Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in pancreatic cancer both in vitro and in vivo
- 562 Downloads
Pancreatic cancer is an aggressive malignancy, which generally develops resistance to chemotherapy. Agents that are safe and can sensitize cancer to chemotherapy are urgently needed. Escin, a natural mixture of triterpene saponins isolated from Aesculus wilsonii Rehd, has been demonstrated to possess anti-cancer activity both in vitro and in vivo. The anti-cancer activity of escin could be, in part, due to the inactivation of nuclear factor-κB (NF-κB). In contrast, chemotherapy including gemcitabine could activate NF-κB and lead to chemoresistance. Here, for the first time, we investigated whether escin, via the inactivation of NF-κB, would potentiate the antitumor activity of gemcitabine in pancreatic cancer.
Cell viability and proliferation, apoptosis, NF-κB activity and the expression of NF-κB-linked genes were all examined in vitro. The antitumor effect of escin with or without gemcitabine in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice.
Escin not only potentiated the proliferation-inhibiting and apoptosis-inducing effect of gemcitabine in both BxPC-3 and PANC-1 cell lines in vitro, but also dramatically enhanced its suppressive effect on tumor growth in nude mice. The mechanism is at least partially due to the inhibition of NF-κB activity and consequent inhibition of c-Myc, COX-2, Cyclin D1, Survivin, Bcl-2 and Bcl-xL, and the activation of caspase-3.
These data suggest that escin, via inactivation of NF-κB, could potentiate the efficacy of gemcitabine in combating pancreatic cancer, which could be a novel and potentially important therapeutic approach for the treatment for pancreatic cancer.
KeywordsPancreatic cancer Escin Gemcitabine Nuclear factor-κB
- Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, Wang Z, Philip PA, Sarkar FH (2010) Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res 70:3606–3617PubMedCrossRefGoogle Scholar
- Bai J, Sui J, Demirjian A, Vollmer CM Jr, Marasco W, Callery MP (2005) Predominant Bcl- XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Cancer Res 65:2344–2352PubMedCrossRefGoogle Scholar
- Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 67:3853–3861PubMedCrossRefGoogle Scholar
- Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey S, Koca C, Yadav VR, Tong Z, Gelovani JG, Guha S, Krishnan S, Aggarwal BB (2010) γ-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment. Cancer Res 70:8695–8705PubMedCrossRefGoogle Scholar
- Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R (2004) Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer 101:2351–2362PubMedCrossRefGoogle Scholar
- Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, National Cancer Institute of Canada Clinical Trials Group (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
- Tan SM, Li F, Rajendran P, Kumar AP, Hui KM, Sethi G (2010) Identification of β-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J Pharmacol Exp Ther 334:285–293PubMedCrossRefGoogle Scholar
- Wang SJ, Sun B, Cheng ZX, Zhou HX, Gao Y, Kong R, Chen H, Jiang HC, Pan SH, Xue DB, Bai XW (2011b) Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-kappaB pathway. Cancer Chemother Pharmacol: Epub ahead of printGoogle Scholar