(+)-Episesamin exerts anti-neoplastic effects in human hepatocellular carcinoma cell lines via suppression of nuclear factor-kappa B and inhibition of MMP-9
- 323 Downloads
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Treatment options, especially in advanced tumor stages, are still limited. Inhibition of signaling cascades involved in the pathogenesis of HCC - such as NF-ĸB - offer a promising therapeutic approach. Aim of this study was to examine anti-neoplastic effects of (+)-episesamin which has been isolated from an anti-fibrotic extract of Lindera obtusiloba on human HCC cells with particular interest in activation of NF-κB. The human HCC cell lines HepG2, Huh-7 and SK-Hep1 were treated with (+)-episesamin. Beside measurement of proliferation, invasion and apoptosis, effects of (+)-episesamin on NF-κB-activity, VEGF secretion and enzymatic MMP-9 activity were determined. Anti-inflammatory effects were assessed by IL-6 ELISA using HCC cells and RAW264.7 macrophages. 10 μM (+)-episesamin reduced the proliferation of HCC cells by ~50%, suppressed invasion and induced apoptosis. DNA-binding ELISA experiments revealed that (+)-episesamin treated HCC cells showed a suppressed basal and TNFα-induced activation of NF-κB and a subsequent suppression of TNFα- and LPS-induced IL-6 production. Further, (+)-episesamin exhibited inhibitory effects on the enzymatic activity of recombinant MMP-9 and the secretion of MMP-9 and VEGF by HCC cells into their supernatants. Our findings show that anti-neoplastic effects of (+)-episesamin are mediated via suppressed activation of NF-κB which entails a decreased release of pro-inflammatory IL-6. In addition, (+)-episesamin inhibits MMP-9, which is strongly expressed in invasive HCC, and the production of proangiogenic VEGF. We conclude that (+)-episesamin has the potential to be further explored as a complementary treatment for HCC.
Keywords(+)-episesamin HCC NF-kappaB MMP-9 Lindera obtusiloba
This work was supported by the Collaborative Research Centers (SFB366 C5/C10) and (SFB633 Z1) from the Deutsche Forschungsgemeinschaft and the Berliner Sparkassenstiftung Medizin.
Declaration of interest
The authors declare that they have no conflict of interest.
- 3.Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10(1):25–34PubMedCrossRefGoogle Scholar
- 4.Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390PubMedCrossRefGoogle Scholar
- 8.Sato H, Kita M, Seiki M (1993) v-Src activates the expression of 92-kDa type IV collagenase gene through the AP-1 site and the GT box homologous to retinoblastoma control elements. A mechanism regulating gene expression independent of that by inflammatory cytokines. J Biol Chem 268(31):23460–23468PubMedGoogle Scholar
- 11.Ruehl M, Erben U, Kim K, Freise C, Dagdelen T, Eisele S, Trowitzsch-Kienast W, Zeitz M, Jia J, Stickel F, Somasundaram R (2009) Extracts of Lindera obtusiloba induce antifibrotic effects in hepatic stellate cells via suppression of a TGF-beta-mediated profibrotic gene expression pattern. J Nutr Biochem 20(8):597–606PubMedCrossRefGoogle Scholar
- 12.Freise C, Ruehl M, Erben U, Neumann U, Seehofer D, Kim KY, Trowitzsch-Kienast W, Stroh T, Zeitz M, Somasundaram R (2011) A hepatoprotective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines. BMC Complement Altern Med 11:39PubMedCrossRefGoogle Scholar
- 13.Trowitzsch-Kienast W, Ruehl M, Kim KY, Emmerling F, Erben U, Somasundaram R, Freise C (2011) Absolute configuration of antifibrotic (+)-episesamin isolated from Lindera obtusiloba BLUME. Z Naturforsch C 66c, #–# (in press)Google Scholar
- 22.Dalwadi H, Krysan K, Heuze-Vourc'h N, Dohadwala M, Elashoff D, Sharma S, Cacalano N, Lichtenstein A, Dubinett S (2005) Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin Cancer Res 11(21):7674–7682PubMedCrossRefGoogle Scholar
- 23.Calvisi DF, Pinna F, Ladu S, Pellegrino R, Muroni MR, Simile MM, Frau M, Tomasi ML, De Miglio MR, Seddaiu MA, Daino L, Sanna V, Feo F, Pascale RM (2008) Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. Carcinogenesis 29(8):1639–1647PubMedCrossRefGoogle Scholar
- 29.Shimada C, Ninomiya Y, Suzuki E, Umezawa K (2010) Efficient cellular uptake of the novel NF-kappaB inhibitor (−)-DHMEQ and irreversible inhibition of NF-kappaB in neoplastic cells. Oncol 18(11–12):529–535.Google Scholar