Abstract
Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy has received considerable attention in recent years. YLT322, a novel synthesized benzothiazole derivative, exhibits potent anti-tumor activity via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT322 showed growth inhibition against a broad spectrum of human cancer cells and induced apoptosis of HepG2 cells in a dose- and time-dependent manner. The occurrence of its apoptosis was associated with activation of caspases-3 and -9, but not caspase-8. YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway. The down-regulation of phosphorylated p42/44 MAPK and phosphorylated Akt was also observed. Moreover, YLT322 suppressed the growth of established tumors in xenograft models in mice without obvious side effects. Histological and immunohistochemical analyses revealed an increase in TUNEL and caspase-3-positive cells and a decrease in Ki67-positive cells upon YLT322. These results suggest that YLT322 may be a potential candidate for cancer therapy.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third cause of cancer-related death [1,2]
We demonstrated that YLT322 can induce apoptosis in human hepatocellular carcinoma cells via the mitochondrial apoptotic pathway and the down-regulation of phosphorylated Akt/MAPK, and inhibit tumor growth in vivo by inducing apoptosis
YLT322 inhibited proliferation of cancer cell lines In order to determine whether YLT322 possesses the potential to be an effective anti-cancer agent, we first examined whether YLT322 exerts a growth inhibition effect on cancer cells by treating a panel of 24 established cancer cell lines of different histotypes with YLT322 for 48 hours and assaying cell viability by MTT assay
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third cause of cancer-related death [1,2]. Drugs induce apoptosis in cancer cells through two pathways: cell death receptor-mediated extrinsic pathway and mitochondrial-mediated intrinsic pathway. The ligation of so-called death receptors results in the activation of the protease caspase-8 which cleaves and activates downstream effectors caspase-3 and/or -7, resulting in chromatin condensation, DNA degradation, cell shrinkage and formation of apoptotic bodies [7]. As a consequence of these changes, cytochrome c interacts with the Apaf-1 (apoptotic protease activating factor - 1) and ATP, and binds to procaspase-9. This interaction results in the cleavage of pro-caspase-9, which in turn activates the effector caspase-3 and/or -7 [8]
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