GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

Li, Jianlong; Cai, Jinquan; Zhao, Shijun; Yao, Kun; Sun, Ying; Li, Yongli; Chen, Lingchao; Li, Ruiyan; Zhai, Xiuwei; Zhang, Junhe

doi:10.1186/s13046-016-0463-3

Cited by 59 publications

(53 citation statements)

References 44 publications

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“…In all combined treatment conditions, we observed a significant decrease in cell viability, as described in previous studies [25,42]. The pharmacological combination of TMZ and cyclopamine (TMZ+Cyclo) showed a cooperative effect, corroborating the idea that the pharmacological combination of TMZ with other drugs, such as SHH inhibitor GANT61, are more successful than monotherapy by decreasing the cell viability of GBM cells [1,[60][61][62].…”

Section: Discussionsupporting

confidence: 87%

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Carballo

Matias

Honorato

et al. 2020

Preprint

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AimGlioblastoma is an extremely aggressive glioma, resistant to radio and chemotherapy usually performed with temozolomide. One of the main reasons for glioblastoma resistance to conventional therapies is due to the presence of cancer stem-like cells. These cells could recapitulate some signaling pathways important for embryonic development, such as Sonic hedgehog. Here, we investigated if the inhibitor of the Sonic hedgehog pathway, cyclopamine, could potentiate the temozolomide effect in cancer stem-like cells and glioblastoma cell lines in vitro.Main methodsThe viability of glioblastoma cells exposed to cyclopamine and temozolomide treatment was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while the induction of apoptosis was assessed by western blot. The stemness properties of glioma cells were verified by clonogenic and differentiation assay and the expression of stem cell markers were measured by fluorescence microscopy and western blot.Key findingsThe glioblastoma viability was reduced by cyclopamine treatment. Cyclopamine potentiated temozolomide treatment in glioblastoma cell lines by inducing apoptosis through activation of caspase-3 cleaved. Conversely, the combined treatment of cyclopamine and temozolomide potentiated the stemness properties of glioblastoma cells by inducing the expression of SOX-2 and OCT-4.SignificanceCyclopamine plays an effect on glioblastoma cell lines but also sensibilize them to temozolomide treatment. Thus, first-line treatment with Sonic hedgehog inhibitor followed by temozolomide could be used as a new therapeutic strategy for glioblastoma patients.

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Section: Discussionsupporting

confidence: 87%

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Carballo

Matias

Honorato

et al. 2020

Preprint

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“…Therefore, new therapeutic strategies are urgently needed. Molecular targeted therapy has become a hot topic in the study of the molecular mechanisms underlying GBM resistance [3, 4]. However, the blood-brain barrier (BBB) restricts the application of many drugs.…”

Section: Introductionmentioning

confidence: 99%

Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades

Wang

et al. 2017

J Exp Clin Cancer Res

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BackgroundGlioblastoma multiforme (GBM) is one of the most refractory and palindromic central nervous system (CNS) neoplasms, and current treatments have poor effects in GBM patients. Hence, the identification of novel therapeutic targets and the development of effective treatment strategies are essential. Alantolactone (ATL) has a wide range of pharmacological activities, and its anti-tumor effect is receiving increasing attention. However, the molecular mechanism underlying the anti-GBM activity of ATL remains poorly understood.MethodsThe biological functions of ATL in GBM cells were investigated using migration/invasion, colony formation and cell cycle/apoptosis assays. The localization of nuclear factor kappa B (NF-κB) p50/p65 and its binding to the cyclooxygenase 2 (COX-2) promoter were determined using confocal immunofluorescence, a streptavidin-agarose pulldown assay and a chromatin immunoprecipitation (ChIP) assay. IKKβ kinase activity was determined using a cell IKKβ kinase activity spectrophotometry quantitative detection kit and a molecular docking study. LC-MS/MS analysis was performed to determine the ability of ATL to traverse the blood-brain barrier (BBB). The in vivo anti-tumor efficacy of ATL was also analyzed in xenografted nude mice. Western blot analysis was performed to detect the protein expression levels.ResultsATL significantly suppressed the growth of GBM in vivo and in vitro. ATL significantly reduced the expression of COX-2 by inhibiting the kinase activity of IKKβ by targeting the ATP-binding site and then attenuating the binding of NF-κB to the COX-2 promoter region. Furthermore, ATL induced apoptosis by activating the cytochrome c (cyt c)/caspase cascade signaling pathway. Moreover, ATL could penetrate the BBB.ConclusionsATL exerts its anti-tumor effects in human GBM cells at least in part via NF-κB/COX-2-mediated signaling cascades by inhibiting IKKβ kinase activity. ATL, which is a natural small molecule inhibitor, is a promising candidate for clinical applications in the treatment of CNS tumors.

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“…U-251MG cells were divided into 4 groups and treated with NC (Ctrl), 2.5 µM MTB (MTB), 100 µM TMZ (TMZ) and combination treatment (2.5 µM MTB + 100 µM TMZ), separately. TMZ at a concentration of 100 µM was used as previously reported (21).…”

Section: Methodsmentioning

confidence: 99%

Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition

et al. 2019

Oncol Rep

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Temozolomide (TMZ) is a widely used chemotherapeutic agent for glioblastoma multiforme (GBM). However, chemoresistance to TMZ is still a major obstacle for GBM patients. An abundance of candidates has been reported to improve the chemotherapeutic sensitization of TMZ. In the present study, it was demonstrated that momelotinib (MTB) enhanced the sensitivity of glioma cells to TMZ in vitro, as evidenced by a noticeable decrease in cell growth and a significant increase in apoptosis and autophagy following treatment with the combination of TMZ and MTB compared to TMZ alone. Mechanistically, MTB and TMZ combination treatment reduced U251 cell growth by activating both apoptosis and autophagy pathways. MTB potentiated TMZ to inhibit the phosphorylation of JAK2 and STAT3 in U251 cells, resulting in the inactivation of JAK2/STAT3 signaling pathways. Moreover, we investigated the effect of MTB in xenograft tumor model mice. MTB and TMZ combination reduced tumor weight, decreased the expression of Ki-67, P62, p-STAT3 and p-JAK2, while increased the ratio of LC3-II/I and the expression of caspase-3 and Beclin1 in vivo. Importantly, this combination was well tolerated, and caused significant tumor growth inhibition in the GBM xenografts. In summary, the present study provides pharmacological evidence that MTB has potential value in the treatment of GBM.Abbreviations: MTB, momelotinib; TMZ, temozolomide; GBM, glioblastoma multiforme; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; p-STAT3, Tyr705-phosphorylated STAT3; DMSO, dimethyl sulfoxide; JAK2, janus kinase 2

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GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

Cited by 59 publications

References 44 publications

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades

Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition

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