Inhibition of Hedgehog/Gli Signaling by Botanicals: A Review of Compounds with Potential Hedgehog Pathway Inhibitory Activities

Drenkhahn, Sara K.; Jackson, Glenn A.; Ślusarz, Anna; Starkey, Nicholas J.E.; Lubahn, Dennis B.

doi:10.2174/15680096113139990003

Cited by 23 publications

(16 citation statements)

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“…Similar to cyclopamine, these drugs act by inhibition of SMO (23, 57, 58). The most studied of these analogs is Vismodegib (GDC-0449), however, much of the research have been conducted in basal cell carcinomas (BCCs) rather than medulloblastomas because an increased prevalence of BCCs and a similar molecular pathogenesis (23).…”

Section: Therapeutic Targeting Of Medulloblastomasmentioning

confidence: 99%

Pediatric Medulloblastoma â€“ Update on Molecular Classification Driving Targeted Therapies

et al. 2014

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As advances in the molecular and genetic profiling of pediatric medulloblastoma evolve, associations with prognosis and treatment are found (prognostic and predictive biomarkers) and research is directed at molecular therapies. Medulloblastoma typically affects young patients, where the implications of any treatment on the developing brain must be carefully considered. The aim of this article is to provide a clear comprehensible update on the role molecular profiling and subgroups in pediatric medulloblastoma as it is likely to contribute significantly toward prognostication. Knowledge of this classification is of particular interest because there are new molecular therapies targeting the Shh subgroup of medulloblastomas.

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Section: Therapeutic Targeting Of Medulloblastomasmentioning

confidence: 99%

Pediatric Medulloblastoma â€“ Update on Molecular Classification Driving Targeted Therapies

et al. 2014

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“…The Hh signaling pathway has been found to play a critical role in many human cancers including basal cell carcinoma, medulloblastoma, glioma, colon, breast, lung, pancreas and recently in OSA [6], [7], [11]. This pathway mediates cell growth and survival through activation of pathways associated with transcription factors GLI1 and GLI2 [12], [13].…”

Section: Introductionmentioning

confidence: 99%

Blocking Signaling at the Level of GLI Regulates Downstream Gene Expression and Inhibits Proliferation of Canine Osteosarcoma Cells

2014

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The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.

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“…Activation of GLI transcription factors can promote the transcription of Hh target genes (36,37). GLI1 is one of the members of the GLI transcription factor family, with an exclusively full-length transcriptional activator (38,39). GLI1 is upstream in the signaling pathway, thus targeting GLI1 can be useful in tumors harboring mutations of SMO or mediation downstream of SMO (36).…”

Section: Discussionmentioning

confidence: 99%

Sclareolide enhances gemcitabine-induced cell death through mediating the NICD and Gli1 pathways in gemcitabine-resistant human pancreatic cancer

Chen¹,

Wang

Zhang³

et al. 2017

Molecular Medicine Reports

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Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc-1 and ASPC-1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine-resistant cells (GR-HPCCs). The anticancer effect of gemcitabine combined with sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GR-HPCCs, and the mechanisms were investigated. Sclareolide resensitized the GR-HPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GR-HPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabine-induced EMT through the TWIST1/Slug pathway in the GR-HPCCs. In addition, sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/glioma-associated oncogene 1 (Gli1) pathway, which triggered TWIST1/Slug-hENT1/RRM1 signaling and resensitized GR-HPCCs to gemcitabine. Finally, sclareolide resensitized GR-HPCCs to gemcitabine through inducing apoptosis; in vivo, the co-administraion of sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabine-resistant pancreatic cancer, which resensitizes GR-HPCCs to gemcitabine through mediating NICD and Gli1.

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Inhibition of Hedgehog/Gli Signaling by Botanicals: A Review of Compounds with Potential Hedgehog Pathway Inhibitory Activities

Cited by 23 publications

References 0 publications

Pediatric Medulloblastoma â€“ Update on Molecular Classification Driving Targeted Therapies

Pediatric Medulloblastoma â€“ Update on Molecular Classification Driving Targeted Therapies

Blocking Signaling at the Level of GLI Regulates Downstream Gene Expression and Inhibits Proliferation of Canine Osteosarcoma Cells

Sclareolide enhances gemcitabine-induced cell death through mediating the NICD and Gli1 pathways in gemcitabine-resistant human pancreatic cancer

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