Induction of Mitosis Delay and Apoptosis by CDDO-TFEA in Glioblastoma Multiforme

Abstract

Background: Glioblastoma multiforme (GBM) is the vicious malignant brain tumor in adults. Despite advances multi-disciplinary treatment, GBM constinues to have a poor overall survival. CDDO-trifluoroethyl-amide (CDDO-TEFA), a trifluoroethylamidederivative of CDDO, is an Nrf2/ARE pathway activator. CDDO-TEFEA is used to inhibit proliferation and induce apoptosis in glioma cells. However, it not clear what effect it may have on tumorigenesis in GBM.Methods: This in vitro study evaluated the effects of CDDO-TFEA on GBM cells. To do this, we treated GBM8401 cell lines with CDDO-TFEA and assessed apoptosis, cell cycle. DNA content and induction of apoptosis were analyzed by flow cytometry and protein expression by Western blot analysis.Results: CDDO-TFEA significantly inhibited the cell viability and induced cell apoptosis on GBM 8401 cell line. The annexin-FITC/PI assay revealed significant changes in the percentage of apoptotic cells. Treatment with CDDO-TFEA led to a significant reduction in the GBM8401 cells’ mitochondrial membrane potential. A significant rise in the percentage of caspase-3 activity was detected in the treated cells. In addition, treatment with CDDO-TFEA led to an accumulation of G2/M-phase cells. In addition, these results suggest that regarding increased protein synthesis during mitosis in the MPM-2 staining, indicative of a delay in the G2 checkpoint. An analysis of Cyclin B1, CDK1, Cyclin B1/CDK1 complex and CHK1 and CHK2 expression suggested that cell cycle progression seems also to be regulated by CDDO-TFEA. Therefore, CDDO-TFEA may not only induce cell cycle G2/M arrest, it may also exert apoptosis in established GBM cells.Conclusion: CDDO-TFEA can inhibit proliferation, cell cycle progression and induce apoptosis in GBM cells in vitro, possibly though its inhibition of Cyclin B1, CDK1 expression, and Cyclin B1/CDK1 association and the promotion of CHK1 and CHK2 expression.

A Novel Synthetic Oleanolic Acid Derivative Inhibits Glioma Cell Proliferation by Regulating Cell Cycle G2/M Arrest

“…Therefore, CDDO and its derivatives have been used to treat chronic inflammatory diseases, such as Friedreich Ataxia [ 27 ] and chronic kidney disease [ 28 ]. Cytotoxic effects on tumor cells have been described for CDDO [ 29 ], derivatives that include CDDO-Me [ 30 ], CDDO-Im [ 20 ], CDDO-EA [ 20 ], CDDO-TFEA [ 22 , 23 ], and omaveloxolone [ 31 ] at moderate and high doses. As a result, CDDO and its derivatives could potentially exhibit anticancer activity at multiple levels.…”

“…Furthermore, Kim et al [ 18 ] demonstrated that the ability of CDDO-Im to inhibit the BRCA1 mutant tumor G2/M cell cycle was associated with DNA damage followed by the activation of the DNA damage checkpoint. Finally, Tsai et al showed that induction of G2/M arrest in the cell cycle may be attributed to CDDO-TFEA treatment in established GBM8401 [ 23 , 36 ] and U87MG cells [ 22 , 36 ]. Taken together, these findings provide evidence that CDDO derivatives such as CDDO-dhTFEA induce cell cycle arrest in the G2/M phase, likely through the regulation of G2/M cell cycle genes.…”

“…As a result, inducing cell cycle arrest and promoting cell apoptosis or autophagy are important therapeutic strategies for treating cancer cells with anticancer drugs [ 15 , 16 , 17 ]. CDDO and its derivatives have shown promise in inducing cell cycle arrest in a variety of cancers, such as breast cancer [ 18 ], leukemia [ 19 ], neuroblastoma [ 20 , 21 ], and glioma [ 22 , 23 ]. CDDO-dhTFEA has been shown to regulate the cancer cell cycle and induce cell cycle arrest.…”