大学学报，2014，36（7）：743-745.
[7] 郝磊，魏现娟，郝坤.p53及bcl-2蛋白在乳腺癌中表达的相关性研究[J].中国妇幼保健，2017，32（4）：695-697.
[8] Pusztai L，Krishnamurti S，Perez CJ，et al. Expression of BAG-1 and BcL-2 proteins before and after neoadjuvant chemotherapy of locally advanced breast cancer [J]. Cancer Invest，2015，22（2）：248-256.
[9] Noh KT，Cha GS，Kang TH，et al． Enhancement of paclitaxel-induced breast cancer cell death via the glycogen synthase kinase-3β-mediated B-cell lymphoma 2 regulation [J]. Bmb Rep，2016，49（1）：51-56.
[10] Akyol Z，?覶oker-Gürkan A，Arisan ED，et al. DENSpm overcame Bcl-2 mediated resistance against Paclitaxel treatment in MCF-7 breast cancer cells via activating polyamine catabolic machinery [J]. Biomed & Pharmacother，2016，84：2029-2041.
[11] 马骥，余惠云，刘颖，等．二甲双胍抗肿瘤效应的基础与临床研究进展[J].现代生物医学进展，2015，15（33）：6587-6589.
[12] Queiroz EAIF，Puukila S，Eichler R，et al． Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress，AMPK and FOXO3a in MCF-7 Breast Cancer Cells [J]. PLoS One，2014，9（5）：e98207.
[13] 赵松，杨金刚，李长岭，等．蛋白激酶A抑制剂H-89通过调节核糖体蛋白S6激酶1的磷酸化阻断SP600125诱导的CMK细胞多倍体化[J].细胞与分子免疫学杂志，2016，32（10）：1321-1326.
[14] Choi JE，Su HK，Lee SJ，et al． Prognostic significance of Bcl-2 expression in non-basal triple-negative breast cancer patients treated with anthracycline-based chemotherapy [J]. Tumor Biol，2014，35（12）：12 255-12 263.
[15] Chen L，Bourguignon LYW． Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells [J]. Mol Cancer，2014，13（1）：52.
[16] 王琼，王佑民，毋飞飞，等．JNK通路在高糖促人乳腺癌MCF-7细胞增殖中的作用[J].安徽医科大学学报，2014， 49（2）：149-154.
[17] Urrutia A，Rubio-Araiz A，Gutierrez-Lopez MD，et al. A study on the effect of JNK inhibitor，SP600125，on the disruption of blood-brain barrier induced by methamphetamine [J]. Neurobiol Dis，2013，50（1）：49.
[18] Jemaà M，Vitale I，Kepp O，et al． Selective killing of p53-deficient cancer cells by SP600125 [J]. Embo Mol Med，2012，4（6）：500.
[19] Si L，Zheng L，Xu L，et al． Dioscin suppresses human laryngeal cancer cells growth via induction of cell-cycle arrest and MAPK-mediated mitochondrial-derived apoptosis and inhibition of tumor invasion [J]. Eur J Pharmacol，2016，774（4）：105-117.
[20] 饶国洲，娄鸣，景娟，等．survivin和bcl-2双基因敲减对人舌癌裸鼠移植瘤的抑制作用[J].陕西医学杂志，2017， 46（2）：145-147.
2018, Vol. 15 
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