GANT-61 Induces Autophagy and Apoptosis in Glioblastoma Cells despite their heterogeneity

Carballo, Gabriela Basile; Ribeiro, Jéssica Honorato; Lopes, Giselle Pinto de Faria; Ferrer, Valéria Pereira; Dezonne, Rômulo Sperduto; Pereira, Cláudia Maria; Spohr, Tânia Cristina Leite de Sampaio e

doi:10.1007/s10571-020-00891-6

Cited by 22 publications

(17 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result contrasts with the fact that the Shh pathway promotes EMT [47], as it is precisely the U87MG line, the most epithelial of the three glioblastoma cell lines, that presents an active Shh pathway. However, T98G cells have been shown to be activated with recombinant Shh treatment but not inhibited after GANT61 treatment [48], which we believe reinforces our results.…”

Section: Expression Of Hdac6 and Mesenchymal And Autophagic Markers In Glioblastoma Samples And Cell Linessupporting

confidence: 91%

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

Urdiciain

Erausquin

Zelaya

et al. 2021

Biology

View full text Add to dashboard Cite

Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor. We treated glioblastoma cell lines with siHDAC6. HDAC6 silencing inhibited proliferation, migration, and clonogenicity of glioblastoma cell lines. They also reversed the mesenchymal phenotype, decreased autophagy, inhibited Shh pathway, and recovered the expression of primary cilia in glioblastoma cell lines. These results demonstrate that HDAC6 might be a good target for glioblastoma treatment.

show abstract

Section: Expression Of Hdac6 and Mesenchymal And Autophagic Markers In Glioblastoma Samples And Cell Linessupporting

confidence: 91%

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

Urdiciain

Erausquin

Zelaya

et al. 2021

Biology

View full text Add to dashboard Cite

show abstract

“…The reports of the resistance to FDA-approved cancer therapies targeting SHH signaling ( 87 ), and the involvement of other pathways, such as PI3K/AKT, in the stimulation of GLI-mediated transcription ( 17 ) suggest that direct inhibition of GLIs may be more effective than targeting the upstream SHH pathway components. Although the promising effects of using GANT61 have been observed in experiments on ovarian ( 88 ) or glioblastoma cells ( 89 ), this compound has not yet been examined in clinical trials. The present analysis revealed that GANT61 arrested ACHN and 786-O kidney cancer cells in the G 2 /M phase and inhibited the migration of 786-O cells.…”

Section: Discussionmentioning

confidence: 99%

Expression levels of sonic hedgehog pathway genes and their targets are upregulated in early clear cell renal cell carcinoma

et al. 2022

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer, with high mortality rates worldwide. The sonic hedgehog (SHH) molecular cascade is altered in various malignancies in tumorigenesis, and several SHH pathway inhibitors have been considered as potential anticancer drugs. The aim of the present study was to determine the expression profile of SHH signaling components and their target genes in ccRCC. Additionally, the present study examined the effects of SHH pathway inhibitory drugs (RU-SKI43, cyclopamine and GLI-antagonist 61) on cell viability, cell cycle progression, expression levels of SHH target genes and migration ability in 786-O, ACHN and HK2 cells. The study also included paired tumor and normal samples from 62 patients with ccRCC. The mRNA levels in clinical samples and cell lines were measured via reverse transcription-quantitative PCR. Cell viability was examined using a sulforhodamine B assay. Flow cytometry was used to investigate cell cycle progression and the migratory rate of cells was assessed using a wound healing assay. High mRNA levels of SHH , smoothened ( SMO ), glioma-associated zinc finger protein ( GLI ) 1-3 , BCL2 apoptosis regulator ( BCL2 ), MYC proto-oncogene ( MYC ), vascular endothelial growth factor A ( VEGFA ) and cyclin D1 ( CCND1 ) were observed in the tumor tissues, especially in early ccRCC, according to the TNM stage or World Health Organization/International Society of Urological Pathology (ISUP) grade. High expression levels of VEGFA , as well as low CCND1 mRNA expression, were associated with short overall survival, and increased VEGFA expression was an independent prognostic factor of a poor outcome in patients with advanced ISUP grade (Cox hazard ratio test). Cyclopamine treatment was found to arrest 786-O cells in the G 2 /M phase and decreased the expression levels of GLI1 , BCL2 , VEGFA and CCND1 . RU-SKI43 inhibited cell migration and decreased the expression levels of BCL2 , MYC and CCND1 in ACHN cells. Overall, the results of the present study suggested that SHH signaling may be involved in the early development of ccRCC, and the expression levels of CCND1 and VEGFA may serve as prognostic factors of this disease. Cyclopamine and RU-SKI43 appear to be potential anti-renal cell carcinoma drugs; however, this hypothesis requires verification by further in vivo studies.

show abstract

“…Next, efforts were made to unveil the underlying mechanism of action of antiliver cancer effects of irigenin. Apoptosis is one of the leading targets of anticancer drugs and occurs naturally in multicellular organisms to discard damaged, aged, and malfunctioning cells [5]. Apoptosis gets stimulated by intrinsic (mitochondrial mediated) and extrinsic (death receptors) factors.…”

Section: Discussionmentioning

confidence: 99%

Irigenin exerts anticancer effects on human liver cancer cells via induction of mitochondrial apoptosis and cell cycle arrest

Kuang

Wang

et al. 2021

Appl Biol Chem

View full text Add to dashboard Cite

Irigenin has been reported to exhibit remarkable anticancer effects against several human cancers. Nonetheless, the anticancer effects of irigenin against the human liver cancer cells are still largely unexplored. Consistently, this study was designed to evaluate the anticancer effects of irigenin against human liver cancer cells and to unveil the underlying molecular mechanisms. The results showed that irigenin significantly (p < 0.05) inhibited the growth of the human HepG2 and SNU-182 liver cancer cells with an IC50 value of 14 µM. Nonetheless, the cytotoxic effects of irigenin against the normal THLE-2 cells were comparatively lower as evident from the IC50 of 120 μM. The AO/EB and DAPI staining showed that irigenin induces apoptosis in the human liver cancer cells. Annexin V/PI staining assay revealed a significant (p < 0.05) increase in the percentage of apoptotic HepG2 and SNU-182 liver cancer cells upon treatment with irigenin. It was found that the number of apoptotic HepG2 and SNU-182 cells enhanced from 2.3 to 41.75% and 1.16 to 51.9% at IC50, respectively. Western blot showed a considerable increase in Bax and decrease in the Bcl-2 expression upon irigenin treatment further confirming the induction of apoptosis. Flow cytometric analysis revealed that irigenin also induces G2/M cell cycle arrest of HepG2 and SNU-182 cells. The percentage of G2/M phase HepG2 and SNU-182 cells increased from 17.92 to 34.35% and 23.97 to 38.23% at IC50, respectively This was also accompanied by decrease in the expression of CDK1 and Cyclin-B in HepG2 and SNU-182 cells. Taken together, the results of the present study suggest that irigenin inhibits the growth of the human liver cancer cells via induction of apoptosis and cell cycle arrest. These results point towards the potential of irigenin as a lead for the development of chemotherapy for liver cancer.

show abstract

GANT-61 Induces Autophagy and Apoptosis in Glioblastoma Cells despite their heterogeneity

Cited by 22 publications

References 82 publications

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

Expression levels of sonic hedgehog pathway genes and their targets are upregulated in early clear cell renal cell carcinoma

Irigenin exerts anticancer effects on human liver cancer cells via induction of mitochondrial apoptosis and cell cycle arrest

Contact Info

Product

Resources

About