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    • Medulloblastoma predominantly occurs in infants and children

    2022-01-15

    Medulloblastoma predominantly occurs in infants and children, and is the most-common type of paediatric malignant Adenosine Kinase Inhibitor hydrate synthesis tumour, accounting for about 20% of all childhood brain tumors [63]. According to cancer genomics, medulloblastoma consists of at least 4 distinct subgroups: Hh driven, Wnt driven, c-Myc driven and a fourth group associated with chromosomal copy number variations [64]. It has been a tantalizing idea to treat Hh driven medulloblastoma by inhibiting Hh pathway. Clinical trials found that the response to Smo antagonist (GDC-0449 or LDE-225) for the subgroup of Hh driven medulloblastoma were desirable [[65], [66], [67], [68]]. However, only patients with Ptch1 mutations or certain Smo mutations have benefited from the treatment, whereas patients with Sufu and Gli1 mutations were less affected by these drugs. Moreover, prolonged exposure to these drugs induces mutations in Smo that changes the structure of the protein and prevents binding of the drug, resulting in drug resistance [69,70]. In the present studies, CBC and CBD exhibited desirable activities against growth of Ptchp53 medulloblastoma with efficient blood-brain barrier penetration. Furthermore, they overcame GDC-0449 resistant Hh pathway activation induced by Smo mutation. These results implied that CBC and CBD may be potent in the treatment of Hh driven medulloblastoma. It is possible that this pair of epimers might suppress other Hh-dependent malignancy, which warrants further evaluation. Since Gli is the last effector of the Hh pathway, whatever alteration leads to aberrant activation of Hh pathway, such as genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all trigger the down-stream effector Gli. For this reason, Gli factors are emerging as attractive targets for the development of novel anticancer drugs and the Gli inhibitors would in theory be more broadly applicable than upstream inhibitors. However, due to the lack of structural details of Gli and poor mechanism of Gli-mediated transcription, only a few Gli antagonists have been identified [19]. GANT61 inhibited Gli-dependent transcription by at the pre-initiation complex during the initiation process of RNA synthesis, and the coordination of transcription and DNA replication licensing at sites in promoter regions that bond by the specific Gli1 [71]. Tang et al. revealed that BRD4 directly occupies Gli1 and Gli2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1 [47]. Arsenic trioxide (ATO), used in the treatment of acute promyelocytic leukemia, has been shown to act as a Gli inhibitor and is being evaluated in clinical trials to treat BCC (NCT02699723 and NCT01791894, referring to http://www.clinicaltrials.gov/). Kim et al. suggested that ATO inhibited the Hh pathway by preventing ciliary trafficking and destabilizing Gli2 [72]. Later, Beauchamp et al. found that ATO directly bound to Gli1 protein and inhibited its transcriptional activity [73]. Physalin H, a natural product from Solanum nigrum, disrupted GLI1 binding to its DNA binding domain [74]. FN1-8, a synthetic small molecule interfered the interaction between Gli and a transcription coactivator TBP-associated factor 9 (TAF9) and downregulate Gli/TAF9-dependent transcriptional activity [75]. HPI 1–4 are four Hh pathway inhibitors that regulate processing, activation, or ciliary trafficking of Gli1/2 [76]. Most significantly, Infante et al. clarified the structural requirements of Gli1 for binding to DNA and identify Glabrescione B, a natural isoflavone as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA [77]. Our present studies showed that CBC and CBD inhibited the Hh pathway at the level of Gli. However, whether they directly recognize and block Gli transcriptional functions or inhibit Gli functions indirectly is still unknown, the precise mechanism necessitates further investigation.