Pseudolaric acid B inhibits the secretion of hepatitis B virus

Yu,Jinghua; Wang,Zengyan; Ren,Peiyou; Zhong,Ting; Wang,Yue; Song,Fengmei; Hou,Jingwei; Yu,Xiaoyan; Hua,Shucheng

doi:10.3892/or.2016.5254

Pseudolaric acid B inhibits the secretion of hepatitis B virus

Authors:
- Jinghua Yu
- Zengyan Wang
- Peiyou Ren
- Ting Zhong
- Yue Wang
- Fengmei Song
- Jingwei Hou
- Xiaoyan Yu
- Shucheng Hua
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Affiliations: Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China, Department of Internal Medicine, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China, Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China, Medicinal Chemistry, College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130000, P.R. China, Chemistry of Traditional Chinese Medicine, College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130000, P.R. China, Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin Univrsity, Changhun, Jilin 130021, P.R. China
Published online on: November 16, 2016 https://doi.org/10.3892/or.2016.5254
Pages: 519-525

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Abstract

High hepatitis B virus (HBV) load and chronic hepatitis B infection increase the risk of developing hepatocellular carcinoma (HCC), and is also associated with recurrence of HBV-related HCC. The aim of the present study was to investigate whether pseudolaric acid B (PAB), a diterpene acid isolated from the root and trunk bark of Pseudolarix kaempferi Gordon (Pinaceae), has an inhibitory role on the HBV secretion in HBV-related HCC. By detecting HBV surface antigen (HBsAg) by ELISA it was found that PAB inhibited HBV secretion in HepG2215 compared to control group, but did not decrease the intracellular HBV level, and the results were repeated in HepG2 cell transfect with HBV gene. Therefore, our results proved that PAB had the ability to inhibit HBV secretion. Moreover, it was shown that HepG2215 cells with HBV gene accumulated more in G0/G1 phase than HepG2 cells without HBV gene through detecting cell cycle distribution by flow cytometry, which indicated that HBV replication might favor the cell cycle environment of G0/G1 phase. However, HepG2 cells entered G2/M phase earlier than HepG2215 when PAB treatment induced G2/M arrest, therefore, HBV retarded the entry of G2/M to sustain the status of G0/G1 phase, while PAB finally changed the cell cycle environment favored by HBV virus. In addition, PAB also induced HepG2215 cell apoptosis, which would be helpful to kill the cells infected by HBV and help for devouring HBV by macrophage. Therefore, PAB inhibited HBV secretion through apoptosis and cell cycle arrest. The present findings contribute to a future potential chemotherapeutic drug in the treatment of HBV-related HCC.

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1	Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, et al: Adefovir Dipivoxil 438 Study Group: Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 131:1743–1751. 2006. View Article : Google Scholar : PubMed/NCBI
2	Sangiovanni A, Del Ninno E, Fasani P, De Fazio C, Ronchi G, Romeo R, Morabito A, De Franchis R and Colombo M: Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 126:1005–1014. 2004. View Article : Google Scholar : PubMed/NCBI
3	Bruix J and Sherman M: Practice Guidelines Committee, American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma. Hepatology. 42:1208–1236. 2005. View Article : Google Scholar : PubMed/NCBI
4	Sherman M: Recurrence of hepatocellular carcinoma. N Engl J Med. 359:2045–2047. 2008. View Article : Google Scholar : PubMed/NCBI
5	Newman DJ, Cragg GM and Snader KM: Natural products as sources of new drugs over the period 1981–2002. J Nat Prod. 66:1022–1037. 2003. View Article : Google Scholar : PubMed/NCBI
6	Breinbauer R, Vetter IR and Waldmann H: From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed Engl. 41:2879–2890. 2002. View Article : Google Scholar : PubMed/NCBI
7	Mann J: Natural products in cancer chemotherapy: Past, present and future. Nat Rev Cancer. 2:143–148. 2002. View Article : Google Scholar : PubMed/NCBI
8	Zhou BN, Ying BP, Song GQ, Chen ZX, Han J and Yan YF: Pseudolaric acids from Pseudolarix kaempferi. Planta Med. 47:35–38. 1983. View Article : Google Scholar : PubMed/NCBI
9	Gong X, Wang M, Tashiro S, Onodera S and Ikejima T: Involvement of JNK-initiated p53 accumulation and phosphorylation of p53 in pseudolaric acid B induced cell death. Exp Mol Med. 38:428–434. 2006. View Article : Google Scholar : PubMed/NCBI
10	Gong XF, Wang MW, Tashiro S, Onodera S and Ikejima T: Pseudolaric acid B induces apoptosis through p53 and Bax/Bcl-2 pathways in human melanoma A375-S2 cells. Arch Pharm Res. 28:68–72. 2005. View Article : Google Scholar : PubMed/NCBI
11	Yu J, Li X, Tashiro S, Onodera S and Ikejima T: Bcl-2 family proteins were involved in pseudolaric acid B-induced autophagy in murine fibrosarcoma L929 cells. J Pharmacol Sci. 107:295–302. 2008. View Article : Google Scholar : PubMed/NCBI
12	Yu JH, Cui Q, Jiang YY, Yang W, Tashiro S, Onodera S and Ikejima T: Pseudolaric acid B induces apoptosis, senescence, and mitotic arrest in human breast cancer MCF-7. Acta Pharmacol Sin. 28:1975–1983. 2007. View Article : Google Scholar : PubMed/NCBI
13	Yu JH, Wang HJ, Li XR, Tashiro S, Onodera S and Ikejima T: Protein tyrosine kinase, JNK, and ERK involvement in pseudolaric acid B-induced apoptosis of human breast cancer MCF-7 cells. Acta Pharmacol Sin. 29:1069–1076. 2008. View Article : Google Scholar : PubMed/NCBI
14	Ma G, Chong L, Li XC, Khan IA, Walker LA and Khan SI: Selective inhibition of human leukemia cell growth and induction of cell cycle arrest and apoptosis by pseudolaric acid B. J Cancer Res Clin Oncol. 136:1333–1340. 2010. View Article : Google Scholar : PubMed/NCBI
15	Xu R, Zhang X, Zhang W, Fang Y, Zheng S and Yu XF: Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B × antigen mutants and hepatocellular carcinoma. Hepatology. 46:1810–1820. 2007. View Article : Google Scholar : PubMed/NCBI
16	Yu J, Zhang L, Ren P, Zhong T, Li Z, Wang Z, Li J, Liu X, Zhao K, Zhang W, et al: Enterovirus 71 mediates cell cycle arrest in S phase through non-structural protein 3D. Cell Cycle. 14:425–436. 2015. View Article : Google Scholar : PubMed/NCBI
17	Sciorati C, Rigamonti E, Manfredi AA and Rovere-Querini P: Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ. 23:927–937. 2016. View Article : Google Scholar : PubMed/NCBI
18	Khan M, Zheng B, Yi F, Rasul A, Gu Z, Li T, Gao H, Qazi JI, Yang H and Ma T: Pseudolaric Acid B induces caspase-dependent and caspase-independent apoptosis in u87 glioblastoma cells. Evid Based Complement Alternat Med. 2012:9575682012. View Article : Google Scholar : PubMed/NCBI
19	Wong VK, Chiu P, Chung SS, Chow LM, Zhao YZ, Yang BB and Ko BC: Pseudolaric acid B, a novel microtubule-destabilizing agent that circumvents multidrug resistance phenotype and exhibits antitumor activity in vivo. Clin Cancer Res. 11:6002–6011. 2005. View Article : Google Scholar : PubMed/NCBI
20	Sells MA, Chen ML and Acs G: Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc Natl Acad Sci USA. 84:1005–1009. 1987. View Article : Google Scholar : PubMed/NCBI
21	Ding XR, Yang J, Sun DC, Lou SK and Wang SQ: Whole genome expression profiling of hepatitis B virus-transfected cell line reveals the potential targets of anti-HBV drugs. Pharmacogenomics J. 8:61–70. 2008. View Article : Google Scholar : PubMed/NCBI
22	Li GQ, Xu WZ, Wang JX, Deng WW, Li D and Gu HX: Combination of small interfering RNA and lamivudine on inhibition of human B virus replication in HepG2.2.15 cells. World J Gastroenterol. 13:2324–2327. 2007. View Article : Google Scholar : PubMed/NCBI
23	Xin XM, Li GQ, Guan XR, Li D, Xu WZ, Jin YY and Gu HX: Combination therapy of siRNAs mediates greater suppression on hepatitis B virus cccDNA in HepG2.2.15 cell. Hepatogastroenterology. 55:2178–2183. 2008.PubMed/NCBI
24	DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsilio E, Paucha E and Livingston DM: SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell. 54:275–283. 1988. View Article : Google Scholar : PubMed/NCBI
25	Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB and Livingston DM: Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 8:869–884. 1994. View Article : Google Scholar : PubMed/NCBI
26	Howe JA, Mymryk JS, Egan C, Branton PE and Bayley ST: Retinoblastoma growth suppressor and a 300-kDa protein appear to regulate cellular DNA synthesis. Proc Natl Acad Sci USA. 87:5883–5887. 1990. View Article : Google Scholar : PubMed/NCBI
27	Werness BA, Levine AJ and Howley PM: Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 248:76–79. 1990. View Article : Google Scholar : PubMed/NCBI
28	Flemington EK: Herpesvirus lytic replication and the cell cycle: Arresting new developments. J Virol. 75:4475–4481. 2001. View Article : Google Scholar : PubMed/NCBI
29	Goh WC, Rogel ME, Kinsey CM, Michael SF, Fultz PN, Nowak MA, Hahn BH and Emerman M: HIV-1 Vpr increases viral expression by manipulation of the cell cycle: A mechanism for selection of Vpr in vivo. Nat Med. 4:65–71. 1998. View Article : Google Scholar : PubMed/NCBI
30	He J, Choe S, Walker R, Di Marzio P, Morgan DO and Landau NR: Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J Virol. 69:6705–6711. 1995.PubMed/NCBI
31	Dove B, Brooks G, Bicknell K, Wurm T and Hiscox JA: Cell cycle perturbations induced by infection with the coronavirus infectious bronchitis virus and their effect on virus replication. J Virol. 80:4147–4156. 2006. View Article : Google Scholar : PubMed/NCBI
32	Li FQ, Tam JP and Liu DX: Cell cycle arrest and apoptosis induced by the coronavirus infectious bronchitis virus in the absence of p53. Virology. 365:435–445. 2007. View Article : Google Scholar : PubMed/NCBI
33	Wang T, Zhao R, Wu Y, Kong D, Zhang L, Wu D, Li C, Zhang C, Yu Z and Jin X: Hepatitis B virus induces G1 phase arrest by regulating cell cycle genes in HepG2.2.15 cells. Virol J. 8:2312011. View Article : Google Scholar : PubMed/NCBI
34	Tong YG, Zhang XW, Geng MY, Yue JM, Xin XL, Tian F, Shen X, Tong LJ, Li MH, Zhang C, et al: Pseudolarix acid B, a new tubulin-binding agent, inhibits angiogenesis by interacting with a novel binding site on tubulin. Mol Pharmacol. 69:1226–1233. 2006. View Article : Google Scholar : PubMed/NCBI