Skip to main content
SpringerLink
Log in

Chemoprevention of DMH-induced rat colon carcinoma initiation by combination administration of piroxicam and C-phycocyanin

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Cancer research illustrated that combinatorial studies can provide significant improvement in safety and effectiveness over the monotherapy regimens. A combination of two drugs may restrain precancerous colon polyps, opening a new possible opportunity for chemoprevention of colon cancer. In this context, chemopreventive efficacy of a combination regimen of C-phycocyanin, a biliprotein present in Spirulina platensis, a cyanobacterium, which is a selective cycloxygenase-2 (COX-2) inhibitor and piroxicam, a traditional non-steroidal anti-inflammatory drug was considered in 1,2 dimethylhyadrazine (DMH)-induced colon carcinogenesis in rats. Western blotting, immunohistochemistry, DNA fragmentation, fluorescent staining, PGE2 enzyme immunoassay, and carrageenan-induced paw edema test were performed along with morphological and histological analysis. DMH treatment showed a rich presence of preneoplastic lesions such as multiple plaque lesions, aberrant crypt foci, and well-characterized dysplasia. These features were reduced with piroxicam and C-phycocyanin administration. The number of apoptotic cells was featured prominently in all the groups compared with DMH. DMH treatment revealed intact high molecular weight genomic DNA with no signs of laddering/DNA fragmentation while it was noticeable significantly in control and DMH + piroxicam + C-phycocyanin. DMH group showed highest COX-2 expression and PGE2 level in comparison with other groups. Doses of piroxicam and C-phycocyanin used in the present study were established at an anti-inflammatory range. A combination regimen of piroxicam and C-phycocyanin, rather than individually has the much greater potential for reduction of DMH-induced colon cancer development and COX-2 being the prime possible target in such chemoprevention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Tammali R, Ramana KV, Singhal SS, Awasthi S, Srivastava SK (2006) Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colon cancer cells. Cancer Res 66:9705–9713. doi:10.1158/0008-5472.CAN-06-2105

    Article  PubMed  CAS  Google Scholar 

  2. Sarkar FH, Adsule S, Li Y, Padhye S (2007) Back to future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem 7:599–608

    Article  PubMed  CAS  Google Scholar 

  3. Saini MK, Sharma P, Kaur J, Sanyal SN (2008) The cycloxygenase-2 inhibitor etoricoxib is a potent chemopreventive agent of colon carcinogenesis in rat model. J Environ Pathol Toxicol Oncol 28:39–46

    Google Scholar 

  4. Vaish V, Tanwar L, Kaur J, Sanyal SN (2010) Chemopreventive effects of non-steroidal anti-inflammatory drugs in early neoplasm of experimental colorectal cancer: an apoptosome study. J Gastrointest Cancer. doi:10.1007/s12029-010-9188-2

  5. Hinz B, Brune K (2001) Cycloxygenase-2: 10 years later. J Pharm Exp Ther 33(2):367–375

    Google Scholar 

  6. Doherty GA, Byrne SM, Molloy ES, Malhotra V, Austin S, Kay EW, Murray FE, Fitzgerald DJ (2009) Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer. BMC Cancer 9(207):1–13. doi:10.1186/1471-2407-9-207

    Google Scholar 

  7. Grosch S, Maier JT, Schiffmann S, Geisslinger G (2006) Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Nat Can Inst 98(11):736–747. doi:10.1093/jnci/djj206

    Article  Google Scholar 

  8. Ding H, Han C, Gibson R, Steele V, Ambrosio SMD (2003) Piroxicam selectively inhibits the growth of premalignant and malignant human oral cell lines by limiting their progression through the S phase and reducing the levels of cyclins and AP-1. Int J Cancer 107:830–836. doi:10.1002/ijc.11499

    Article  PubMed  CAS  Google Scholar 

  9. Jacoby RF, Seibert KK, Cole CE, Kelloff G, Lubet RA (2000) The cycloxygenase-2 inhibitor celecoxib is a potent chemopreventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 60:5040–5044

    PubMed  CAS  Google Scholar 

  10. Komers R, Anderson S, Epstein M (2001) Renal and cardiovascular effects of selective cyclooxygenase-2 inhibitors. Am J Kidney Dis 38(6):1145–1157. doi:10.1053/ajkd.2001.29203

    Article  PubMed  CAS  Google Scholar 

  11. Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubert R, Sigman CC (1994) Chemopreventive drug development: perspectives and progress. Cancer Epidemiol Biomarkers Prev 3:85–98

    PubMed  CAS  Google Scholar 

  12. Vadiraja BB, Gaikwad NW, Madyastha KM (1998) Hepatoprotective effect of C-phycocyanin protective for carbon tetrachloride and R-(+)-pulegone mediated hepatotoxicity in rats. Biochem Biophys Res Com 249:428–431. doi:10.1006/bbrc.1998.9149

    Article  PubMed  CAS  Google Scholar 

  13. Remirej D, Gonzalez A, Merino N, Gonzalez R, Ancheta O, Romey C, Rodriguez S (1999) Effect of phycocyanin in zymogen-induced arthritis in mice. Phycocyanin as an anti-arthritis compound. Drug Dev Res 48:70–75

    Article  Google Scholar 

  14. Romay C, Armesto J, Remrej D, Gonzalez R, Ieden N, Garces I (1998) Antioxidant and anti-inflammatory properties of C-phycocyanin from blue green algae. Inflamm Res 47:36–41

    Article  PubMed  CAS  Google Scholar 

  15. Romay C, Ledon N, Gongalez R (2000) Effects of phycocyanin extract on prostaglandin E2 levels in mouse ear inflammation test. Arzneim Forsch 50:1106–1109

    CAS  Google Scholar 

  16. Dubois RN, Radhika A, Reddy BS, Estingh AJ (1996) Increased cycloxygenase-2 levels in carcinogen induced rat colonic tumors. Gastroenterology 110:1259–1262. doi:10.1053/gast.1996.v110.pm8613017

    Article  PubMed  CAS  Google Scholar 

  17. Bhat VB, Madhyastha KM (2000) C-phycocyanin: a potent peroxyl radical scavenger in vivo and in vitro. Biochem Biophys Res Commun 275:20–25. doi:10.1006/bbrc.2000.3270

    Article  PubMed  CAS  Google Scholar 

  18. Agarwal B, Rao CV, Bhendwal S (1999) Lovastatin augment sulindac-induced apoptosis in colon cancer cells and potentiates the chemopreventive effects of sulindac. Gastroenterology 117:838–847. doi:10.1016/SOO16-5085(99)70342-2

    Article  PubMed  CAS  Google Scholar 

  19. Torrance CJ, Jackson PE, Montgomery E (2000) Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6:1024–1028

    Article  PubMed  CAS  Google Scholar 

  20. Kanwar SS, Vaiphei K, Nehru B, Sanyal SN (2008) Antioxidative effects of non-steroidal anti-inflammatory drugs during the initiation stages of experimental colon carcinogenesis in rats. J Environ Pathol Toxicol Oncol 27(2):89–100

    PubMed  CAS  Google Scholar 

  21. Tanwar L, Vivek V, Sanyal SN (2009) Chemoprevention of 1,2-dimethylhydrazine-induced colon carcinogenesis by a non-steroidal anti-inflammatory drug, etoricoxib, in rats: inhibition of nuclear factor κB. Res Commun 10:1141–1146

    Google Scholar 

  22. Rao CV, Indranie C, Simi B, Manning PT, Connor JR, Reddy BS (2002) Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor. Cancer Res 62:165–170

    PubMed  CAS  Google Scholar 

  23. Bird RP, Good CK (2000) The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer. Toxicol Lett. 112–113:395–402. doi:10.1016/SO378-4274(99)00261-1

    Article  PubMed  Google Scholar 

  24. Park HS, Goodlad RA, Wright NA (1997) The incidence of aberrant crypt foci and colonic carcinoma in dimethyl hydrazine treated rats varies in site specific manner and depends on tumor histology. Cancer Res 57:4507–4510

    PubMed  CAS  Google Scholar 

  25. Mouille B, Robert V, Blacheir F (2004) Adaptative increase of ornithine production and decrease of ammonia metabolism in rat colonocytes after hyperproteic diet ingestion. J Physiol Gastrointest Liver Physiol 287:G344–G351. doi:10.1152/ajpgi.00445.2003.0193-1857/04

    Article  CAS  Google Scholar 

  26. Roediger WE, Truelove SC (1979) Method of preparing isolated colonic epithelial cells (colonocytes) for metabolic studies. Gut 20:484–488

    Article  PubMed  CAS  Google Scholar 

  27. Duke RC, Cohen JJ (1992) Morphological and biochemical assays of apoptosis. Curr Protoc Immunol Suppl 3(17):1–16

    Google Scholar 

  28. Baker AJ, Mooney A, Hughes J, Lombardi D, Johnson RJ, Savill J (1994) Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis. J Clin Investig 94:2105–2116

    Article  PubMed  CAS  Google Scholar 

  29. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 72:248–250. doi:10.1016/0300-9629(90)90739-F

    Article  PubMed  CAS  Google Scholar 

  30. Winter CA, Risley EA, Nuss GW (1962) Carrageenan-induced oedema in the hind paw of rat as an assay for anti-inflammatory activity. Proc Soc Exp Biol Ther 111:544–547

    CAS  Google Scholar 

  31. Samud AW, Asmawi MZ, Sharma JN, Yusof AP (1999) Anti-inflammatory activity of Crinum asiaticum plant and its effect on bradykinin-induced contractions on isolated uterus. Immunopharmacology 43:311–316

    Article  PubMed  CAS  Google Scholar 

  32. Melen-Mucha G, Niewiadowska H (2002) Frequency of proliferation, apoptosis and their ratio during rat colon carcinogenesis and their characteristic pattern in the dimethylhydrazine-induced colon adenoma and carcinoma. Cancer Invest 20:700–712

    Article  PubMed  Google Scholar 

  33. Nath R, Scott M, Nadimpalli R, Gupta R, Wang KKW (2000) Activation of apoptosis-linked caspases(s) in NMDA-injured brains in neonatal rats. Neurochem Int 36:119–126. doi:10.1016/SO197-0186(99)00112-6

    Article  PubMed  CAS  Google Scholar 

  34. Wyllie A (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556

    Article  PubMed  CAS  Google Scholar 

  35. Buadonpri W, Wichitnithad W, Rojsitthisak P, Towiwat P (2009) Synthetic curcumin inhibits carrageenan-induced paw edema in rats. J Health Res 23(1):11–16

    CAS  Google Scholar 

  36. Reddy BS, Nayini J, Tokumo J, Rigotty J, Zang E, Kelloff G (1990) Chemoprevention of colon carcinogenesis by concurrent administration of piroxicam, a non-steroidal anti-inflammatory drug with DL-α difluoromethylornithine, an ornithine decarboxylase inhibitor in diet. Cancer Res 50:2562–2568

    PubMed  CAS  Google Scholar 

  37. Rao CV, Tokumo K, Rigotty J, Zang E, Kelloff G, Reddy BS (1991) Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, α difluoromethylornithine, 16 α-fluoro-5-androsten-17-one and ellagic acid singly and alone. Cancer Res 51:4528–4534

    PubMed  CAS  Google Scholar 

  38. Pretlow TP, Riordan MA, Pretlow TG, Stellato TA (1992) Aberrant crypts in human colonic mucosa: putative preneoplastic lesions. J Cell Biochem 16G:55–62

    Article  CAS  Google Scholar 

  39. Tayakama T, Katsuki S, Takahashi Y (1998) Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med 339:1277–1284

    Article  Google Scholar 

  40. Pereira MA, Barnes LH, Rassman VL, Kelloff GV, Steele VE (1994) Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents. Carcinogenesis 15:1049–1054. doi:10.1093/carcin/15.5.1049

    Article  PubMed  CAS  Google Scholar 

  41. Corpet DE, Tache S (2002) Most effective colon cancer chemopreventive agents in rats: a review of aberrant crypt foci and tumor data, ranked by potency. Nutr Cancer 43:1–21

    Article  PubMed  CAS  Google Scholar 

  42. Pollard M, Luckert PH (1984) Effect of piroxicam on primary intestinal tumors induced in rats by N-methylnitrosourea. Cancer Lett 25:117–121

    Article  PubMed  CAS  Google Scholar 

  43. Earnest DL, Alberts DS, Hixon LJ (1997) Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention. J Cell Biochem 161:156–166

    Google Scholar 

  44. Sheng H, Shao J, Morrow JD, Beauchamp RD, Dubois RN (1998) Modulation of apoptosis and BCl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58:362–366

    PubMed  CAS  Google Scholar 

  45. Hold GL, El-Omar EM (2008) Genetic aspects of inflammation and cancer. Biochem J 410:225–235. doi:10.1042/BJ20071341

    Article  PubMed  CAS  Google Scholar 

  46. Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M (2010) The Role of Cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol 1-21. doi: 10.1155/2010/215158

  47. Srinivasan BD, Kulkarni PS (1989) Inhibitors of the arachidonic acid cascade in the management of ocular inflammation. Prog Clin Biol Res 312:229–249

    PubMed  CAS  Google Scholar 

  48. Accioly MT, Pacheco P, Maya-Monteiro CM, Carrossini N, Robbs BK, Oliveira SS, Kaufmann C, Morgado-Diaz JA, Bozza PT, Viola JP (2008) Lipid bodies are reservoir of cycloxygenase-2 and sites of prostaglandin E2 synthesis in colon cancer cells. Cancer Res 68(6):1732–1740

    Article  PubMed  CAS  Google Scholar 

  49. Chandrashekaran NV, Simmons DL (2004) The cyclooxygenases. Genome Biol 5(9):241.1–241.7. doi:10.1186/qb-2004-5-9-241

  50. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501. doi:10.1083/jcb.119.3.493

    Article  PubMed  CAS  Google Scholar 

  51. Pardhasaradthi P, Khar A (2003) Phycocyanin mediated apoptosis in AK-5 tumor cells involves down regulation of Bcl-2 and generation of ROS. Mol Cancer Ther 2:1165–1170

    Google Scholar 

Download references

Acknowledgment

Financial assistance for this study was received from the Department of Science and Technology, Government. of India [Reference No. (SR/SO/BB-05/2008)]. The support is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Biophysics, Panjab University, Chandigarh, 160 014, India

    Manpreet Kaur Saini & Sankar Nath Sanyal

  2. Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India

    Kim Vaiphei

Authors
  1. Manpreet Kaur Saini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim Vaiphei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sankar Nath Sanyal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sankar Nath Sanyal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saini, M.K., Vaiphei, K. & Sanyal, S.N. Chemoprevention of DMH-induced rat colon carcinoma initiation by combination administration of piroxicam and C-phycocyanin. Mol Cell Biochem 361, 217–228 (2012). https://doi.org/10.1007/s11010-011-1106-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-1106-9

Keywords

Search

Navigation