Abstract
Gliomas are the most common and lethal primary tumors of the central nervous system (CNS). Despite current rigorous treatment protocols, effect of chemotherapy has failed to improve patient outcome significantly. Curcumin is a potent antioxidant that possesses both anti-inflammatory and anti-tumor activities, can suppress the initiation, promotion, and metastasis of different tumors. Its anti-tumor properties in various cancer models and negligible toxicity in normal cells make it a promising chemotherapeutic candidate. But the effect and the molecular mechanism of curcumin on gliomas are still recognized limitedly. The goal of the study is to elucidate the inhibitory effect and possible mechanisms of curcumin on glioma. After the treatment of curcumin, glioma cells U251 growth in vitro were significantly inhibited in a dose-dependent manner, and the low dose of curcumin induced G2/M cell cycle arrest. The high dose of curcumin not only enhanced G2/M cell cycle arrest, but also induced S phase of cell cycle arrest. But no obvious pre-G1 peak was observed at the different doses of curcumin. Genome DNA electrophoresis further confirmed that no DNA ladder was formed after the treatment of curcumin in U251 cells. Results of Western blot analysis demonstrated that ING4 expression was almost undetectable in U251 cells, but significantly up-regulated during cell cycle arrest induced by curcumin, and p53 expression was up-regulated followed by induction of p21WAF−1/CIP−1 and ING4. The results demonstrate that curcumin exerts inhibitory action on glioma cell growth and proliferation via induction of cell cycle arrest instead of induction of apoptosis in a p53-dependent manner, and ING4 possibly is in part involved in the signal pathways.
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Abbreviations
- ING:
-
Inhibitor of growth
- CNS:
-
The central nervous system
- GBM:
-
Glioblastoma multiforme
References
Maher EA, Furnari FB, Bachoo RM,Rowitch DH,Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a gravematter. Genes Dev 15:1311–1333
Norden AD, Wen PY (2006) Glioma therapy in adults. Neurologist 12(6):279–292
Ahsan H, Parveen N, Khan NU, Hadi SM (1999) Pro-oxidant, antioxidant and cleavage activities on DNA of curcumin and derivatives demethoxycurcumin and isdeme- thoxycurcumin. Chem-Biol Inter 121:161–175
Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398
Han SS, Keum YS, Seo HJ, Surh YJ (2002) Curcumin suppresses activation of NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells. J Biochem Mol Biol 31:337–342
Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB (1999) Curcumin blocks cytokine-mediated NF-B activation and proinflammatory gene expression by inhibiting inhibitory factor I-B kinase activity. J Immunol 163:3474–3483
Ambegaokar SS, Wu L, Alamshahi K, Lau J, Jazayeri L, Chan S, Khanna P, Hsieh E, Timiras PS (2003) Curcumin inhibits dose-dependently and time-dependently neuroglial cell proliferation and growth. Neuro Endocrinol Lett. 24(6):469–473
Woo MS, Jung SH, Kim SY, Hyun JW, Ko KH, Kim WK, Kim HS (2005) Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochem Biophys Res Commun 335(4):1017–1025
Jiang H, Deng CS, Zhang M, Xia J (2006) Curcumin-attenuated trinitrobenzene sulphonic acid induces chronic colitis by inhibiting expression of cyclooxygenase-2. World J Gastroenterol 12(24):3848–3853
Kim SY, Jung SH, Kim HS (2005) Curcumin is a potent broad spectrum inhibitor of matrix metalloproteinase gene expression in human astroglioma cells. Biochem Biophys Res Commun 337(2):510–516
Su CC, Chen GW, Lin JG, Wu LT, Chung JG (2006) Curcumin inhibits cell migration of human colon cancer colo 205 cells through the inhibition of nuclear factor kappa B/p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2 expressions. Anticancer Res 26(2A):1281–1288
Lee KW, Kim JH, Lee HJ, Surh YJ (2005) Curcumin inhibits phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human breast epithelial cells. Antioxid Redox Signal. 7(11–12):1612–1620
Shi X, Gozani O (2005) The fellowships of the INGs. J Cell Biochem 96:1127–1136
Gong W, Suzuki K, Russell M, Riabowol K (2005) Function of the ING family of PHD proteins in cancer. Int J Biochem Cell Biol 37(5):1054–1065
Campos EI, Chin MY, Kuo WH, Li G (2004). Biological functions of the ING family tumor suppressors. Cell Mol Life Sci 61(19–20):2597–2613
Nagashima M, Shiseki M, Miura K, Hagiwara K, Linke SP, Pedeux R, Wang XW, Yokota J, Riabowol K, Harris CC (2001) DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53. Proc Natl Acad Sci USA 98(17):9671–9676
Feng X, Hara Y, Riabowol K (2002) Different HATS of the ING1 gene family. Trends Cell Biol 12(11):532–538
Zhu Z, Lin J, Qu JH, Feitelson MA, Ni CR, Li FM, Zhu MH (2005) Inhibitory effect of tumor suppressor p33(ING1b) and its synergy with p53 gene in hepatocellular carcinoma. World J Gastroenterol 11(13):1903–1909
Goeman F, Thormeyer D, Abad M, Serrano M, Schmidt O, Palmero I, Baniahmad A (2005) Growth inhibition by the tumor suppressor p33ING1 in immortalized and primary cells: involvement of two silencing domains and effect of Ras. Mol Cell Biol 25(1):422–431
Nouman GS, Anderson JJ, Lunec J, Angus B (2003) The role of the tumour suppressor p33 ING1b in human neoplasia. J Clin Pathol 56(7):491–496
Wang Y, Wang J, Li G (2006) Leucine zipper like domain is required for tumor suppressor ING2-mediated nucleotide excision repair and apoptosis. FEBS Lett 580(16):3787–3793
Nagashima M, Shiseki M, Pedeux RM, Okamura S, Kitahama Shiseki M, Miura K, Yokota J, Harris CC (2003) A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis. Oncogene 22(3):343–350
Kim S, Chin K, Gray JW, Bishop JM (2004) A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer. Proc Natl Acad Sci USA 101(46):16251–16256
Gunduz M, Nagatsuka H, Demircan K, Gunduz E, Cengiz B, Ouchida M, Tsujigiwa H, Yamachika E, Fukushima K, Beder L, Hirohata S, Ninomiya Y, Nishizaki K, Shimizu K, Nagai N (2005) Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas. Gene 356:109–117
Garkavtsev I, Kozin SV, Chernova O, Xu L, Winkler F, Brown E, Barnett GH, Jain RK (2004) The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 428(6980):328–332
Zhang X, Xu LS, Wang ZQ, Wang KS, Li N, Cheng ZH, Huang SZ, Wei DZ, Han ZG (2004) ING4 induces G2/M cell cycle arrest and enhances the chemosensitivity to DNA-damage agents in HepG2 cells. FEBS Lett 570(1–3):7–12
Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Henry E, Dicato M, Diederich M (2005) Chemopreventive and therapeutic effects of curcumin. Cancer Lett 223(2):181–190
Moragoda L, Jaszewski R, Majumdar AP (2001) Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res 21(2A):873–878
Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. (2002) Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 62(13):3868–3875
Manson MM, Farmer PB, Gescher A, Steward WP (2005) Innovative agents in cancer prevention. Recent-Results-Cancer-Res 166:257–275
Karunagaran D, Rashmi R, Kumar TR (2005) Induction of apoptosis by curcumin and its implications for cancer therapy. Curr Cancer Drug Targets 5(2):117–129
Hong JH, Ahn KS, Bae E, Jeon SS, Choi HY (2006) The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo. Prostate Cancer Prostatic Dis 9(2):147–152
Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23(1A):363–398
Ambegaokar SS, Wu L, Alamshahi K, Lau J, Jazayeri L, Chan S, Khanna P, Hsieh E, Timiras PS (2003) Curcumin inhibits dose-dependently and time-dependently neuroglial cell proliferation and growth. Neuro Endocrinol Lett 24(6):469–473
Kim SY, Jung SH, Kim HS (2005) Curcumin is a potent broad spectrum inhibitor of matrix metalloproteinase gene expression in human astroglioma cells. Biochem Biophys Res Commun 337(2):510–516
Kim GY, Kim KH, Lee SH, Yoon MS, Lee HJ, Moon DO, Lee CM, Ahn SC, Park YC, Park YM (2005) Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J Immunol 174(12):8116–8124
Bharti AC, Takada Y, Aggarwal BB (2004) Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. J Immunol 172(10):5940–5947
Nagai S, Kurimoto M, Washiyama K, Hirashima Y, Kumanishi T, Endo S (2005) Inhibition of cellular proliferation and induction of apoptosis by curcumin in human malignant astrocytoma cell lines. J Neurooncol 74(2):105–111
Kang SK, Cha SH, Jeon HG (2006) Curcumin induced histone hypoacetylation enhances caspase-3 dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev 15(2):165–174
Nourani A, Howe L, Pray Grant MG, Workman JL, Grant PA, Cote J (2003) Opposite role of yeast ING family members in p53 dependent transcriptional activation. J Biol Chem 278(21):19171–19175
Garkavtsev I, Boucher Y (2005) An intact ING1-P53 pathway can potentiate the cytotoxic effects of taxol. Cancer Biol Ther 4(1):48–49
Tachibana M, Kawamata H, Fujimori T, Omotehara F, Horiuchi H, Ohkura Y, Igarashi S, Kotake K, Kubota K (2004) Dysfunction of p53 pathway in human colorectal cancer: analysis of p53 gene mutation and the expression of the p53-associated factors p14ARF, p33ING1, p21WAF1 and MDM2. Int J Oncol 25(4):913–920
Shiseki M, Nagashima M, Pedeux RM, Kitahama Shiseki M, Miura K, Okamura S, Onogi H, Higashimoto Y, Appella E, Yokota J, Harris CC (2003) p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res 63(10):2373–2378
Kim S (2005) HuntING4 new tumor suppressors. Cell Cycle 4(4):516–517
Zhang X, Wang KS, Wang ZQ, Xu LS, Wang QW, Chen F, Wei DZ, Han ZG (2005) Nuclear localization signal of ING4 plays a key role in its binding to p53. Biochem-Biophys Res Commun 331(4):1032–1038
Motoko U, Jiang CS, Zhi-Ming Z, Curtis CH (2006) Novel splice variants of ING4 and their possible roles in the regulation of cell growth and motility. J Biol Chem 281(45):34677–34686
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Liu, E., Wu, J., Cao, W. et al. Curcumin induces G2/M cell cycle arrest in a p53-dependent manner and upregulates ING4 expression in human glioma. J Neurooncol 85, 263–270 (2007). https://doi.org/10.1007/s11060-007-9421-4
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DOI: https://doi.org/10.1007/s11060-007-9421-4