Therapeutic Potential of RTA 404 in Human Brain Malignant Glioma Cell Lines via Cell Cycle Arrest via p21/AKT Signaling

Abstract

Background. Glioblastoma multiforme (GBM) is the most common malignant brain tumor in the world. Despite advances in surgical resection, radiotherapy, and chemotherapy, GBM continues to have a poor overall survival. CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid), a synthetic triterpenoid, is an Nrf2 activator used to inhibit proliferation and induce differentiation and apoptosis in various cancer cells. One new trifluoroethylamide derivative of CDDO, RTA 404, has been found to have increased ability to cross the blood-brain barrier. However, it is not clear what effect it may have on tumorigenesis in GBM. Methods. This in vitro study evaluated the effects of RTA 404 on GBM cells. To do this, we treated GBM840 and U87 MG cell lines with RTA 404 and assessed apoptosis, cell cycle, cell locomotion, and senescence. DNA content and induction of apoptosis were analyzed by flow cytometry and protein expression by Western blot analysis. Results. RTA 404 significantly inhibited the proliferation of tumor cells at concentrations higher than 100 nM ( p < 0.05 ) and reduced their locomotion ability. In addition, treatment with RTA 404 led to an accumulation of RTA 404-treated G 2 / M phase cells and apoptosis. An analysis of the p21/AKT expression suggested that RTA 404 may not only help prevent brain cancer but it may also exert antitumor activities in established GBM cells. Conclusion. RTA404 can inhibit proliferation, cell locomotion, cell cycle progression, and induce apoptosis in GBM cells in vitro, possibly through its inhibition of N-cadherin and E-cadherin expression via its inhibition of the AKT pathway.

RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma

“…Therefore, these results indicated that incubation with RTA404 inhibited cell viability and initiated cell apoptosis through an intrinsic apoptotic pathway. Although treatment with RTA404 led to cell cycle arrests in previous studies [ 19 ], without significantly change in mitosis index have found in RTA404 treatment. Based on the above results, it seems to imply that RTA404 activated the DNA checkpoint system and induced apoptosis through an intrinsic apoptotic pathway in established U87MG cells.…”

“…Moreover, in one study, it induced apoptosis in neuroblastoma cells [ 18 ]. In addition, in GMC cells, RTA404 can inhibit proliferation, cell locomotion, and cell cycle progression and induce apoptosis [ 19 ].…”

Induction of Mitosis Delay And Apoptosis By RTA 404 In Glioblastoma Multiforme

“…Severe depletion in S-phase indicates that DNA synthesis is extremely sensitive to RTA 404. However, the author also cannot rule out G2/M block in addition to the S-phase depletion, since cells trapped in the G2/M at the time of treatment by triterpenoids did not progress into G1/G0 phase [14].In the human brain, malignant glioma cell lines incubated with RTA 404 resulted in cell cycle arrest in the G2/M phase [15].As shown in Fig. 5, treatment with RTA 404 led to an increment in the G2/M phase cell population, implying that GBM 8401 cells underwent a delay in the G2/M phase checkpoint.…”

“…RTA 404 has been found to have neuroprotective effects in some animal models of degenerative diseases, including ischemic stroke [9] and autoimmune encephalomyelitis [11].It has also been found to induce apoptosis of neuroblastoma cells [14]. Furthermore, RTA 404 can inhibit proliferation, cell locomotion, cell cycle progression and induce apoptosis in GBM cells [15].…”

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

“…Moreover, in one study, it induced apoptosis in neuroblastoma cells ( Alabran et al, 2008 ). In addition, in GMC cells, CDDO-TFEA can inhibit proliferation, cell locomotion, and cell cycle progression and induce apoptosis ( Tsai et al, 2021 ).…”