A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway

Abstract

Through cell-based screening models, we have identified a new compound IMB5043, a thiophenylated pyridazinone, which exerted cytotoxicity against cancer cells. In the present study, we evaluated its antitumor efficacy and the possible mechanism. By MTT assay, IMB5043 inhibited the proliferation of various human cancer cells lines, especially hepatocarcinoma SMMC-7721 cells. IMB5043 blocked cell cycle with G2/M arrest, induced cell apoptosis, and inhibited the migration and invasion of SMMC-7721 cells. As verified by comet assay and γ-H2AX foci formation, IMB5043 caused DNA damage and activated ATM, Chk2 and p53 through phosphorylation. As shown by Gene microarray analysis, the differentially expressed genes in SMMC-7721 cells treated with IMB5043 were highly related to cell death and apoptosis. IMB5043 suppressed the growth of hepatocarcinoma SMMC-7721 xenograft in athymic mice. By histopathological examination, no lesions were found in bone marrow and various organs of the treated mice. Our findings reveal that IMB5043 as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway. IMB5043 may serve as a promising leading compound for the development of antitumor drugs.

A new pyridazinone exhibits potent cytotoxicity on human cancer cells via apoptosis and poly-ubiquitinated protein accumulation

“…This process causes DNA fragmentation, cytoskeleton degradation, and disintegration of the cell into apoptotic bodies (Elmore 2007; Wu and Bratton 2013). The involvement of caspase-3-induced apoptosis has been previously shown for other pyridazinone derivatives (Gong et al 2018). Interestingly, other studies have shown that oxidative stress can negatively regulate caspase-3 activation (Huang et al 2008; Lee and Shacter 2000; Rossig et al 1999).…”

“…Under homeostasis, phosphatidylserine (PS) is found preferentially in the inner leaflet (cytosolic) of the plasma membrane, but upon cell death induction, it is translocated to the outer leaflet and serves as a sensitive indicator of cells undergoing apoptosis (Leventis and Grinstein 2010). It was previously reported that a pyridazinone (IMB5043) induced apoptosis via PS externalization in the human SMMC-7721 hepatoma cell line (Gong et al 2018). In addition, increased ROS production resulted in phosphatidylserine oxidation and facilitated the PS extemalization to the plasma membrane in HL-60 cells (Matsura et al 2002).…”

“…For instance, the pan-Bcl-2 inhibitor obatoclax, which is active in various cancer cell lines, causes S-G2 arrest, leading to apoptosis (Bates and Lewis 2006). In addition, a compound comprising pyridazinone and thiophene moieties was recently reported to induce apoptosis by arresting the cell cycle in the G2/M-phase (Gong et al 2018). In the present study, the effects of Pyr-1 treatment on cell cycle progression were investigated.…”

Pyridazinone Derivatives Limit Osteosarcoma-Cells Growth In Vitro and In Vivo

“…Indeed, compounds 4aa and 4ba induced a similar increase of intracellular cAMP in both cell types, despite a differential response having been highlighted by Sun et al, who studied the anti-cancer effect of zardaverine in different hepatocarcinoma cell lines [ 44 ]. Another hypothesis relies on the fact that PDE4 inhibitors possessing a pyridazinone scaffold could exhibit anti-cancer effects independently of PDE4 activity, as demonstrated by Sun et al Among hypotheses to investigate further, the pyridazinone-based compound inhibition of c-Met kinase, activation of ATM-Chk2 pathway and ROS accumulation and proteasome function impairment have already been suggested [ 45 , 46 , 47 ]. These could explain part of our results, since zardaverine induced a high increase of intracellular cAMP and a slight decrease in cell proliferation, contrary to the effects of compounds 4aa and 4ba .…”

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

“…By histopathological study, no lesions were found in bone marrow and various organs of the treated mice. IMB5043 is as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway and may serve as a promising leading compound for the development of antitumor drugs (Gong at al., 2018).…”