The runt-related transcription factor-2 (RUNX2) promotes breast cancer (BC) progression and metastasis through transcriptional activation of its target genes. CADD522 is identified as a novel inhibitor of RUNX2-DNA binding with an IC50 of 10 nM. CADD522 inhibited the DNA binding activity of all RUNX proteins, but most prominent inhibition was observed for RUNX2-DNA binding. CADD522 also inhibited RUNX2 binding to the MMP13 (a well-known RUNX2 target gene) oligonucleotides in a dose-dependent manner. CADD522 significantly inhibited RUNX2 enrichment in the MCF7-RUNX2 cells. CADD522 (0 ∼ 100 μM) displayed a dose- and time-dependent cell growth inhibition over 72 hrs. However, the sensitivity of non-malignant cells to CADD522 was much lower than that of BC cell lines, indicating that CADD522 might not exhibit serious cytotoxicity for normal cell growth. CADD522 at 50 μM for 72 hrs exerted mild but significant growth inhibition (< 50%) in the majority of TNBC and luminal type BC cells. Among them, MDA-MB-468 (MDA-468) cells were most sensitive to CADD522 (> 50%). Moreover, this CADD522 treatment increased cell populations at the G1 phase with reduction at the S phase, indicating that the anti-proliferative effect of CADD522 might be associated with cell cycle arrest. Further, CADD522 dramatically decreased the size as well as the number of tumorspheres and tumorspheres were severely disrupted a few days after CADD522 treatment at the initial day of cell plating. In vivo, the intraperitoneal (i.p.) administration of CADD522 into the MMTV-PyMT mice (up to 20 mg/kg) delayed tumor development and reduced tumor burden in transgenic MMTV-PyMT mice[1].
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