A Novel Synthetic Inhibitor of CDC25 Phosphatases

Abstract

CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models.BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G 1 -S, in S phase and at the G 2 -M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G 1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice.BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.

Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells

“…Validation of this model can be explored in transgenic animals harboring selectively these oncogenic alterations, in cooperation with forced expression of TFF1 in intestinal stem cells, through intestinal promoters that are functional in this cellular compartment, such as the villin (pVIL) and carcinoembryonic antigen (pCEA) regulatory regions. Taken together, our data validate the therapeutic targeting of the TFF1 and Cdc25 signaling pathways (Brezak et al, 2005) in colon and breast cancer patients with TFF1-positive tumors.…”

“…The human phosphatase Cdc25A is an oncogenic protein (Galaktionov et al, 1995). Both Cdc25a and b genes are involved in tumor growth and play critical roles in regulating apoptosis and cell cycle progression (Mitra and Enders, 2004;Brezak et al, 2005). Increased expression of Cdc25A, B and C in active dephosphorylated forms are observed in aggressive human cancers (Kallstrom et al, 2005).…”

IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

“…Initial results support the view that CDC25 is an interesting and important anticancer target, 12,13,23 and considerable effort is currently directed to the identification additional candidate drugs. Here, we describe a novel small molecule bearing two quinone moieties that is a potent inhibitor of CDC25 family members and which inhibits human tumor cell proliferation in both in vitro and in vivo models.…”

“…2 For instance, when specifically targeted to the mammary gland, overexpression of CDC25B, in association with the carcinogen DMBA (9,10-dimethyl-1,2-benzanthracene), has been shown to induce neoplasia. 3,4 Further, hemizygous disruption of CDC25A inhibits cellular transformation and mammary tumorigenesis in mice, suggesting that a low level of CDC25A protein plays a rate-limiting role in transformation and tumor initiation mediated by oncogene such as H-ras 12 and neu. 5,6 Finally, overexpression of CDC25A and CDC25B proteins has been observed in a wide variety of human tumors (see ref.…”

Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases

“…After 2 h at 30˚C, fluorescence emission from the dephosphorylated product, 3-O-methyl fluorescein (OMF), was measured with Cytofluor ® (Biosystem; excitation filter: 485 nm and emission filter: 510 nm). The efficiency of this method was controlled using a known Cdc25 inhibitor, BN82002 (Sigma-Aldrich) (18). Data represent means of at least three independent experiments.…”