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Cancers 2019, 11(3), 357; https://doi.org/10.3390/cancers11030357

Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death

1
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA
2
University of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
3
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136, USA
4
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1120 NW 14th St, Miami, FL 33136, USA
5
Department of Molecular and Cellular Pharmacology, Center for Computational Science, University of Miami Miller School of Medicine, 1120 NW 14th St, Miami, FL 33136, USA
6
Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
*
Author to whom correspondence should be addressed.
Received: 28 January 2019 / Revised: 4 March 2019 / Accepted: 7 March 2019 / Published: 13 March 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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Abstract

Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target. View Full-Text
Keywords: cancer stem cell; endoplasmic reticulum stress; glioblastoma multiforme; unfolded protein response; curcumin; bis-chalcones; brain tumor; glioblastoma stem cell cancer stem cell; endoplasmic reticulum stress; glioblastoma multiforme; unfolded protein response; curcumin; bis-chalcones; brain tumor; glioblastoma stem cell
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Sansalone, L.; Veliz, E.A.; Myrthil, N.G.; Stathias, V.; Walters, W.; Torrens, I.I.; Schürer, S.C.; Vanni, S.; Leblanc, R.M.; Graham, R.M. Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death. Cancers 2019, 11, 357.

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