Applied Biochemistry and Biotechnology

, Volume 176, Issue 7, pp 1996–2017 | Cite as

A Novel Approach for Overcoming Drug Resistance in Breast Cancer Chemotherapy by Targeting new Synthetic Curcumin Analogues Against Aldehyde Dehydrogenase 1 (ALDH1A1) and Glycogen Synthase Kinase-3 β (GSK-3β)

  • Rajesh Kumar KesharwaniEmail author
  • Vandana Srivastava
  • Prabhakar Singh
  • Syed Ibrahim Rizvi
  • Kuruba Adeppa
  • Krishna Misra


Breast cancer stem cells are well known to resist the traditional methods like chemo and radio therapy. Aldehyde dehydrogenase 1 (ALDHIA1) and glycogen synthase kinase-3 β (GSK-3β) are the two selected proteins for study, due to their overexpression and upregulation in breast cancer cells. Curcumin, the yellow pigment of the spice turmeric, is widely reported as an antioxidant and acts as a synergist along with traditional drugs. Under hypoxic conditions, it gets converted to free radical which causes apoptosis. Three naturally occurring curcuminoids, i.e. curcumin, demethoxycurcumin, and bisdemethoxycurcumin along with five derivatives/analogues of curcumin, viz. 4,4′-di-O-(carboxy-methyl)-curcumin, 4-O-(2-hydroxyethyl)curcumin, 4,4′-di-O-allyl-curcumin, 4,4′-di-O-(acetyl)-curcumin, and 3,3′-bisdemethylcurcumin were synthesized and evaluated for their anti-breast cancer potential by docking simulation and assessment of their antioxidant character, studied via 2, 2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS·+) radical cation scavenging assay, 2,2-diphenyl-1-picrylhydrazyl (DPPH·) radical, and ferric reducing ability potential (FRAP) assay. A co-relation between structure and activity of curcuminoids/its analogues and derivatives has been worked out.


Aldehyde dehydrogenase 1 Analogues Antioxidant Breast cancer Curcumin Docking Glycogen synthase kinase-3β Glide synthesis 



Rajesh Kr. Kesharwani acknowledges the Indian Council of Medical Research (ICMR), New Delhi, India, for providing senior research fellowship and wishes to thank the Director, IIIT-A, for providing computational facilities to carry out research work smoothly. Prabhakar Singh acknowledges the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for providing senior research fellowship.

Conflict of Interest

The authors declare that they have no competing interests.


  1. 1.
    Aggarwal B. B., Sundaram C., Malani N., & Ichikawa H. (2007). Curcumin: the Indian solid gold. Advances in Experimental Medicine and Biology, 595, 1–75.CrossRefGoogle Scholar
  2. 2.
    John D. (1984). One hundred useful raw drugs of the Kani tribes of Trivandrum Forest Division, Kerala, India. Pharmaceutical Biology, 22(1), 17–39.CrossRefGoogle Scholar
  3. 3.
    Mishra S., Karmodiya K., Suroliab N., & Surolia A. (2008). Synthesis and exploration of novel curcumin analogues as anti-malarial agents. Bioorganic & Medicinal Chemistry Letters, 16(6), 2894–2902.CrossRefGoogle Scholar
  4. 4.
    Singh D. B., Gupta M. K., Kesharwani R. K., & Misra K. (2013). Comparative docking and ADMET study of some curcumin derivatives and herbal congeners targeting β-amyloid. Network Modeling Analysis in Health Informatics and Bioinformatics, 2(1), 13–27.CrossRefGoogle Scholar
  5. 5.
    Kesharwani R. K., & Misra K. (2011). Prediction of binding site for curcuminoids at human topoisomerase II a protein; an in silico approach. Current Science, 101(8), 1060–1065.Google Scholar
  6. 6.
    Singh D. V., Agarwal S., Kesharwani R. K., & Misra K. (2013). 3D QSAR and pharmacophore study of curcuminoids and curcumin analogs: interaction with thioredoxin reductase. Interdisciplinary Sciences: Computational Life Sciences, 5(4), 286–295.Google Scholar
  7. 7.
    Anand P., Thomas S. G., Kunnumakkara A. B., Sundaram C., Harikumar K. B., Sung B., Tharakan S. T., Misra K., Priyadarsini I. K., Rajasekharan K. N., & Aggarwal B. B. (2008). Biological activities of curcumin and its analogues (congeners) made by man and mother nature. Biochemical Pharmacology, 76(11), 1590–1611.CrossRefGoogle Scholar
  8. 8.
    Singh P., & Rizvi S. I. (2013). Curcumin activates erythrocyte membrane acetylcholinesterase. Letters in Drug Design & Discovery, 10(6), 550–556.CrossRefGoogle Scholar
  9. 9.
    Ma I., & Allan A. L. (2011). The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Reviews and Reports, 7(2), 292–306.CrossRefGoogle Scholar
  10. 10.
    Lohberger, B., Rinner, B., Stuendl, N., Absenger, M., Liegl-Atzwanger, B. Walzer S. M., Windhager, R., & Leithner A. (2012). Aldehyde dehydrogenase 1, a potential marker for cancer stem cells in human sarcoma. PloS One, 7(8), e43664.Google Scholar
  11. 11.
    Abdullah, L. N., & Chow, E. K. (2013). Mechanisms of chemoresistance in cancer stem cells. Clinical and Translational Medicine, 2(3).Google Scholar
  12. 12.
    Keysar, S. B., & Jimeno, A. (2010). More than markers: biological significance of cancer stem cell-defining molecules. Molecular Cancer Therapeutics, 9(9), 2450–2457.Google Scholar
  13. 13.
    Kakarala M., Brenner D. E., Khorkaya H., Cheng C., Tazi K., Ginestier C., Liu S., Dontu G., & Wicha M. S. (2010). Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Research and Treatment, 122(3), 777–785.CrossRefGoogle Scholar
  14. 14.
    Bustanji Y., Taha M. O., Almasri I. M., Al-Ghussein M. A., Mohammad M. K., & Alkhatib H. S. (2009). Inhibition of glycogen synthase kinase by curcumin: investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation. Journal of Enzyme Inhibition and Medicinal Chemistry, 24(3), 771–778.CrossRefGoogle Scholar
  15. 15.
    Cheng A. L., Hsu C. H., Lin J. K., Hsu M. M., Ho Y. F., Shen T. S., Ko J. Y., Lin J. T., Lin B. R., Ming-Shiang W., Yu H. S., Jee S. H., Chen G. S., Chen T. M., Chen C. A., Lai M. K., Pu Y. S., Pan M. H., Wang Y. J., Tsai C. C., & Hsieh C. Y. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Research, 21(4B), 2895–2900.Google Scholar
  16. 16.
    Aggarwal B. B., & Shishodia S. (2006). Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical Pharmacology, 71(10), 1397–1421.CrossRefGoogle Scholar
  17. 17.
    Dubey S. K., Sharma A. K., Narain U., Misra K., & Pati U. (2008). Design, synthesis and characterization of some bioactive conjugates of curcumin with glycine, glutamic acid, valine and demethylenated piperic acid and study of their antimicrobial and antiproliferative properties. European Journal of Medicinal Chemistry, 43(9), 1837–1846.CrossRefGoogle Scholar
  18. 18.
    Anand P., Nair H. B., Sung B., Kunnumakkara A. B., Yadav V. R., Tekmal R. R., & Aggarwal B. B. (2010). Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo. Biochemical Pharmacology, 79(3), 330–338.CrossRefGoogle Scholar
  19. 19.
    Bisht S., Feldmann G., Soni S., Ravi R., Karikar C., Maitra A., & Maitra A. (2007). Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. Journal of Nanobiotechnology, 5, 3.CrossRefGoogle Scholar
  20. 20.
    Tiyaboonchai W., Tungpradit W., & Plianbangchang P. (2007). Formulation and characterization of curcuminoids loaded solid lipid nanoparticles. International Journal of Pharmaceutics, 337(1–2), 299–306.CrossRefGoogle Scholar
  21. 21.
    Li, L., Braiteh, F. S., & Kurzrock, R. (2005). Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer, 104(6), 1322-1331.CrossRefGoogle Scholar
  22. 22.
    Mishra S., Narain U., Mishra R., & Misra K. (2005). Design, development and synthesis of mixed bioconjugates of piperic acid-glycine, curcumin-glycine/alanine and curcumin-glycine-piperic acid and their antibacterial and antifungal properties. Bioorganic & Medicinal Chemistry, 13(5), 1477–1486.CrossRefGoogle Scholar
  23. 23.
    Mishra S., Kapoor N., Ali A. M., Pardhasaradhi B. V., Kumari A. L., Khar A., & Misra K. (2005). Differential apoptotic and redox regulatory activities of curcumin and its derivatives. Free Radical Biology and Medicine, 38(10), 1353–1360.CrossRefGoogle Scholar
  24. 24.
    Kumar S., Narain U., Tripathi S., & Misra K. (2001). Syntheses of curcumin bioconjugates and study of their antibacterial activities against beta-lactamase-producing microorganisms. Bioconjugate Chemistry, 12(4), 464–469.CrossRefGoogle Scholar
  25. 25.
    Shoba G., Joy D., Joseph T., Majeed M., Rajendran R., & Srinivas P. S. (1998). Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Medica, 64(4), 353–356.CrossRefGoogle Scholar
  26. 26.
    Mosley C. A., Liotta D. C., & Snyder J. P. (2007). Highly active anticancer curcumin analogues. Advances in Experimental Medicine and Biology, 595, 77–103.CrossRefGoogle Scholar
  27. 27.
    Wehrli, C. (2007). Curcumin synthesis, WO 2007/110168A1, World Intellectual Property Organization.Google Scholar
  28. 28.
    Changtam C., Hongmanee P., & Suksamrarn A. (2010). Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity. European Journal of Medicinal Chemistry, 45(10), 4446–4457.CrossRefGoogle Scholar
  29. 29.
    Venkateswarlu S., Ramachandra M. S., & Subbaraju G. V. (2005). Synthesis and biological evaluation of polyhydroxycurcuminoids. Bioorganic & Medicinal Chemistry, 13, 6374–6380.CrossRefGoogle Scholar
  30. 30.
    Moore S. A., Baker H. M., Blythe T. J., Kitson K. E., Kitson T. M., & Baker E. N. (1998). Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases. Structure, 6(12), 1541–1551.CrossRefGoogle Scholar
  31. 31.
    Gentile G., Merlo G., Pozzan A., Bernasconi G., Bax B., Bamborough P., Bridges A., Carter P., Neu M., Yao G., Brough C., Cutler G., Coffin A., & Belyanskaya S. (2012). 5-Aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK−3 inhibitors. Bioorganic & Medicinal Chemistry Letters, 22(5), 1989–1994.CrossRefGoogle Scholar
  32. 32.
    Berman H. M., Westbrook J., Feng Z., Gilliland G., Bhat T. N., Weissig H., Shindyalov I. N., & Bourne P. E. (2000). The protein data bank. Nucleic Acids Research, 28(1), 235–242.CrossRefGoogle Scholar
  33. 33.
    Durdagi S., Duff H. J., & Noskov S. Y. (2011). Combined receptor and ligand-based approach to the universal pharmacophore model development for studies of drug blockade to the hERG1 pore domain. Journal of Chemical Information and Modeling, 51(2), 463–474.CrossRefGoogle Scholar
  34. 34.
    ACD/ChemSketch, version 8.0, 2006. Advanced Chemistry Development, Inc., Toronto ON, Canada,
  35. 35.
    Albers, H. M. H. G., Hendrickx, L. J. D., van Tol, R. J. P., Hausmann, J., Perrakis, A., & Ovaa, H. (2011). Structure-based design of novel boronic acid-based inhibitors of autotaxin. Journal of Chemical Information and Modeling, 54(13), 4619-4626.Google Scholar
  36. 36.
    Maestro (v7.0.113)—a unified interface for all Schrodinger products, developed and marketed by Schrodinger, LLC. NY, Copyright 2005;
  37. 37.
    Friesner R. A., Murphy R. B., Repasky M. P., Frye L. L., Greenwood J. R., Halgren T. A., Sanschagrin P. C., & Mainz D. T. (2006). Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. Journal of Medicinal Chemistry, 49(21), 6177–6196.CrossRefGoogle Scholar
  38. 38.
    Gadakar P. K., Phukan S., Dattatreya P., & Balaji V. N. (2007). Pose prediction accuracy in docking studies and enrichment of actives in the active site of GSK-3beta. Journal of Chemical Information and Modeling, 47(4), 1446–1459.CrossRefGoogle Scholar
  39. 39.
    Miller J. N., & Rice-Evans C. A. (1997). Factors influencing the antioxidant activity determined by the ABTS+ radical cation assay. Free Radical Research, 26(3), 195–199.CrossRefGoogle Scholar
  40. 40.
    Szabo M. R., Iditoiu C., Chambre D., & Lupea A. X. (2007). Improved DPPH determination for antioxidant activity spectrophotometric assay. Chemical Papers- Slovak Academy of Sciences, 61(3), 214–216.Google Scholar
  41. 41.
    Benzie I. F., & Strain J. J. (1996). The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Analytical Biochemistry, 239(1), 70–76.CrossRefGoogle Scholar
  42. 42.
    Rice-Evans C. A., Miller N. J., & Paganga G. (1996). Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radical Biology and Medicine, 20(7), 933–956.CrossRefGoogle Scholar
  43. 43.
    Lissi E. A., Modak B., Torres R., Escobar G., & Urzua A. (1999). Total antioxidant potential of resinous exudates from Heliotropium species, and a comparison of the ABTS and DPPH methods. Free Radical Research, 30(6), 471–477.CrossRefGoogle Scholar
  44. 44.
    Duda-Chodak A., Tarko T., Sroka P., & Satora P. (2008). Antioxidant activity of different kinds of commercially available teas—diversity and changes during storage. Electronic Journal of Polish Agricultural Universities, 11(4), 1–7.Google Scholar
  45. 45.
    Furiga A., Lonvaud-Funel A., & Badet C. (2009). In vitro study of antioxidant capacity and antibacterial activity on oral anaerobes of a grape seed extract. Food Chemistry, 113(4), 1037–1040.CrossRefGoogle Scholar
  46. 46.
    Singh P., & Rizvi S. I. (2012). Anti-oxidative effect of curcumin against tert-butylhydroperoxide induced oxidative stress in human erythrocytes. The Natural Products Journal, 2(1), 69–73.CrossRefGoogle Scholar
  47. 47.
    Singh, P., Kesharwani, R. K., Misra, K., & Rizvi, S. I. (2015). The modulation of erythrocyte Na+/K+- ATPase activity by curcumin. Journal of Advanced Research, doi: 10.1016/j.jare.2014.12.007.

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Rajesh Kumar Kesharwani
    • 1
    Email author
  • Vandana Srivastava
    • 2
  • Prabhakar Singh
    • 3
  • Syed Ibrahim Rizvi
    • 3
  • Kuruba Adeppa
    • 4
  • Krishna Misra
    • 1
    • 2
  1. 1.Indian Institute of Information TechnologyAllahabadIndia
  2. 2.Center of Biomedical Research, SGPGIMS CampusLucknowIndia
  3. 3.Department of BiochemistryUniversity of AllahabadAllahabadIndia
  4. 4.R & D Centre, India Pesticides LimitedLucknowIndia

Personalised recommendations