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Mechanism of inhibition of ascites tumor growth in mice by curcumin is mediated by NF-kB and caspase activated DNase

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Abstract

One of the most clinically relevant biological activities of curcumin is its anti-cancer property, implicating multiple intracellular pathways in the process. In the present report, we investigated the effect of curcumin on the activation of apoptotic and anti-angiogenic pathways in Ehrlich Ascites Tumor (EAT) cells. Treatment with curcumin in vivo resulted in inhibition of proliferation of EAT cells and ascites formation. Further, we demonstrate that the induction of apoptosis in EAT cells showed nuclear condensation, DNA fragmentation and translocation of caspase-activated DNase (CAD) to nucleus upon curcumin treatment. Curcumin-induced apoptosis is mediated through activation of caspase-3, which is specifically inhibited by the caspase-3 inhibitor, Ac-DEVD-CHO. On the other hand, the decreased secretion of ascites by EAT cells is corroborated by reduction in VEGF secretion upon curcumin treatment. Further, CD31 immunohistological staining of peritoneum sections in curcumin-treated mice suggests its efficacy in acting as anti-angiogenic compound in EAT cells by inhibiting proliferation of endothelial cells in mouse peritoneum. However, immunoflurescence studies of NF-kB revealed that the inhibition of nuclear translocation of NF-kB p65, a transcription factor required for VEGF gene expression, in curcumin-treated EAT cells. These results suggest a further possible clinical application of this diet-derived compound curcumin, as both proapoptotic and anti-angiogenic compound in association with conventional chemotherapeutic agents.

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Abbreviations

VEGF:

vascular endothelial cell growth factor

CAD:

caspase activated DNase

NF-kB:

Nuclear Factor kB

References

  1. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med 1: 27–31, 1995

    CAS  PubMed  Google Scholar 

  2. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364, 1996

    Article  CAS  PubMed  Google Scholar 

  3. Brem S: Angiogenesis and cancer control: From concept to therapeutic trials. Cancer Control 6: 436–458, 1999

    PubMed  Google Scholar 

  4. Boehm T, Folkman J, Browder T, O’ Reilly MS: Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390: 404–407, 1997

    Article  CAS  PubMed  Google Scholar 

  5. Pluda JM: Tumor-associated angiogenesis: Mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 24: 203–218, 1997

    CAS  PubMed  Google Scholar 

  6. Rak J, Kerbel RS: Treating cancer by inhibiting angiogenesis: New hopes and potential pitfalls. Cancer Metastasis Rev 15: 231–236, 1996

    Article  CAS  PubMed  Google Scholar 

  7. Taraboletti G, Margosio B: Antiangiogenic and antivascular therapy for cancer. Curr Opin Pharmacol 1: 378–384, 2001

    Article  CAS  PubMed  Google Scholar 

  8. Cao Y: Endogenous angiogenesis inhibitors and their therapeutic implications. Int J Biochem Cell Biol 33: 357–369, 2001

    Article  CAS  PubMed  Google Scholar 

  9. Min JK, Han KY, Kim EC, Kim YM, Lee SW, Kim OH, Kim KW, Gho YS, Kwon YG: Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res 64: 644–651, 2004

    CAS  PubMed  Google Scholar 

  10. You YJ, Nam NH, Kim Y, Bae KH, Ahn BZ: Antiangiogenic activity of lupeol from Bombax ceiba. Phytother Res 17: 341–344, 2003

    Article  CAS  PubMed  Google Scholar 

  11. Chow LM, Chui CH, Tang JC, Lau FY, Yau MY, Cheng GY, Wong RS, Lai PB, Leung TW, Teo IT, Cheung F, Guo D, Chan AS: Antiangiogenic potential of Gleditsia sinensis fruit extract. Int J Mol Med 12: 269–273, 2003

    CAS  PubMed  Google Scholar 

  12. 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 7: 1894–1900, 2001

    CAS  PubMed  Google Scholar 

  13. Stoner GD, Mukhtar H: Polyphenols as cancer chemopreventive agents. J Cell Biochem 22: 169–180, 1995

    CAS  PubMed  Google Scholar 

  14. Nandkarni KM: Curcuma longa, Popular Prakashan, Bombay, 1976.

    Google Scholar 

  15. Govindaraja VS: Turmeric: Chemistry, technology, and quality. Crit Rev Food Sci Nutr 12: 199, 1980

    PubMed  Google Scholar 

  16. Ammon HP, Wahl MA: Pharmacology of Curcuma longa. Planta Medica 57: 1–7, 1991

    CAS  PubMed  Google Scholar 

  17. Huang MT, Want ZY, Georgiadis CA, Laskin JD, Conney AH: Inhibitory effects of curcumin on tumor initiation by benzo[a]pyrene and 7,12-dimethylbenz[a] anthracene. Carcinogenesis 13: 2183–2186, 1992

    CAS  PubMed  Google Scholar 

  18. Azuine MA, Bhide SV: Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice. Nutr Cancer 17: 77–83, 1992

    CAS  PubMed  Google Scholar 

  19. Nagbhusan M, Bhide SV: Curcumin as an inhibitor of cancer. J Am Coll Nutr 11: 192–198, 1992

    PubMed  Google Scholar 

  20. Huang MT, Smart RC, Wong C-Q, Conney AH: Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 48: 5941–5946, 1988

    CAS  PubMed  Google Scholar 

  21. Conney AH, Lysz T, Ferraro T, Abidi TF, Manchand PS, Laskin JD, Huang MT: Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin. Adv Enzyme Regulation 31: 385–396, 1991

    Article  CAS  Google Scholar 

  22. Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV, Reddy BS: Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 59: 597–601, 1999

    CAS  PubMed  Google Scholar 

  23. Liu JY, Lin SJ, Lin SK: Inhibitory effects of curcumin on protein kinase C activity induced by 12-O-tetradecanoyl-phorbol-13-acetate in NIH 3T3 cells. Carcinogenesis 14: 857–861, 1993

    CAS  PubMed  Google Scholar 

  24. Pal S, Choudhuri T, Chattopadhyay S, Bhattacharya A, Datta G, Das T, Sa G: Mechanisms of curcumin-induced apoptosis of Ehrlich’s ascites carcinoma cells. Biochem Biophys Res Commun 288: 658–665, 2001

    Article  CAS  PubMed  Google Scholar 

  25. Jee SH, Shen SC, Tseng CR, Chiu HC, Kuo ML: Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells. J Invest Dermatol 111: 656–661, 1998

    Article  CAS  PubMed  Google Scholar 

  26. Pan M, Lin-Shiau S, Lin J: Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages. Biochem Pharmacol 60: 1665–1676, 2000

    Article  CAS  PubMed  Google Scholar 

  27. Korutla L, Kumar R: Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells. Biochim Biophys Acta 1224: 597–600, 1994

    Article  CAS  PubMed  Google Scholar 

  28. Singh S, Aggarwal BB: Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). J Biol Chem 270: 24995–25000, 1995

    Article  CAS  PubMed  Google Scholar 

  29. Jiang MC, Yang-Yen HF, Lin JK, Yen JJ: Differential regulation of p53, c-Myc, Bcl-2 and Bax protein expression during apoptosis induced by widely divergent stimuli in human hepatoblastoma cells. Oncogene 13: 609–616, 1996

    CAS  PubMed  Google Scholar 

  30. Alfranca A, Gutierrez MD, Vara A, Aragones J, Vidal F, Landazuri MO: c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. Mol Cell Biol 22: 12–22, 2002

    Article  CAS  PubMed  Google Scholar 

  31. Shibata A, Nagaya T, Imai T, Funahashi H, Nakao A, Seo H: Inhibition of NF-kappa B activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells. Breast Cancer Res Treat 73: 237–243, 2002

    Article  CAS  PubMed  Google Scholar 

  32. Thaloor D, Singh AK, Sidhu GS, Prasad PV, Kleinman HK, Maheswari RK: Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin. Cell Growth Differ 9: 305–312, 1998

    CAS  PubMed  Google Scholar 

  33. Mohan R, Sivak J, Ashton P, Russo LA, Pham BQ, Kasahara N, Raizman MB, Fini ME: Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. J Biol Chem 275: 10405–10412, 2000

    Article  CAS  PubMed  Google Scholar 

  34. Shim JS, Kim JH, Cho HY, Yum YN, Kim SH, Park HJ, Shim BS, Choi SH, Kwon HJ: Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin. Chem Biol 8: 695–704, 2003

    Article  Google Scholar 

  35. Shao ZM, Shen ZZ, Liu CH, Sartippour MR, Go VL, Heber D, Nguyen M: Curcumin exerts multiple suppressive effects on human breast carcinoma cells. Int J Cancer 98: 234–240, 2002

    Article  CAS  PubMed  Google Scholar 

  36. Arbiser JL, Klauber N, van Rohan R, Leeuwen R, Huang MT, Fisher C, Flynn E, Byers HR: Curcumin is an in vivo inhibitor of angiogenesis. Mol Med 4: 376–383, 1998

    CAS  PubMed  Google Scholar 

  37. Gururaj AE, Belakavadi M, Venkatesh DA, Marme D, Salimath BP: Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun 297: 934–942, 2002

    Article  CAS  PubMed  Google Scholar 

  38. Srinivas G, John Anto R, Srinivas P, Vidhyalakshmi S, Priya Senan V, Karunagaran D: Emodin induces apoptosis of human cervical cancer cells through poly (ADP-ribose) polymerase cleavage and activation of caspase-9. Euro J Pharmacol 473: 117–125, 2003

    Article  CAS  Google Scholar 

  39. Keifer JA, Guttridge DC, Ashbumer BP, Baldwin AS Jr.: Inhibition of NF-kappa B activity by thalidomide through suppression of I kappa B kinase activity. J Biol Chem 276: 22382–22387, 2001

    CAS  PubMed  Google Scholar 

  40. Kapahi P, Takahashi T, Natoli G, Adams SR, Chen Y, Tsien RY, Karin M: Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of I kappa B kinase. J Bid Chem 275: 36062–36066, 2000

    CAS  Google Scholar 

  41. Surh YJ, Han SS, Keum YS, Seo HJ, Lee SS: Inhibitory effects of curcumin and capsaicin on phorbol ester-induced activation of eukaryotic transcription factors, NF-kappa B and AP-1. Biofactors 12: 107–112, 2000

    CAS  PubMed  Google Scholar 

  42. Huang MT, Lou YR, Ma M, Newmark HL, Reuhl KR, Conney AR: Inhibitory effects of dietary curcumin on fore stomach, duodenal, and colon carcinogenesis in mice. Cancer Res 54: 5841–5847, 1994

    CAS  PubMed  Google Scholar 

  43. Rao CV, Rivenson A, Simi B, Reddy BS: Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 55: 259–266, 1995

    CAS  PubMed  Google Scholar 

  44. Jiang M-C, Yang-Yen HF, Yen JJ, Lin JK: Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr Cancer 26: 111–120, 1996

    CAS  PubMed  Google Scholar 

  45. Eamshaw WC, Martins LM, Kaufmann SH: Mammalian caspases: Structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68: 383–424, 1999

    CAS  PubMed  Google Scholar 

  46. Thornberry N, Lazebnik Y: Caspases: Enemies within. Science 281: 1312–1316, 1998

    CAS  PubMed  Google Scholar 

  47. Widlak P: The DFF40/CAD endonuclease and its role in apoptosis. Acta Biochim Pol 47: 1037–1044, 2000

    CAS  PubMed  Google Scholar 

  48. Weidner N, Carroll PR, Flax J, Bluementhal W, Folkman J: Tumor angiogenesis correlates with metastasis in invasive prostate cancer. Am J Pathol 143: 401–409, 1993

    CAS  PubMed  Google Scholar 

  49. Shibuya M: Role of VEGF-FLT receptor system in normal and tumor angiogenesis. Adv Cancer Res 67: 281–316, 1995

    CAS  PubMed  Google Scholar 

  50. Thaloor D, Singh AK, Sidhu GS, Prasad PV, Kleinman H, Maheswari RK: Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin. Cell Growth Differ 9: 305–312, 1998

    CAS  PubMed  Google Scholar 

  51. Perkins ND: The Rel/NF/kB family: Friend and Foe. Trends Biochem Sci 25: 434–440, 2000

    CAS  PubMed  Google Scholar 

  52. Baldwin AS, Jr.: The NF-kB and IkB proteins: New discoveries and insights. Annu Rev Immunol 14: 649–683, 1996

    CAS  PubMed  Google Scholar 

  53. Verma IM, Stevenson J: IkB kinase: Beginning not the end. Proc Natl Acad Sci USA, 94: 11758–11760, 1997

    CAS  PubMed  Google Scholar 

  54. Gutteridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS, Jr.: NF-kB controls cell growth and differentiation through transcriptional regulation of cyclin Dl. Mol Cell Biol 19: 5785–5799, 1999

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Applied Botany and Biotechnology, University of Mysore, Karnataka, India

    Madesh Belakavadi & Bharathi P. Salimath

  2. Department of Applied Botany and Biotechnology, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India

    Bharathi P. Salimath

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  1. Madesh Belakavadi
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  2. Bharathi P. Salimath
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Correspondence to Bharathi P. Salimath.

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Belakavadi, M., Salimath, B.P. Mechanism of inhibition of ascites tumor growth in mice by curcumin is mediated by NF-kB and caspase activated DNase. Mol Cell Biochem 273, 57–67 (2005). https://doi.org/10.1007/s11010-005-7717-2

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  • DOI: https://doi.org/10.1007/s11010-005-7717-2

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