Skip to main content
Springer Nature Link
Log in

Fluorocurcumins as Cyclooxygenase-2 Inhibitor: Molecular Docking, Pharmacokinetics and Tissue Distribution in Mice

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The purpose of the current study was to assess the effect of newly synthesized Curcumin analogs on COX-2 protein by molecular docking studies and by assessments of the effect of one such analog (CDF) on nuclear factor NF-κB and PGE2. In addition, we have determined the pharmacokinetics and tissue distribution of CDF in mice compared to Curcumin.

Methods

Molecular docking on COX-2 protein was assessed by standard computer modeling studies. PGE2 assay in conditioned media was done utilizing high sensitivity immunoassay kit following manufacturer’s instructions, while NF-κB was done by routine EMSA. Serum pharmacokinetics and tissue distribution studies were carried out using the validated high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods.

Results

The molecular docking showed that fluorocurcumin analogs do not introduce any major steric changes compared to the parent Curcumin molecule, which was consistent with down-regulation of NF-κB and reduced PGE2 levels in cells treated with CDF. Pharmacokinetic parameters revealed that CDF had better retention and bioavailability and that the concentration of CDF in the pancreas tissue was 10-fold higher compared to Curcumin.

Conclusion

Our observations clearly suggest that the bioavailability of CDF is much superior compared to Curcumin, suggesting that CDF would be clinically useful.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–77.

    Article  CAS  PubMed  Google Scholar 

  3. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg. 1998;175:76–83.

    Article  CAS  PubMed  Google Scholar 

  4. Friess H, Guo XZ, Nan BC, Kleeff O, Buchler MW. Growth factors and cytokines in pancreatic carcinogenesis. Ann N Y Acad Sci. 1999;880:110–21.

    Article  CAS  PubMed  Google Scholar 

  5. Le X, Shi Q, Wang B, Xiong Q, Qian C, Peng Z, et al. Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interferon Cytokine Res. 2000;20:935–46.

    Article  CAS  PubMed  Google Scholar 

  6. Baldwin AS Jr. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest. 2001;107:3–6.

    Article  CAS  PubMed  Google Scholar 

  7. Kokawa A, Kondo H, Gotoda T, Ono H, Saito D, Nakadaira S, et al. Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer. 2001;91:333–8.

    Article  CAS  PubMed  Google Scholar 

  8. Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res. 1999;59:987–90.

    CAS  PubMed  Google Scholar 

  9. Hermanova M, Trna J, Nenutil R, Dite P, Kala Z. Expression of COX-2 is associated with accumulation of p53 in pancreatic cancer: analysis of COX-2 and p53 expression in premalignant and malignant ductal pancreatic lesions. Eur J Gastroenterol Hepatol. 2008;20:732–9.

    Article  CAS  PubMed  Google Scholar 

  10. Matsubayashi H, Infante JR, Winter J, Klein AP, Schulick R, Hruban R, et al. Tumor COX-2 expression and prognosis of patients with resectable pancreatic cancer. Cancer Biol Ther. 2007;6:1569–75.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 1998;58:362–6.

    CAS  PubMed  Google Scholar 

  13. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 2001;480–481:243–68.

    PubMed  Google Scholar 

  14. Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci. 2004;1030:434–41.

    Article  CAS  PubMed  Google Scholar 

  15. Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. Adv Exp Med Biol. 2007;595:1–75.

    Article  PubMed  Google Scholar 

  16. Bharti AC, Takada Y, Aggarwal BB. Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. J Immunol. 2004;172:5940–7.

    CAS  PubMed  Google Scholar 

  17. Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14:4491–9.

    Article  CAS  PubMed  Google Scholar 

  18. Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199–225.

    Article  CAS  PubMed  Google Scholar 

  19. Milacic V, Banerjee S, Landis-Piwowar KR, Sarkar FH, Majumdar AP, Dou QP. Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. Cancer Res. 2008;68:7283–92.

    Article  CAS  PubMed  Google Scholar 

  20. Ravindran J, Prasad S, Aggarwal BB. Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J. 2009.

  21. Sharma C, Kaur J, Shishodia S, Aggarwal BB, Ralhan R. Curcumin down regulates smokeless tobacco-induced NF-kappaB activation and COX-2 expression in human oral premalignant and cancer cells. Toxicology. 2006;228:1–15.

    Article  CAS  PubMed  Google Scholar 

  22. Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis. 2003;24:1269–79.

    Article  CAS  PubMed  Google Scholar 

  23. Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer. 2006;106:2503–13.

    Article  CAS  PubMed  Google Scholar 

  24. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003;9:161–8.

    Article  PubMed  Google Scholar 

  25. Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharm Toxicol (Copenh). 1978;43:86–92.

    CAS  Google Scholar 

  26. Bhutani MK, Bishnoi M, Kulkarni SK. Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes. Pharmacol Biochem Behav. 2009;92:39–43.

    Article  CAS  PubMed  Google Scholar 

  27. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64:353–6.

    Article  CAS  PubMed  Google Scholar 

  28. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4:807–18.

    Article  CAS  PubMed  Google Scholar 

  29. Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A, et al. Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin"): a novel strategy for human cancer therapy. J Nanobiotechnology. 2007;5:3.

    Google Scholar 

  30. Cui J, Yu B, Zhao Y, Zhu W, Li H, Lou H, et al. Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int J Pharm. 2009;371:148–55.

    Article  CAS  PubMed  Google Scholar 

  31. Gupta V, Aseh A, Rios CN, Aggarwal BB, Mathur AB. Fabrication and characterization of silk fibroin-derived curcumin nanoparticles for cancer therapy. Int J Nanomedicine. 2009;4:115–22.

    CAS  PubMed  Google Scholar 

  32. Sahu A, Kasoju N, Bora U. Fluorescence study of the curcumin-casein micelle complexation and its application as a drug nanocarrier to cancer cells. Biomacromolecules. 2008;9:2905–12.

    Article  CAS  PubMed  Google Scholar 

  33. Mosley CA, Liotta DC, Snyder JP. Highly active anticancer curcumin analogues. Adv Exp Med Biol. 2007;595:77–103.

    Article  PubMed  Google Scholar 

  34. Liang G, Yang S, Zhou H, Shao L, Huang K, Xiao J, et al. Synthesis, crystal structure and anti-inflammatory properties of curcumin analogues. Eur J Med Chem. 2009;44:915–9.

    Article  CAS  PubMed  Google Scholar 

  35. Liang G, Yang S, Jiang L, Zhao Y, Shao L, Xiao J, et al. Synthesis and anti-bacterial properties of mono-carbonyl analogues of curcumin. Chem Pharm Bull (Tokyo). 2008;56:162–7.

    Article  CAS  Google Scholar 

  36. Poma P, Notarbartolo M, Labbozzetta M, Maurici A, Carina V, Alaimo A, et al. The antitumor activities of curcumin and of its isoxazole analogue are not affected by multiple gene expression changes in an MDR model of the MCF-7 breast cancer cell line: analysis of the possible molecular basis. Int J Mol Med. 2007;20:329–35.

    CAS  PubMed  Google Scholar 

  37. Anand P, Thomas SG, Kunnumakkara AB, et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol. 2008;76:1590–611.

    Article  CAS  PubMed  Google Scholar 

  38. John VD, Kuttan G, Krishnankutty K. Anti-tumour studies of metal chelates of synthetic curcuminoids. J Exp Clin Cancer Res. 2002;21:219–24.

    CAS  PubMed  Google Scholar 

  39. Zambare AP, Jamadar A, Padhye S, Kulkarni VM. Copper conjugates of Knoevenagel condesates of Curcumin and their Schiff base derivatives: synthesis, spectroscopy, magnetism, EPR and electrochemistry. Synth React Inorg, Metal-Org and Nano-Metal Chemistry. 2007;37:19–27.

  40. Padhye S, Yang H, Jamadar A, Cui QC, Chavan D, Dominiak K, et al. New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm Res. 2009;26:1874–80.

    Article  CAS  PubMed  Google Scholar 

  41. Banerjee S, Wang Z, Kong D, Sarkar FH. 3, 3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res. 2009;69:5592–600.

    Article  CAS  PubMed  Google Scholar 

  42. Somparn P, Phisalaphong C, Nakornchai S, Unchern S, Morales NP. Comparative antioxidant activities of curcumin and its demethoxy and hydrogenated derivatives. Biol Pharm Bull. 2007;30:74–8.

    Article  CAS  PubMed  Google Scholar 

  43. Pan MH, Huang TM, Lin JK. Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos. 1999;27:486–94.

    CAS  PubMed  Google Scholar 

  44. Ravindranath V, Chandrasekhara N. Metabolism of curcumin–studies with [3H]curcumin. Toxicology. 1981;22:337–44.

    Article  PubMed  Google Scholar 

  45. Giri B, Gomes A, Sengupta R, Banerjee S, Nautiyal J, Sarkar FH, et al. Curcumin synergizes the growth inhibitory properties of Indian toad (Bufo melanostictus Schneider) skin-derived factor (BM-ANF1) in HCT-116 colon cancer cells. Anticancer Res. 2009;29:395–401.

    CAS  PubMed  Google Scholar 

  46. 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;67:3853–61.

    Article  CAS  PubMed  Google Scholar 

  47. Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, et al. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008;14:2128–36.

    Article  CAS  PubMed  Google Scholar 

  48. Sung B, Kunnumakkara AB, Sethi G, Anand P, Guha S, Aggarwal BB. Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model. Mol Cancer Ther. 2009;8:959–70.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. D.Y.Patil Institute of Pharmaceutical Sciences, Pune, 411018, India

    Subhash Padhye & Deepak Chavan

  2. Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Room-740 HWCRC Bldg., 4100 John R Street, Detroit, Michigan, 48201, USA

    Sanjeev Banerjee, Shadan Ali, Q. Ping Dou & Fazlul H. Sarkar

  3. D.Y.Patil Biotechnology and Bioinformatics Institute, Pune, 411044, India

    Shubhangini Pandye & K.Venkateswara Swamy

  4. Department of Pharmacology, Pharmacology Core Services at Karmanos Cancer Center, Wayne State University, Detroit, Michigan, 48201, USA

    Jing Li

Authors
  1. Subhash Padhye
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Sanjeev Banerjee
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Deepak Chavan
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Shubhangini Pandye
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. K.Venkateswara Swamy
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Shadan Ali
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Jing Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Q. Ping Dou
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Fazlul H. Sarkar
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Fazlul H. Sarkar.

Additional information

Subhash Padhye and Sanjeev Banerjee contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Padhye, S., Banerjee, S., Chavan, D. et al. Fluorocurcumins as Cyclooxygenase-2 Inhibitor: Molecular Docking, Pharmacokinetics and Tissue Distribution in Mice. Pharm Res 26, 2438–2445 (2009). https://doi.org/10.1007/s11095-009-9955-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-9955-6

KEY WORDS