All Title Author
Keywords Abstract

PLOS ONE  2012 

Pristimerin Causes G1 Arrest, Induces Apoptosis, and Enhances the Chemosensitivity to Gemcitabine in Pancreatic Cancer Cells

DOI: 10.1371/journal.pone.0043826

Full-Text   Cite this paper   Add to My Lib

Abstract:

Despite rapid advances in chemotherapy and surgical resection strategies, pancreatic cancer remains the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 5%. Therefore, novel therapeutic agents for the prevention and treatment of pancreatic cancer are urgently needed. The aim of this study was to investigate the effect of pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, on inhibition of cell proliferation and induction of apoptosis in three pancreatic cancer cells, BxPC-3, PANC-1 and AsPC-1, in both monotherapy and in combination with gemcitabine. Treatment with pristimerin decreased the cell proliferation of all three pancreatic cancer cells in a dose- and time-dependent manner. Treatment of pancreatic cancer cells with pristimerin also resulted in G1-phase arrest which was strongly associated with a marked decrease in the level of cyclins (D1 and E) and cyclin-dependent kinases (cdk2, cdk4 and cdk6 ) with concomitant induction of WAF1/p21 and KIP1/p27. Pristimerin treatment also resulted in apoptotic cell death, cleavage of caspase-3, modulation in the expressions of Bcl-2 family proteins, inhibition of the translocation and DNA-binding activity of NF-κB. In addition, pristimerin potentiated the growth inhibition and apoptosis inducing effects of gemcitabine in all three pancreatic cancer cells, at least in part, by inhibiting constitutive as well as gemcitabine-induced activation of NF-κB in both its DNA-binding activity and transcriptional activity. Taken together, these data provide the first evidence that pristimerin has strong potential for development as a novel agent against pancreatic cancer.

References

[1]  Wang SJ, Gao Y, Chen H, Kong R, Jiang HC, et al. (2010) Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. Cancer Lett 293: 99–108.
[2]  Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60: 277–300.
[3]  Duffy JP, Eibl G, Reber HA, Hines OJ (2003) Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer 2: 12.
[4]  Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15: 2403–2413.
[5]  Maitra A, Hruban RH (2008) Pancreatic cancer. Annu Rev Pathol 3: 157–188.
[6]  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: 2351–2362.
[7]  Liptay S, Weber CK, Ludwig L, Wagner M, Adler G, et al. (2003) Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer. Int J Cancer 105: 735–746.
[8]  Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, et al. (2010) NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 295: 214–228.
[9]  Weichert W, Boehm M, Gekeler V, Bahra M, Langrehr J, et al. (2007) High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer 97: 523–530.
[10]  Greten FR, Weber CK, Greten TF, Schneider G, Wagner M, et al. (2002) Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology 123: 2052–2063.
[11]  Kornmann M, Ishiwata T, Itakura J, Tangvoranuntakul P, Beger HG, et al. (1998) Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival. Oncology 55: 363–369.
[12]  Xiong HQ, Abbruzzese JL, Lin E, Wang L, Zheng L, et al. (2004) NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int J Cancer 108: 181–188.
[13]  Fujioka S, Sclabas GM, Schmidt C, Frederick WA, Dong QG, et al. (2003) Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 9: 346–354.
[14]  Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6: 203–208.
[15]  Arlt A, Gehrz A, Müerk?ster S, Vorndamm J, Kruse ML, et al. (2003) Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 22: 3243–3251.
[16]  Dirsch VM, Kiemer AK, Wagner H, Vollmar AM (1997) The triterpenoid quinonemethide pristimerin inhibits induction of inducible nitric oxide synthase in murine macrophages. Eur J Pharmacol 336: 211–217.
[17]  Wu CC, Chan ML, Chen WY, Tsai CY, Chang FR, et al. (2005) Pristimerin induces caspase-dependent apoptosis in MDA-MB-231 cells via direct effects on mitochondria. Mol Cancer Ther 4: 1277–1285.
[18]  Yang H, Landis-Piwowar KR, Lu D, Yuan P, Li L, et al. (2008) Pristimerin induces apoptosis by targeting the proteasome in prostate cancer cells. J Cell Biochem 103: 234–244.
[19]  Byun JY, Kim MJ, Eum DY, Yoon CH, Seo WD, et al. (2009) Reactive oxygen species-dependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells. Mol Pharmacol 76: 734–744.
[20]  Tiedemann RE, Schmidt J, Keats JJ, Shi CX, Zhu YX, et al. (2009) Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo. Blood 113: 4027–4037.
[21]  Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70: 440–446.
[22]  Wang YW, Wang SJ, Zhou YN, Pan SH, Sun B (2012) 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. J Cancer Res Clin Oncol 138: 785–797.
[23]  Call JA, Eckhardt SG, Camidge DR (2008) Targeted manipulation of apoptosis in cancer treatment. Lancet Oncol 9: 1002–1011.
[24]  Molinari M (2000) Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif 33: 261–274.
[25]  Nakanishi M, Shimada M, Niida H (2006) Genetic instability in cancer cells by impaired cell cycle checkpoints. Cancer Sci 97: 984–989.
[26]  Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, et al. (1999) The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev 20: 501–534.
[27]  Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18: 2699–2711.
[28]  Sherr CJ (1996) Cancer cell cycles. Science 274: 1672–1677.
[29]  Gupta S, Afaq F, Mukhtar H (2002) Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene 21: 3727–3738.
[30]  Pucci B, Kasten M, Giordano A (2000) Cell cycle and apoptosis. Neoplasia 2: 291–299.
[31]  Swanton C (2004) Cell-cycle targeted therapies. Lancet Oncol 5: 27–36.
[32]  Llambi F, Green DR (2011) Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr Opin Genet Dev 21: 12–20.
[33]  Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 122: 437–441.
[34]  Yip KW, Reed JC (2008) Bcl-2 family proteins and cancer. Oncogene 27: 6398–6406.
[35]  Srivastava SK, Singh SV (2004) Cell cycle arrest, apoptosis induction and inhibition of nuclear factor kappa B activation in anti-proliferative activity of benzyl isothiocyanate against human pancreatic cancer cells. Carcinogenesis 25: 1701–1709.
[36]  Arora S, Bhardwaj A, Srivastava SK, Singh S, McClellan S, et al. (2011) Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS One 6: e21573.
[37]  Jutooru I, Chadalapaka G, Lei P, Safe S (2010) Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem 285: 25332–25344.
[38]  Chen H, Sun B, Wang S, Pan S, Gao Y, et al. (2010) Growth inhibitory effects of dihydroartemisinin on pancreatic cancer cells: involvement of cell cycle arrest and inactivation of nuclear factor-kappaB. J Cancer Res Clin Oncol 136: 897–903.
[39]  Murtaza I, Adhami VM, Hafeez BB, Saleem M, Mukhtar H (2009) Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int J Cancer 125: 2465–2473.
[40]  Neumann M, Naumann M (2007) Beyond IkappaBs: alternative regulation of NF-kappaB activity. FASEB J 21: 2642–2654.
[41]  Gilmore TD (2006) Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25: 6680–6684.
[42]  Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, et al. (2008) Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res 14: 8143–8151.
[43]  Sliva D (2004) Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr Cancer Drug Targets 4: 327–336.
[44]  Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, et al. (2003) NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22: 90–97.

Full-Text

comments powered by Disqus