Swainsonine inhibits growth and potentiates the cytotoxic effect of paclitaxel in hepatocellular carcinoma in vitro and in vivo

You,Nan; Liu,Weihui; Wang,Tao; Ji,Ru; Wang,Xing; Gong,Zhenbing; Dou,Kefeng; Tao,Kaishan

doi:10.3892/or.2012.2035

Swainsonine inhibits growth and potentiates the cytotoxic effect of paclitaxel in hepatocellular carcinoma in vitro and in vivo

Authors:
- Nan You
- Weihui Liu
- Tao Wang
- Ru Ji
- Xing Wang
- Zhenbing Gong
- Kefeng Dou
- Kaishan Tao
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, P.R. China
Published online on: September 17, 2012 https://doi.org/10.3892/or.2012.2035
Pages: 2091-2100

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

Swainsonine, an extract from Astragalus membranaceus, exhibits broad inhibition of growth and pro-apoptotic activity in a number of tumor types. However, the underlying mechanism involved remains unclear. To investigate the effects and mechanisms of swainsonine on hepatocellular carcinoma (HCC), we performed experiments on HepG2, SMCC7721, Huh7 and MHCC97-H human hepatoma and HL-7702 human hepatocyte cells. We observed that swainsonine significantly inhibited the viability of human hepatoma cells in a dose- and time-dependent manner, but did not affect human hepatocytes. Due to their highly proliferative and tumorigenic nature, we selected MHCC97-H cells as a model system to examine. Swainsonine significantly inhibited MHCC97-H cell growth by causing cell cycle arrest at the G0/G1 phase and the induction of apoptosis. Blockage of G0/G1 phase was accompanied by a decrease in cyclins (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4) and an increase in the Cdk inhibitors p21 and p27. Furthermore, swainsonine enhanced the apoptosis of MHCC97-H cells with the induction of the upregulation of Bax and the downregulation of Bcl-2, whereas the expressionof Fas and Fas-L remained almost unchanged. These changes were accompanied by the enhanced cytoplasmic accumulation of nuclear factor κB (NF-κB) with a concomitant decrease in the nuclear fraction. Importantly, swainsonine also potentiated the cytotoxic effects of paclitaxel in vitro and in vivo, in part, by restricting the paclitaxel-induced nuclear accumulation of NF-κB. Taken together, these results suggest that swainsonine may be an important agent against HCC via directly inhibiting HCC cell growth and enhancing the responsiveness of HCC cells to paclitaxel.

View Figures

View References

1	Lin H, van den Esschert J, Liu C and van Gulik TM: Systematic review of hepatocellular adenoma in China and other regions. J Gastroenterol Hepatol. 26:28–35. 2011. View Article : Google Scholar : PubMed/NCBI
2	Villanueva A and Llovet JM: Targeted therapies for hepatocellular carcinoma. Gastroenterology. 140:1410–1426. 2011. View Article : Google Scholar : PubMed/NCBI
3	Yang JD and Roberts LR: Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 7:448–458. 2010. View Article : Google Scholar : PubMed/NCBI
4	Sanoff HK, Bernard S, Goldberg RM, et al: Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma. Gastrointest Cancer Res. 4:8–83. 2011.PubMed/NCBI
5	Okano J, Nagahara T, Matsumoto K and Murawaki Y: The growth inhibition of liver cancer cells by paclitaxel and the involvement of extracellular signal-regulated kinase and apoptosis. Oncol Rep. 17:1195–1200. 2007.PubMed/NCBI
6	Caicedo-Granados EE, Wuertz BR, Marker PH, Lee GS and Ondrey FG: The effect of indomethacin on paclitaxel sensitivity and apoptosis in oral squamous carcinoma cells: the role of nuclear factor-κB inhibition. Arch Otolaryngol Head Neck Surg. 137:799–805. 2011.PubMed/NCBI
7	Sreekanth CN, Bava SV, Sreekumar E and Anto RJ: Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer. Oncogene. 30:3139–3152. 2011. View Article : Google Scholar : PubMed/NCBI
8	Kelly MG, Alvero AB, Chen R, et al: TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 66:3859–3868. 2006. View Article : Google Scholar : PubMed/NCBI
9	Baines AT, Xu D and Der CJ: Inhibition of Ras for cancer treatment: the search continues. Future Med Chem. 3:1787–1808. 2011. View Article : Google Scholar : PubMed/NCBI
10	Stronach EA, Chen M, Maginn EN, Agarwal R, Mills GB, Wasan H and Gabra H: DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance. Neoplasia. 13:1069–1080. 2011.PubMed/NCBI
11	Luedde T and Schwabe RF: NF-κB in the liver - linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 8:108–118. 2011.
12	Luqman S and Pezzuto JM: NFkappaB: a promising target for natural products in cancer chemoprevention. Phytother Res. 24:949–963. 2010.PubMed/NCBI
13	Nogueira L, Ruiz-Ontañon P, Vazquez-Barquero A, Moris F and Fernandez-Luna JL: The NFκB pathway: a therapeutic target in glioblastoma. Oncotarget. 2:646–653. 2011.
14	Goss PE, Baptiste J, Fernandes B, Baker M and Dennis JW: A phase I study of swainsonine in patients with advanced malignancies. Cancer Res. 54:1450–1457. 1994.PubMed/NCBI
15	Santos FM, Latorre AO, Hueza IM, Sanches DS, Lippi LL, Gardner DR and Spinosa HS: Increased antitumor efficacy by the combined administration of swainsonine and cisplatin in vivo. Phytomedicine. 18:1096–1101. 2011. View Article : Google Scholar : PubMed/NCBI
16	Sun JY, Yang H, Miao S, et al: Suppressive effects of swainsonine on C6 glioma cell in vitro and in vivo. Phytomedicine. 16:1070–1074. 2009. View Article : Google Scholar : PubMed/NCBI
17	You N, Liu W, Zhong X, et al: Tg737 inhibition results in malignant transformation in fetal liver stem/progenitor cells by promoting cell-cycle progression and differentiation arrest. Mol Carcinog. 51:659–673. 2012. View Article : Google Scholar : PubMed/NCBI
18	Alves RC, Alves D, Guz B, et al: Advanced hepatocellular carcinoma. Review of targeted molecular drugs. Ann Hepatol. 10:21–27. 2011.PubMed/NCBI
19	Karikas GA: Anticancer and chemopreventing natural products: some biochemical and therapeutic aspects. J BUON. 15:627–638. 2010.PubMed/NCBI
20	Tulsiani DR and Touster O: Swainsonine, a potent mannosidase inhibitor, elevates rat liver and brain lysosomal alpha-D-mannosidase, decreases Golgi alpha-D-mannosidase II, and increases the plasma levels of several acid hydrolases. Arch Biochem Biophys. 224:594–600. 1983. View Article : Google Scholar
21	van den Elsen JM, Kuntz DA and Rose DR: Structure of Golgi alpha-mannosidase II: a target for inhibition of growth and metastasis of cancer cells. EMBO J. 20:3008–3017. 2001.PubMed/NCBI
22	Shaheen PE, Stadler W, Elson P, Knox J, Winquist E and Bukowski RM: Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma. Invest New Drugs. 23:577–581. 2005. View Article : Google Scholar : PubMed/NCBI
23	Yanagida K, Natsuka S and Hase S: Structural diversity of cytosolic free oligosaccharides in the human hepatoma cell line, HepG2. Glycobiology. 16:294–304. 2006. View Article : Google Scholar : PubMed/NCBI
24	Yeo TK, Yeo KT, Parent JB and Olden K: Swainsonine treatment accelerates intracellular transport and secretion of glycoproteins in human hepatoma cells. J Biol Chem. 260:2565–2569. 1985.PubMed/NCBI
25	Williams GH and Stoeber K: The cell cycle and cancer. J Pathol. 226:352–364. 2012. View Article : Google Scholar
26	Fang J, Yu Z, Lian M, Ma H, Tai J, Zhang L and Han D: Knockdown of zinc finger protein, X-linked (ZFX) inhibits cell proliferation and induces apoptosis in human laryngeal squamous cell carcinoma. Mol Cell Biochem. 360:301–307. 2012. View Article : Google Scholar : PubMed/NCBI
27	Hu W, Shen T and Wang MH: Cell cycle arrest and apoptosis induced by methyl 3,5-dicaffeoyl quinate in human colon cancer cells: Involvement of the PI3K/Akt and MAP kinase pathways. Chem Biol Interact. 194:48–57. 2011. View Article : Google Scholar : PubMed/NCBI
28	Palumbo C, Bei R, Procopio A and Modesti A: Molecular targets and targeted therapies for malignant mesothelioma. Curr Med Chem. 15:855–867. 2008. View Article : Google Scholar : PubMed/NCBI
29	Rahbari NN, Mehrabi A, Mollberg NM, Müller SA, Koch M, Büchler MW and Weitz J: Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 253:453–469. 2011. View Article : Google Scholar : PubMed/NCBI
30	Johansson M and Persson JL: Cancer therapy: targeting cell cycle regulators. Anticancer Agents Med Chem. 8:723–731. 2008. View Article : Google Scholar : PubMed/NCBI
31	Chang HR, Lian JD, Lo CW, Chang YC, Yang MY and Wang CJ: Induction of urothelial proliferation in rats by aristolochic acid through cell cycle progression via activation of cyclin D1/cdk4 and cyclin E/cdk2. Food Chem Toxicol. 44:28–35. 2006. View Article : Google Scholar : PubMed/NCBI
32	Chen K, Perez-Stable C, D’Ippolito G, Schiller PC, Roos BA and Howard GA: Human bone marrow-derived stem cell proliferation is inhibited by hepatocyte growth factor via increasing the cell cycle inhibitors p53, p21 and p27. Bone. 49:1194–1204. 2011. View Article : Google Scholar : PubMed/NCBI
33	Sayers TJ: Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunol Immunother. 60:1173–1180. 2011. View Article : Google Scholar : PubMed/NCBI
34	Chowdhury I, Tharakan B and Bhat GK: Current concepts in apoptosis: the physiological suicide program revisited. Cell Mol Biol Lett. 11:506–525. 2006. View Article : Google Scholar : PubMed/NCBI
35	He G and Karin M: NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res. 21:159–168. 2011.
36	Deeb D, Gao X, Dulchavsky SA and Gautam SC: CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NF-kappaB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. J Exp Ther Oncol. 7:31–39. 2008.
37	Ma Y, Wang J, Liu L, et al: Genistein potentiates the effect of arsenic trioxide against human hepatocellular carcinoma: role of Akt and nuclear factor-κB. Cancer Lett. 301:75–84. 2011.PubMed/NCBI
38	Matsubara J, Shimada Y, Kato K, et al: Phase II study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel as first-line therapy for advanced gastric cancer. Oncology. 81:291–297. 2011. View Article : Google Scholar : PubMed/NCBI
39	Fujiwara Y, Furukawa K, Shimada Y, et al: Combination paclitaxel and inhibitor of nuclear factor κB activation improves therapeutic outcome for model mice with peritoneal dissemination of pancreatic cancer. Pancreas. 40:600–607. 2011.
40	Pasqualetti G, Ricciardi S, Mey V, Del Tacca M and Danesi R: Synergistic cytotoxicity, inhibition of signal transduction pathways and pharmacogenetics of sorafenib and gemcitabine in human NSCLC cell lines. Lung Cancer. 74:197–205. 2011. View Article : Google Scholar : PubMed/NCBI