Chlorambucil-conjugated PI-polyamides (Chb-M'), a transcription inhibitor of RUNX family, has an anti-tumor activity against SHH-type medulloblastoma with p53 mutation.

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. • RUNXs were significantly highly expressed in SHH medulloblastoma. • Chb-M′ inhibits growth of SHH-type medulloblastoma with p53 mutation. • Knocking down of RUNX1 or RUNX2 retards proliferation of medulloblastoma. • Chb-M′ can be a novel drug for the SHH-type medulloblastoma with p53 mutation. [ABSTRACT FROM AUTHOR]