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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)

Abstract

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.

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Acknowledgments

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.

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The authors declare that they have no competing interests.

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Correspondence to Rajesh Kumar Kesharwani.

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Kesharwani, R.K., Srivastava, V., Singh, P. et al. 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). Appl Biochem Biotechnol 176, 1996–2017 (2015). https://doi.org/10.1007/s12010-015-1696-x

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Keywords

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