Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells

Abstract

Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC 50 20.4 µM)and U-251 MG non-CSCs (IC 50 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γbutyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,β-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.

MicroRNA-Dependent Mechanisms Underlying the Function of a β-Amino Carbonyl Compound in Glioblastoma Cells

“…Several studies have reported the effectiveness of compounds possessing a carbonyl motif in GB management. For instance, the α,β-unsaturated carbonyl moiety of guaianolide sesquiterpene lactone cynaropicrin (1) expressed strong antiproliferative activity within U251MG glioblastoma cancer stem cells, suggesting potential therapeutic applications in targeting GB . In addition, a different sesquiterpene compound, compound 12 (oxyphyllanene B, OLB), which also possess an α,β-unsaturated carbonyl moiety was observed to induce apoptosis in time- and dose-dependent manners within TMZ-resistant GB cells …”

“…For instance, the α,β-unsaturated carbonyl moiety of guaianolide sesquiterpene lactone cynaropicrin (1) expressed strong antiproliferative activity within U251MG glioblastoma cancer stem cells, suggesting potential therapeutic applications in targeting GB. 11 In addition, a different sesquiterpene compound, compound 12 (oxyphyllanene B, OLB), which also possess an α,β-unsaturated carbonyl moiety was observed to induce apoptosis in time-and dose-dependent manners within TMZ-resistant GB cells. 12 In the current study, we sought to investigate the efficacy of an in-house synthesized β-AC compound, b3-(4-bromophenyl)-1-phenyl-3-(phenylamino)propan-1-one (SHG-8), and its effects upon miRNA regulation within GB cell models.…”