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)
- 737 Downloads
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.
KeywordsAldehyde 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.
- 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.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.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
- 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.Abdullah, L. N., & Chow, E. K. (2013). Mechanisms of chemoresistance in cancer stem cells. Clinical and Translational Medicine, 2(3).Google Scholar
- 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
- 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.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
- 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.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
- 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
- 27.Wehrli, C. (2007). Curcumin synthesis, WO 2007/110168A1, World Intellectual Property Organization.Google Scholar
- 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
- 34.ACD/ChemSketch, version 8.0, 2006. Advanced Chemistry Development, Inc., Toronto ON, Canada, www.acdlabs.com.
- 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.Maestro (v7.0.113)—a unified interface for all Schrodinger products, developed and marketed by Schrodinger, LLC. NY, Copyright 2005; http://www.schrodinger.com.
- 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
- 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
- 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
- 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.