RRC ID 73118
Author Matsui Y, Mineharu Y, Noguchi Y, Hattori EY, Kubota H, Hirata M, Miyamoto S, Sugiyama H, Arakawa Y, Kamikubo Y.
Title Chlorambucil-conjugated PI-polyamides (Chb-M'), a transcription inhibitor of RUNX family, has an anti-tumor activity against SHH-type medulloblastoma with p53 mutation.
Journal Biochem Biophys Res Commun
Abstract Malignancy of medulloblastoma depends on its molecular classification. Sonic Hedgehog (SHH)-type medulloblastoma with p53 mutation was recognized as one of the most aggressive types of tumors. We developed a novel drug, chlorambucil-conjugated PI-polyamides (Chb-M'), which was designed to compete with the RUNX consensus DNA-binding site. Chb-M' specifically recognizes this consensus sequence and alkylates it to inhibit the RUNX transcriptional activity. In-silico analysis showed all the RUNX families were upregulated in the SHH-type medulloblastoma. Thus, we tested the anti-tumor effects of Chb-M' in vitro and in vivo using Daoy cell lines, which belong to SHH with p53 mutation. Chb-M' inhibited tumor growth of Daoy cells by inducing apoptosis. The same inhibitory effect was also observed by knocking down of RUNX1 or RUNX2, but not RUNX3. Apoptosis array analysis showed that Chb-M' treatment induced phosphorylation of p53 serine 15 residues. In a subcutaneous tumor model, intratumoral injection of Chb-M' induced tumor growth retardation. Chb-M' mediated inhibition of RUNX1 and RUNX2 can be a novel therapeutic strategy for SHH-type medulloblastoma with p53 mutation.
Volume 620
Pages 150-157
Published 2022-9-10
DOI 10.1016/j.bbrc.2022.06.090
PII S0006-291X(22)00951-2
PMID 35792512
MeSH Cerebellar Neoplasms* / drug therapy Cerebellar Neoplasms* / genetics Cerebellar Neoplasms* / metabolism Chlorambucil / pharmacology Core Binding Factor Alpha 1 Subunit / metabolism Core Binding Factor Alpha 2 Subunit / metabolism Hedgehog Proteins / metabolism Humans Medulloblastoma* / drug therapy Medulloblastoma* / genetics Medulloblastoma* / metabolism Mutation Nylons / chemistry Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism
IF 2.985
DNA material pENTR4-H1tetOx1 (RDB07916) CS-RfA-ETBsd (RDB07917) CS-RfA-ETV (RDB08020) CS-RfA-ETR (RDB08362)