GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Srivastavá, R. C.; Kaylani, Samer Zaid; Edrees, Nayf; Li, Changzhao; Talwelkar, Sarang S.; Xu, Jiang; Palle, Komaraiah; Pressey, Joseph G.; Athar, Mohammad

doi:10.18632/oncotarget.2569

Cited by 85 publications

(85 citation statements)

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“…But tumour cells often generated resistant to chemotherapeutic drugs, it is very important to determine the path mechanisms of the drug resistance. Many reports have showed that GLI protein level decreases in a dose-dependent manner in response to GANT61 treatment (Kramann et al 2015; Moshai et al 2014; Srivastava et al 2014). GLI is considered to be a master regulator of the SHH pathway by regulating the genes expression that are crucial for cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis

Lin

Huang

et al. 2016

J Cancer Res Clin Oncol

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PurposeThe sonic hedgehog (SHH) signalling pathway plays the important role in medulloblastoma (MB). Altered GLI expression plays a key role in these processes, and the inhibition of GLI may be a good cancer-targeted therapy. This study aimed to investigate whether GANT61, a GLI inhibitor, may inhibit the SHH signalling pathway promoting cell mitochondria-mediated apoptosis and enhance cisplatin apoptosis antineoplastic therapy.MethodsIn our study, we determined the effect of GANT61-mediated inhibition of GLI in Daoy MB cells. Cells were treated with different concentrations of GANT61 alone or in combination with cisplatin. Cell proliferation was assessed with CCK-8 assays, and cell invasion and migration were performed using 8-µm transwell inserts. Cell apoptosis was assessed with flow cytometric analysis and rhodamine 123. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting.ResultsThe GANT61 significantly inhibited cell proliferation. GANT61 decreased the cell migration and invasion, impairing these crucial steps in tumour progression. Cell apoptosis was significantly increased in Daoy cells. Rhodamine 123 assay showed that GANT61 could decrease the mitochondrial membrane potential promoting cell mitochondria-mediated apoptosis. GANT61 inhibited the expression of GLI and Bcl-2 at both the mRNA and protein levels and might affect the expression of Bax, caspase-3 and caspase-9 to promote cell intrinsic apoptosis. Furthermore, GANT61 could enhance cisplatin-induced apoptosis to decrease the IC50 value of cisplatin. Finally, data suggest that GANT61 could enhance cisplatin-induced apoptosis through promoting the expression of Bax, caspase-3 and caspase-9 protein levels.ConclusionOur data suggest that the SHH signalling pathway plays an important role in MB. GLI is an oncogenic transcription factor in the SHH pathway, and targeting GLI with GANT61 results in favourable antitumour activity and targeted therapy.

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Section: Introductionmentioning

confidence: 99%

Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis

Lin

Huang

et al. 2016

J Cancer Res Clin Oncol

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“…Therefore, the generation of new cyclopamine derivates or inhibitors of other components of Hh signaling opened new avenues for targeting this pathway. For instance, GANT-61, an inhibitor of GLI activity has been reported to reduce RMS tumor growth in the chick chorioallantoic membrane (CAM) assay and in xenograft mouse models, even though at high concentrations [62,65,66].…”

Section: Targeting Hedgehog In Rmsmentioning

confidence: 99%

“…Indeed, rapamycin, an mTOR inhibitor, has been reported to prevent RMS tumor growth by inhibiting both PI3K/AKT/mTOR and Hh signaling [85]. More important, the inhibitory effect of GANT61 on RMS cell proliferation is strongly enhanced by mTOR antagonists or chemotherapeutic agents, suggesting that combination strategies involving Hh inhibitors might be a beneficial therapeutic modality [66]. However, different scenarios of non-canonical activation of Gli transcription factors may occur and account for SMOindependent activation of Hh signaling.…”

Section: Challenges Of Targeting Hedgehog Pathway and Future Directionsmentioning

confidence: 99%

Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

Manzella¹,

Schäfer

2016

CDT

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Rhabdomyosarcoma (RMS) is the most frequent pediatric soft-tissue tumor accounting for about 7% of childhood malignancies. Multimodal therapy is the standard treatment for individuals with RMS but generally fails to cure high-risk group patients and can result in long-term side effects. Therefore, understanding the mechanisms driving RMS might help to find new candidate targets for more specific and effective therapeutic modalities. One of the molecular machineries, which is often deregulated in cancer and specifically involved in the tumorigenesis of RMS, is Hedgehog (Hh) signaling. There is increasing evidence that targeting this developmental pathway may hold promise in future treatment strategies for RMS. In this review, we discuss the contribution of the Hh pathway in RMS, the challenges of inhibiting this embryonic signaling in children with an update on recent preclinical data and ongoing clinical trials.

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“…GANT61 is a GLI inhibitor that has been shown to reduce GLI expression in a rhabdomyosarcoma model [71] . However, more recently, a study demonstrated in vitro that GLI expression was not significantly decreased by the treatment with GANT61 in the leukemia cell lines but GANT61 inhibited proliferation of the cell lines and the viability of the cells [72] .…”

Section: Gli Inhibitionmentioning

confidence: 99%

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

2016

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Basal cell carcinoma (BCC) is the most common type of human malignancy. It is a slow-growing skin cancer with little ability to metastasize, but it is aggressive and can cause local tissue destruction. Descriptions of Basal Cell Nevus Syndrome (BCNS), characterized by a predisposition to the formation of BCC and other neoplasms, and identification of the genetic defect in this syndrome, has led to significant advancement in our understanding of the pathogenesis of BCC. Unregulated expression of target genes in the sonic Hedgehog (SHH) signaling pathway plays a prominent role in the pathogenesis of BCC. An understanding of the signaling components has allowed for the development of pharmacologic agents that inhibit the SHH pathway. The first inhibitor of the SHH pathway approved by the Food and Drug Administration (FDA) for the treatment of BCC is vismodegib. In this review, we will discuss the biochemical pathways involved in BCC as targets of novel pharmacologic therapies.

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GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Cited by 85 publications

References 50 publications

Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis

Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis

Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

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