Abstract
We previously reported that 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N′-methylpropylamino]-3,4-dihydroquinazoline (KCP10043F) can induce G1-phase arrest and synergistic cell death in combination with etoposide in lung cancer cells. Here, we investigated the underlying mechanism by which KCP10043F induces cell death in non-small cell lung cancer (NSCLC). Propidium iodide (PI) and annexin V staining revealed that KCP10043F-induced cytotoxicity was caused by apoptosis. KCP10043F induced a series of intracellular events: (1) downregulation of Bcl-2 and Bcl-xL and upregulation of Bax and cleaved Bid; (2) loss of mitochondrial membrane potential; (3) increase of cytochrome c release; (4) cleavage of procaspase-8, procaspase-9, procaspase-3, and poly (ADP-ribose) polymerase (PARP). In addition, KCP10043F exhibited potent inhibitory effects on constitutive or interleukin-6 (IL-6)-induced signal transducer and activator of transcription (STAT3) phosphorylation and STAT3-regulated genes including survivin, Mcl-1, and cyclin D1. Furthermore, STAT3 overexpression attenuated KCP10043F-induced apoptosis and the cleavage of caspase-9, caspase-3, and PARP. Docking analysis disclosed that KCP10043F could bind to a pocket in the SH2 domain of STAT3 and prevent STAT3 phosphorylation. The oral administration of KCP10043F decreased tumor growth in an A549 xenograft mouse model, as associated with the reduced phosphorylated STAT3, survivin, Mcl-1, and Bcl-2 expression and increased TUNEL staining and PARP cleavage in tumor tissues. Collectively, our data suggest that KCP10043F suppresses NSCLC cell growth through apoptosis induction via STAT3 inactivation.
Highlights
Lung cancer is one of the most frequent cancers and the leading cause of worldwide cancer-related mortality
One is an intrinsic pathway mediated by stimuli targeting the mitochondria, which induce mitochondrial outer membrane permeabilization regulated by B cell lymphoma (Bcl) family proteins such as Bcl-2, Bcl-xL, and other pro-apoptotic or anti-apoptotic proteins, while the other is an extrinsic pathway engaged with extracellular ligands such as TNF, Fas-L (Fas ligand), and TRAIL (TNF-related apoptosis-inducing ligand) which are attached to the extracellular domain of their specific receptors [6]
We previously reported that KCP10043F attenuated G1 cell cycle progression and caused apoptotic cell death when co-treated with etoposide in A549 cells [22]
Summary
Lung cancer is one of the most frequent cancers and the leading cause of worldwide cancer-related mortality. Advanced studies have shown that STAT3 plays a vital role in restricting apoptotic cell death and promoting cell proliferation during tumor development [11]. Anti-cancer drugs such as icotinib can inhibit lung cancer development mediated by the EGFR-JAK-STAT3 transduction pathway [12]. We previously reported that 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2[3-(N,N-dimethylureido)-N -methylpropylamino]-3,4-dihydroquinazoline (KCP10043F) can induce cell cycle arrest by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels and synergistic inducing apoptosis with etoposide in A549 human lung cancer cells [22]; anti-proliferative potential or the underlying mechanism of this compound has not been determined. We studied the molecular mechanism underlying the anti-proliferative properties of KCP10043F by examining its effect on STAT3 in NSCLC cells and the mouse model bearing xenografts of A549 human lung cancer
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