Anesthetic effects of isoflurane and the molecular mechanism underlying isoflurane‑inhibited aggressiveness of hepatic carcinoma

Hu,Jing; Hu,Jingli; Jiao,Hongmei; Li,Qingguo

doi:10.3892/mmr.2018.8945

Anesthetic effects of isoflurane and the molecular mechanism underlying isoflurane‑inhibited aggressiveness of hepatic carcinoma

Authors:
- Jing Hu
- Jingli Hu
- Hongmei Jiao
- Qingguo Li
View Affiliations

Affiliations: Department of Anesthesiology, Linyi Cancer Hospital, Linyi, Shandong 276001, P.R. China
Published online on: May 2, 2018 https://doi.org/10.3892/mmr.2018.8945
Pages: 184-192
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Anesthesia is produced by drugs or other methods, and refers to the attenuation of pain via reversible suppression of neuronal transmission in the central and peripheral nervous systems, during surgery. Clinical investigations have indicated that the anesthetic action of isoflurane is efficient to alleviate pain during tumor resection clinical trials. In addition, it has been reported that isoflurane can induce caspase‑3 activation and is associated with apoptosis of tumor cells. The present study investigated the anesthetic effects and molecular mechanisms underlying isoflurane‑induced apoptosis in patients with hepatic carcinoma. Furthermore, the pain of patients with hepatic carcinoma was evaluated during the perioperative period according to the pain index. The apoptotic rate of hepatic carcinoma cells was analyzed in tumor tissues using TUNEL assay. The expression levels of apoptosis‑associated proteins were detected in liver cancer cells following anesthesia in patients. Phosphoinositide 3‑kinase/protein kinase B (PI3K/AKT) and nuclear factor (NF)‑κB signaling pathways were also analyzed in liver cancer cells following treatment with isoflurane. The results demonstrated that isoflurane inhibited growth and decreased viability of liver cancer cells in vitro and in vivo. In addition, the apoptotic rate was increased in cells obtained from isoflurane‑treated patients. The results also demonstrated that isoflurane upregulated the expression levels of proapoptotic genes and downregulated anti‑apoptotic mRNA expression. In addition, a molecular mechanism analysis indicated that isoflurane inhibited PI3K and AKT expression in liver cancer cells. Isoflurane also induced caspase‑3 activation in liver cancer cells. Furthermore, isoflurane treatment attenuated NF‑κB activity and inhibited migration and invasion of liver cancer cells. In conclusion, these findings indicated that isoflurane treatment efficiently attenuated surgical pain and inhibited tumor aggressiveness via regulation of NF‑κB activity and the PI3K/AKT signaling pathway, thus suggesting that isoflurane is an efficient anesthetic drug that induces pain remission and promotes apoptosis of liver cancer cells.

View Figures

View References

1	Kao HK, Guo LF, Cheng MH, Chen IH, Liao CT, Fang KH, Yu JS and Chang KP: Predicting postoperative morbidity and mortality by model for endstage liver disease score for patients with head and neck cancer and liver cirrhosis. Head Neck. 33:529–534. 2011. View Article : Google Scholar : PubMed/NCBI
2	Menon KV, Hakeem AR and Heaton ND: Review article: Liver transplantation for hepatocellular carcinoma-a critical appraisal of the current worldwide listing criteria. Aliment Pharmacol Ther. 40:893–902. 2014. View Article : Google Scholar : PubMed/NCBI
3	Shariff MI, Cox IJ, Gomaa AI, Khan SA, Gedroyc W and Taylor-Robinson SD: Hepatocellular carcinoma: Current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Expert Rev Gastroenterol Hepatol. 3:353–367. 2009. View Article : Google Scholar : PubMed/NCBI
4	Philip-Ephraim EE, Eyong KI, Williams UE and Ephraim RP: The role of radiotherapy and chemotherapy in the treatment of primary adult high grade gliomas: Assessment of patients for these treatment approaches and the common immediate side effects. ISRN Oncol. 2012:9021782012.PubMed/NCBI
5	Bai P, Zhang R, Li XG, Ma SK, Wu LY and Zhang WH: Efficiency and side effects of concurrent radiotherapy and chemotherapy for advanced cervical cancers. Zhonghua Zhong Liu Za Zhi. 29:467–469. 2007.(In Chinese). PubMed/NCBI
6	Huang YH, Wu JC, Chen SC, Chen CH, Chiang JH, Huo TI, Lee PC, Chang FY and Lee SD: Survival benefit of transcatheter arterial chemoembolization in patients with hepatocellular carcinoma larger than 10 cm in diameter. Aliment Pharmacol Ther. 23:129–135. 2006. View Article : Google Scholar : PubMed/NCBI
7	Joseph JD, Peng Y, Mak DO, Cheung KH, Vais H, Foskett JK and Wei H: General anesthetic isoflurane modulates inositol 1,4,5-trisphosphate receptor calcium channel opening. Anesthesiology. 121:528–537. 2014. View Article : Google Scholar : PubMed/NCBI
8	Yu C, Luo YL, Xiao SS, Zhang Q and Chen SL: Influence of propofol and isoflurane on cytokines response to cancer surgery during perioperative period. Hua Xi Kou Qiang Yi Xue Za Zhi. 25:554–556. 2007.(In Chinese). PubMed/NCBI
9	Jiang J and Jiang H: Effect of the inhaled anesthetics isoflurane, sevoflurane and desflurane on the neuropathogenesis of Alzheimer's disease (review). Mol Med Rep. 12:3–12. 2015. View Article : Google Scholar : PubMed/NCBI
10	Liu TC: Influence of propofol, isoflurane and enflurance on levels of serum interleukin-8 and interleukin-10 in cancer patients. Asian Pac J Cancer Prev. 15:6703–6707. 2014. View Article : Google Scholar : PubMed/NCBI
11	Yang H, Deng J, Jiang Y, Chen J, Zeng X, He Z, Jiang X, Li Z and Jiang C: Emulsified isoflurane treatment inhibits the cell cycle and respiration of human bronchial epithelial 16HBE cells in a p53-independent manner. Mol Med Rep. 14:349–354. 2016. View Article : Google Scholar : PubMed/NCBI
12	Miura Y, Kamiya K, Kanazawa K, Okada M, Nakane M, Kumasaka A and Kawamae K: Superior recovery profiles of propofol-based regimen as compared to isoflurane-based regimen in patients undergoing craniotomy for primary brain tumor excision: A retrospective study. J Anesth. 26:721–727. 2012. View Article : Google Scholar : PubMed/NCBI
13	Lim KH and Counter CM: Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer cell. 8:381–392. 2005. View Article : Google Scholar : PubMed/NCBI
14	Shi LX, Wang JH and Shi XD: PI3K/AKT/mTOR Pathway and Pediatric T acute lymphoblastic leukemia-review. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 24:1269–1274. 2016.(In Chinese). PubMed/NCBI
15	Dey JH, Bianchi F, Voshol J, Bonenfant D, Oakeley EJ and Hynes NE: Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Res. 70:4151–4162. 2010. View Article : Google Scholar : PubMed/NCBI
16	Wang CM, Cai XL and Wen QP: Astaxanthin reduces isoflurane-induced neuroapoptosis via the PI3K/Akt pathway. Mol Med Rep. 13:4073–4078. 2016. View Article : Google Scholar : PubMed/NCBI
17	Zhao K, Song X, Huang Y, Yao J, Zhou M, Li Z, You Q, Guo Q and Lu N: Wogonin inhibits LPS-induced tumor angiogenesis via suppressing PI3K/Akt/NF-κB signaling. Eur J Pharmacol. 737:57–69. 2014. View Article : Google Scholar : PubMed/NCBI
18	Miao X and Zhao Y: ST6GalNAcII mediates tumor invasion through PI3K/Akt/NF-κB signaling pathway in follicular thyroid carcinoma. Oncol Rep. 35:2131–2140. 2016. View Article : Google Scholar : PubMed/NCBI
19	Al-Sobayil FA and Omer OH: Serum biochemical values of adult ostriches (Struthio camelus) anesthetized with xylazine, ketamine, and isoflurane. J Avian Med Surg. 25:97–101. 2011. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Nilsson U and Idvall E: Pain assessments in day surgery patients. J Clin Nurs. 19:2942–2943. 2010. View Article : Google Scholar : PubMed/NCBI
22	Zheng N, Wei X, Zhang D, Chai W, Che M, Wang J and Du B: Hepatic resection or transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus. Medicine (Baltimore). 95:e39592016. View Article : Google Scholar : PubMed/NCBI
23	Jia YS, Hu XQ, Gabriella H, Qin LJ and Meggyeshazi N: Antitumor activity of tenacissoside H on esophageal cancer through arresting cell cycle and regulating PI3K/Akt-NF-κB transduction cascade. Evid Based Complement Alternat Med. 2015:4649372015. View Article : Google Scholar : PubMed/NCBI
24	Simonetti RG, Cammà C, Fiorello F, Politi F, D'Amico G and Pagliaro L: Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci. 36:962–972. 1991. View Article : Google Scholar : PubMed/NCBI
25	Zidan A, Scheuerlein H, Schüle S, Settmacher U and Rauchfuss F: Epidemiological pattern of hepatitis B and hepatitis C as etiological agents for hepatocellular carcinoma in iran and worldwide. Hepat Mon. 12:e68942012.PubMed/NCBI
26	Marabelle A and Gray J: Tumor-targeted and immune-targeted monoclonal antibodies: Going from passive to active immunotherapy. Pediatr Blood Cancer. 62:1317–1325. 2015. View Article : Google Scholar : PubMed/NCBI
27	Nishimura Y, Tomita Y, Yuno A, Yoshitake Y and Shinohara M: Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. Cancer Sci. 106:505–511. 2015. View Article : Google Scholar : PubMed/NCBI
28	Huang H, Benzonana LL, Zhao H, Watts HR, Perry NJ, Bevan C, Brown R and Ma D: Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination. Br J Cancer. 111:1338–1349. 2014. View Article : Google Scholar : PubMed/NCBI
29	Luo X, Zhao H, Hennah L, Ning J, Liu J, Tu H and Ma D: Impact of isoflurane on malignant capability of ovarian cancer in vitro. Br J Anaesth. 114:831–839. 2015. View Article : Google Scholar : PubMed/NCBI
30	Zhang Y, Dong Y, Wu X, Lu Y, Xu Z, Knapp A, Yue Y, Xu T and Xie Z: The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem. 285:4025–4037. 2010. View Article : Google Scholar : PubMed/NCBI
31	Mu GG, Zhang LL, Li HY, Liao Y and Yu HG: Thymoquinone pretreatment overcomes the insensitivity and potentiates the antitumor effect of gemcitabine through abrogation of Notch1, PI3K/Akt/mTOR regulated signaling pathways in pancreatic cancer. Dig Dis Sci. 60:1067–1080. 2015. View Article : Google Scholar : PubMed/NCBI
32	Coco S, Truini A, Alama A, Dal Bello MG, Venè R, Garuti A, Carminati E, Rijavec E, Genova C, Barletta G, et al: Afatinib resistance in non-small cell lung cancer involves the PI3K/AKT and MAPK/ERK signalling pathways and epithelial-to-mesenchymal transition. Targeted Oncol. 10:393–404. 2015. View Article : Google Scholar
33	Yang Y, Zhang J, Zhu Y, Zhang Z, Sun H and Feng Y: Follicle-stimulating hormone induced epithelial-mesenchymal transition of epithelial ovarian cancer cells through follicle-stimulating hormone receptor PI3K/Akt-Snail signaling pathway. Int J Gynecol Cancer. 24:1564–1574. 2014. View Article : Google Scholar : PubMed/NCBI
34	Kang B, Hao C, Wang H, Zhang J, Xing R, Shao J, Li W, Xu N, Lu Y and Liu S: Evaluation of hepatic-metastasis risk of colorectal cancer upon the protein signature of PI3K/AKT pathway. J Proteome Res. 7:3507–3515. 2008. View Article : Google Scholar : PubMed/NCBI
35	Yan L and Shi G: Effect of IFN-α on hepatic cancer SMCC-7721 cell via PI3K/Akt signaling pathway and related mechanism research. Zhonghua Yi Xue Za Zhi. 95:2960–2963. 2015.(In Chinese). PubMed/NCBI
36	Sha M, Ye J, Zhang LX, Luan ZY, Chen YB and Huang JX: Celastrol induces apoptosis of gastric cancer cells by miR-21 inhibiting PI3K/Akt-NF-κB signaling pathway. Pharmacology. 93:39–46. 2014. View Article : Google Scholar : PubMed/NCBI
37	Rabi T, Huwiler A and Zangemeister-Wittke U: AMR-Me inhibits PI3K/Akt signaling in hormone-dependent MCF-7 breast cancer cells and inactivates NF-κB in hormone-independent MDA-MB-231 cells. Mol Carcinog. 53:578–588. 2014. View Article : Google Scholar : PubMed/NCBI
38	Li C, Li F, Zhao K, Yao J, Cheng Y, Zhao L, Li Z, Lu N and Guo Q: LFG-500 inhibits the invasion of cancer cells via down-regulation of PI3K/AKT/NF-κB signaling pathway. PloS One. 9:e913322014. View Article : Google Scholar : PubMed/NCBI
39	Dastjerdi MN, Babazadeh Z, Rabbani M, Gharagozloo M, Esmaeili A and Narimani M: Effects of disulfiram on apoptosis in PANC-1 human pancreatic cancer cell line. Res Pharm Sci. 9:287–294. 2014.PubMed/NCBI
40	Din Tengku TA, Seeni A, Khairi WN, Shamsuddin S and Jaafar H: Effects of rapamycin on cell apoptosis in MCF-7 human breast cancer cells. Asian Pac J Cancer Prev. 15:10659–10663. 2014.PubMed/NCBI
41	Russe OQ, Möser CV, Kynast KL, King TS, Olbrich K, Grösch S, Geisslinger G and Niederberger E: LPS inhibits caspase 3-dependent apoptosis in RAW264.7 macrophages induced by the AMPK activator AICAR. Biochem Biophys Res Commun. 447:520–525. 2014. View Article : Google Scholar : PubMed/NCBI
42	Mandal R, Raab M, Matthess Y, Becker S, Knecht R and Strebhardt K: Perk 1/2 inhibit Caspase-8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner. Mol Oncol. 8:232–249. 2014. View Article : Google Scholar : PubMed/NCBI
43	EI-Emshaty HM, Saad EA, Toson EA, Malak Abdel CA and Gadelhak NA: Apoptosis and cell proliferation: Correlation with BCL-2 and P53 oncoprotein expression in human hepatocellular carcinoma. Hepatogastroenterology. 61:1393–1401. 2014.PubMed/NCBI
44	Tsai CJ, Liu S, Hung CL, Jhong SR, Sung TC and Chiang YW: BAX-induced apoptosis can be initiated through a conformational selection mechanism. Structure. 23:139–148. 2015. View Article : Google Scholar : PubMed/NCBI