Inhibiting effect of apigenin on hepatocellar carcinoma xenografts in nude mice
GAO Aimei1 CHENG Xiaoli2
1.Department of Pharmacy, the Fifth People′s Hospital of Shanghai, Fudan University, Shanghai 200240, China;
2.Department of Pharmacy, Shenzhen Bao′an District Maternity and Child Health Care Hospital, Guangdong Province, Shenzhen 518133, China
Abstract:Objective To investigate the effect of apigenin (APG) on hepatocellar carcinoma xenografts in nude mice and the possible molecular mechanism. Methods Models of nude mice were transplanted with BEL-7402/doxorubicin (ADM), and randomly divided into 3 groups, each group had 8 mice. The groups of mice were treated i.p. as follow: ADM (3 mg/kg, control group), APG+ADM (50 mg/kg+3 mg/kg, APG group), miR-101 mimics +ADM (50 mg/kg+3 mg/kg, miR-101 mimics group), every three days for a total of seven times. The volumes of tumor were measured. After the end of medication, the mice were sacrificed for measurement of tumor weights. Tumor cell proliferation was analyzed by Ki-67 immunostaining. Nuclear factor erythroid-2-related factor 2 (Nrf2) protein level was measured by Western blot. miR-101 level was detected by Real-time PCR. Results The volumes and weights of tumors in APG group and miR-101 mimics group were decreased compared with the control group (P < 0.05). Compared to the control group, APG and miR-101 mimics resulted in inhibition of tumor cell proliferation (P < 0.05 or P < 0.01), inhibition of Nrf2 expression (P < 0.01), and up-regulation of miR-101 levels (P < 0.05). Conclusion APG can inhibit the growth of hepatocellar carcinoma, its mechanism may partly be to inhibit the expression of Ki-67 and Nrf2, up-regulate the level of miR-101.
[1] Shukla S,Maclennan GT,Fu P,et al. Apigenin Attenuates Insulin Like Growth Factor I Signaling in an Autochthonous Mouse Prostate Cancer Model [J]. Pharm Res,2012,29(6):1506-1517.
[2] Tong X,Pelling JC. Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention [J]. Anticancer Agents Med Chem,2013,13(7):971-978.
[3] Seo HS,Ku JM,Choi HS,et al. Apigeninovercomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells [J]. Oncol Rep,2017,38(2):715-724.
[4] Bao YY,Zhou SH,Fan J,et al. Anticancer mechanism of apigenin and the implications of GLUT-1 expression in head and neck cancers [J]. Future Oncol,2013,9(9):1353-1364.
[5] Lu HF,Chie YJ,Yang MS,et al. Apigenin induces caspase-dependent apoptosis in human lung cancer A549 cells through Bax- and Bcl-2-triggered mitochondrial pathway [J]. Int J Oncol,2010,36(6):1477-1484.
[6] Shukla S,Gupta S. Apigenin:a promising molecule for cancer prevention [J]. Pharm Res,2010,27(6):962-978.
[7] Bauer D,Redmon N,Mazzio E,et al. Apigenininhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells [J]. PLoS One,2017,12(4):e0175558.
[8] Salmani JMM,Zhang XP,Jacob JA,et al. Apigenin's anticancer properties and molecular mechanisms of action: Recent advances and future prospectives [J]. Chin J Nat Med,2017,15(5):321-329.
[9] Nabavi SM,Habtemariam S,Daglia M,et al. Apigeninand Breast Cancers: From Chemistry to Medicine [J]. Anticancer Agents Med Chem,2015,15(6):728-735.
[10] Bao YY,Zhou SH,Fan J,et al. Anticancer mechanism ofapigeninand the implications of GLUT-1 expression in head and neck cancers [J]. Future Oncol,2013,9(9):1353-1364.
[11] Gao AM,Ke ZP,Wang JN,et al. Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway [J]. Carcinogenesis,2013,34(8):1806-1814.
[12] Chen Y,Zhang L,Yang C,et al. Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma [J]. Bioorg Med Chem,2016,24(5):957-966.
[13] Chen X,Guo H,Li F,et al. Physcion 8-O-β-glucopyranoside suppresses the metastasis of breastcancerinvitro andin vivoby modulating DNMT1 [J]. Pharmacol Rep,2017, 69(1):36-44.
[14] Jain M,Zhang L,He M,et al. Interleukin-13 receptor alpha2 is a novel therapeutic target for human adrenocortical carcinoma [J]. Cancer,2012,118(22):5698-5708.
[15] Koleini N,Kardami E. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity [J]. Oncotarget,2017,8(28):46663-46680.
[16] Ni W,Chen B,Zhou G,et al. Overexpressed nuclear BAG-1 in human hepatocellular carcinoma is associated with poor prognosis andresistancetodoxorubicin [J]. J Cell Biochem,2013,114(9):2120-2130.
[17] Fisher G,Yang ZH,Kudahetti S,et al. Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort [J]. Br J Cancer,2013,108(2):271-277.
[18] Park SY,Piao Y,Thomas C,et al.Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma[J].Oncotarget,2016,7(18):26793-26805.
[19] Duregon E,Bertero L,Pittaro A,et al. Ki-67proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas [J]. Oncotarget,2016,7(16):21190-21198.
[20] May M,Burger M,Otto W,et al. Ki-67,mini-chromosome maintenance 2 protein(MCM2)and geminin have no independent prognostic relevance forcancer-specific survival in surgically treated squamous cell carcinoma of the penis [J]. BJU Int,2013,112(4):E383-E390.