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Molecular Cancer
Published in: Molecular Cancer 1/2008

Open Access 01-12-2008 | Research

Curcumin sensitizes TRAIL-resistant xenografts: molecular mechanisms of apoptosis, metastasis and angiogenesis

Authors: Sharmila Shankar, Suthakar Ganapathy, Qinghe Chen, Rakesh K Srivastava

Published in: Molecular Cancer | Issue 1/2008

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Abstract

Background

We have recently shown that curcumin (a diferuloylmethane, the yellow pigment in turmeric) enhances apoptosis-inducing potential of TRAIL in prostate cancer PC-3 cells, and sensitizes TRAIL-resistant LNCaP cells in vitro through multiple mechanisms. The objectives of this study were to investigate the molecular mechanisms by which curcumin sensitized TRAIL-resistant LNCaP xenografts in vivo.

Methods

Prostate cancer TRAIL-resistant LNCaP cells were implanted in Balb c nude mice to examine the effects of curcumin and/or TRAIL on tumor growth and genes related to apoptosis, metastasis and angiogenesis.

Results

Curcumin inhibited growth of LNCaP xenografts in nude mice by inducing apoptosis (TUNEL staining) and inhibiting proliferation (PCNA and Ki67 staining), and sensitized these tumors to undergo apoptosis by TRAIL. In xenogrfated tumors, curcumin upregulated the expression of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibited the activation of NFκB and its gene products such as cyclin D1, VEGF, uPA, MMP-2, MMP-9, Bcl-2 and Bcl-XL. The regulation of death receptors and members of Bcl-2 family, and inactivation of NFκB may sensitize TRAIL-resistant LNCaP xenografts. Curcumin also inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells in mice.

Conclusion

The ability of curcumin to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that curcumin alone or in combination with TRAIL can be used for prostate cancer prevention and/or therapy.
Appendix
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Literature
1.
Hahn WC, Weinberg RA: Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002, 2: 331-341.CrossRefPubMed
2.
Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih IeM, Vogelstein B, Lengauer C: The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA. 2002, 99: 16226-16231.PubMedCentralCrossRefPubMed
3.
Artandi SE, DePinho RA: Mice without telomerase: what can they teach us about human cancer?. Nat Med. 2000, 6: 852-855.CrossRefPubMed
4.
5.
6.
7.
Aggarwal BB, Sundaram C, Malani N, Ichikawa H: Curcumin: the Indian solid gold. Adv Exp Med Biol. 2007, 595: 1-75.CrossRefPubMed
8.
Plummer SM, Hill KA, Festing MF, Steward WP, Gescher AJ, Sharma RA: Clinical development of leukocyte cyclooxygenase 2 activity as a systemic biomarker for cancer chemopreventive agents. Cancer Epidemiol Biomarkers Prev. 2001, 10: 1295-1299.PubMed
9.
Singh S, Khar A: Biological effects of curcumin and its role in cancer chemoprevention and therapy. Anticancer Agents Med Chem. 2006, 6: 259-270.CrossRefPubMed
10.
Bae MK, Kim SH, Jeong JW, Lee YM, Kim HS, Kim SR, Yun I, Bae SK, Kim KW: Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1. Oncol Rep. 2006, 15: 1557-1562.PubMed
11.
Yoysungnoen P, Wirachwong P, Bhattarakosol P, Niimi H, Patumraj S: Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice. Clin Hemorheol Microcirc. 2006, 34: 109-115.PubMed
12.
Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN, Kamat AA, Spannuth WA, Gershenson DM, Lutgendorf SK: Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res. 2007, 13: 3423-3430.CrossRefPubMed
13.
Shankar S, Srivastava RK: Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa. Carcinogenesis. 2007, 28: 1277-1286.CrossRefPubMed
14.
Shankar S, Srivastava RK: Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. Int J Oncol. 2007, 30: 905-918.PubMed
15.
16.
Baldwin AS: The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996, 14: 649-683.CrossRefPubMed
17.
Ghosh S, May MJ, Kopp EB: NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998, 16: 225-260.CrossRefPubMed
18.
19.
Divya CS, Pillai MR: Antitumor action of curcumin in human papillomavirus associated cells involves downregulation of viral oncogenes, prevention of NFkB and AP-1 translocation, and modulation of apoptosis. Mol Carcinog. 2006, 45: 320-332.CrossRefPubMed
20.
Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB: 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. 2007, 67: 3853-3861.CrossRefPubMed
21.
Kamat AM, Sethi G, Aggarwal BB: Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-kappaB and nuclear factor-kappaB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells. Mol Cancer Ther. 2007, 6: 1022-1030.CrossRefPubMed
22.
Chirnomas D, Taniguchi T, de la Vega M, Vaidya AP, Vasserman M, Hartman AR, Kennedy R, Foster R, Mahoney J, Seiden MV, D'Andrea AD: Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther. 2006, 5: 952-961.CrossRefPubMed
23.
HemaIswarya S, Doble M: Potential synergism of natural products in the treatment of cancer. Phytother Res. 2006, 20: 239-249.CrossRefPubMed
24.
Du B, Jiang L, Xia Q, Zhong L: Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. Chemotherapy. 2006, 52: 23-28.CrossRefPubMed
25.
Wahl H, Tan L, Griffith K, Choi M, Liu JR: Curcumin enhances Apo2L/TRAIL-induced apoptosis in chemoresistant ovarian cancer cells. Gynecol Oncol. 2007, 105: 104-112.CrossRefPubMed
26.
Ashkenazi A, Dixit VM: Apoptosis control by death and decoy receptors. Curr Opin Cell Biol. 1999, 11: 255-260.CrossRefPubMed
27.
Shankar S, Chen X, Srivastava RK: Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo. Prostate. 2005, 62: 165-186.CrossRefPubMed
28.
Shankar S, Singh TR, Srivastava RK: Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: Intracellular mechanisms. Prostate. 2004, 61: 35-49.CrossRefPubMed
29.
Shankar S, Srivastava RK: Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Updat. 2004, 7: 139-156.CrossRefPubMed
30.
31.
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A: Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999, 104: 155-162.PubMedCentralCrossRefPubMed
32.
Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N, Srivastava RK: Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene. 2001, 20: 6073-6083.CrossRefPubMed
33.
Deeb DD, Jiang H, Gao X, Divine G, Dulchavsky SA, Gautam SC: Chemosensitization of hormone-refractory prostate cancer cells by curcumin to TRAIL-induced apoptosis. J Exp Ther Oncol. 2005, 5: 81-91.PubMed
34.
Jung EM, Park JW, Choi KS, Park JW, Lee HI, Lee KS, Kwon TK: Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through CHOP-independent DR5 upregulation. Carcinogenesis. 2006
35.
Shankar S, Chen Q, Sarva K, Siddiqui I, Srivastava RK: Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signal. 2007, 2: 10-PubMedCentralCrossRefPubMed
36.
Rothwarf DM, Karin M: The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE. 1999, 1999: RE1-PubMed
37.
38.
39.
Suh J, Rabson AB: NF-kappaB activation in human prostate cancer: important mediator or epiphenomenon?. J Cell Biochem. 2004, 91: 100-117.CrossRefPubMed
40.
Madsen MA, Deryugina EI, Niessen S, Cravatt BF, Quigley JP: Activity-based protein profiling implicates urokinase activation as a key step in human fibrosarcoma intravasation. J Biol Chem. 2006, 281: 15997-16005.CrossRefPubMed
41.
42.
Deryugina EI, Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006, 25: 9-34.CrossRefPubMed
43.
Shenouda NS, Zhou C, Browning JD, Ansell PJ, Sakla MS, Lubahn DB, Macdonald RS: Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro. Nutr Cancer. 2004, 49: 200-208.CrossRefPubMed
44.
Aggarwal BB, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G: Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. Biochem Pharmacol. 2007, 73: 1024-1032.CrossRefPubMed
45.
Srivastava RK, Chen Q, Siddiqui I, Shankar S: Mechanisms of cell cycle regulation by curcumin in prostate cancer. Front Biosci. 2007
46.
Srivastava RK, Chen Q, Siddiqui I, Sarva K, Shankar S: Linkage of curcumin-induced cell cycle arrest and apoptosis by cyclin-dependent kinase inhibitor p21/WAF1/CIP1. Cell Cycle. 2007
47.
Spruck CH, Won KA, Reed SI: Deregulated cyclin E induces chromosome instability. Nature. 1999, 401: 297-300.CrossRefPubMed
48.
Haas K, Johannes C, Geisen C, Schmidt T, Karsunky H, Blass-Kampmann S, Obe G, Moroy T: Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4. Oncogene. 1997, 15: 2615-2623.CrossRefPubMed
49.
Rosen DG, Yang G, Deavers MT, Malpica A, Kavanagh JJ, Mills GB, Liu J: Cyclin E expression is correlated with tumor progression and predicts a poor prognosis in patients with ovarian carcinoma. Cancer. 2006, 106: 1925-1932.CrossRefPubMed
50.
Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, Bedrosian I, Knickerbocker C, Toyofuku W, Lowe M: Cyclin E and survival in patients with breast cancer. N Engl J Med. 2002, 347: 1566-1575.CrossRefPubMed
51.
Singh TR, Shankar S, Chen X, Asim M, Srivastava RK: Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. Cancer Res. 2003, 63: 5390-5400.PubMed
52.
Singh TR, Shankar S, Srivastava RK: HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene. 2005, 24: 4609-4623.CrossRefPubMed
53.
Shankar S, Chen Q, Siddiqui I, Sarva K, Srivastava RK: Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4', 5 tri-hydroxystilbene): molecular mechanisms and therapeutic potential. J Mol Signal. 2007, 2: 7-PubMedCentralCrossRefPubMed
54.
Shankar S, Ganapathy S, Hingorani SR, Srivastava RK: EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Front Biosci. 2008, 13: 440-452.CrossRefPubMed
55.
Shankar S, Siddiqui I, Srivastava RK: Molecular mechanisms of resveratrol (3, 4, 5-trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. Mol Cell Biochem. 2007
56.
Shankar S, Singh G, Srivastava RK: Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci. 2007, 12: 4839-4854.CrossRefPubMed
57.
Shankar S, Singh TR, Chen X, Thakkar H, Firnin J, Srivastava RK: The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. Int J Oncol. 2004, 24: 1133-1140.PubMed
58.
Shankar S, Singh TR, Fandy TE, Luetrakul T, Ross DD, Srivastava RK: Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: Involvement of both death receptor and mitochondrial pathways. Int J Mol Med. 2005, 16: 1125-1138.PubMed
59.
Chen X, Kandasamy K, Srivastava RK: Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 2003, 63: 1059-1066.PubMed
60.
Takimoto R, El-Deiry WS: Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene. 2000, 19: 1735-1743.CrossRefPubMed
61.
Wu GS, Burns TF, McDonald ER, Meng RD, Kao G, Muschel R, Yen T, el-Deiry WS: Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene. 1999, 18: 6411-6418.CrossRefPubMed
62.
Yoshida T, Maeda A, Tani N, Sakai T: Promoter structure and transcription initiation sites of the human death receptor 5/TRAIL-R2 gene. FEBS Lett. 2001, 507: 381-385.CrossRefPubMed
63.
64.
Liu X, Yue P, Khuri FR, Sun SY: p53 upregulates death receptor 4 expression through an intronic p53 binding site. Cancer Res. 2004, 64: 5078-5083.CrossRefPubMed
65.
Wang S, El-Deiry WS: Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res. 2004, 64: 6666-6672.CrossRefPubMed
66.
67.
Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB: Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol. 2006, 69: 195-206.PubMed
68.
Peant B, Diallo JS, Lessard L, Delvoye N, Le Page C, Saad F, Mes-Masson AM: Regulation of IkappaB kinase epsilon expression by the androgen receptor and the nuclear factor-kappaB transcription factor in prostate cancer. Mol Cancer Res. 2007, 5: 87-94.CrossRefPubMed
69.
70.
Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, Pirmohamed M, Marnett LJ, Gescher AJ, Steward WP: Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001, 7: 1894-1900.PubMed
71.
Kim EJ, Suliman A, Lam A, Srivastava RK: Failure of Bcl-2 to block mitochondrial dysfunction during TRAIL-induced apoptosis. Tumor necrosis-related apoptosis-inducing ligand. Int J Oncol. 2001, 18: 187-194.PubMed
Metadata
Title
Curcumin sensitizes TRAIL-resistant xenografts: molecular mechanisms of apoptosis, metastasis and angiogenesis
Authors
Sharmila Shankar
Suthakar Ganapathy
Qinghe Chen
Rakesh K Srivastava
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2008
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-7-16

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