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

Lorenzo Sansalone,Roger Leblanc,Stephan Schürer,Ingrid Torrens,Vasileios Stathias,Regina Graham,Nadia Myrthil,Winston Walters,Steven Vanni,Eduardo Veliz

doi:10.3390/cancers11030357

Lorenzo Sansalone, Roger Leblanc + Show 8 more

Open Access

https://doi.org/10.3390/cancers11030357

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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.

Highlights

Glioblastoma (GBM) is one of the worst diagnoses that a person can receive, with an average survival time of approximately 12–15 months [1]
The synthesis of bis-chalcones 4a–4s is outlined in the following reaction scheme (Figure 1)
Bis-chalcones were prepared by a base-catalyzed Claisen–Schmidt condensation between 2,6The bis-chalcones were prepared by a base-catalyzed Claisen–Schmidt condensation between diacetylpyridine (1 equivalent) and the appropriate aryl aldehyde (2.1 equivalents) using either

Summary

Introduction

Glioblastoma (GBM) is one of the worst diagnoses that a person can receive, with an average survival time of approximately 12–15 months [1]. It is the most common and malignant form of primary. Cancers 2019, 11, 357 brain cancer and is currently treated with surgery to remove the tumor followed by radiotherapy with concurrent chemotherapy. It is a highly invasive cancer, invading into the normal tissue surrounding the tumor, making a total resection virtually impossible. Treatment failure has been attributed to the highly invasive nature of these tumors as well as the presence of treatment resistant glioblastoma stem-like cancer cell known as tumor initiating cells or glioblastoma stem cells (GSCs) [3]

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