Artesunate induces apoptosis via a Bak‐mediated caspase‐independent intrinsic pathway in human lung adenocarcinoma cells

Abstract

This report is designed to explore the exact molecular mechanism by which artesunate (ART), a semisynthetic derivative of the herbal antimalaria drug artemisinin, induces apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines. ART treatment induced ROS-mediated apoptosis in a concentration- and time-dependent fashion accompanying the loss of mitochondrial potential and subsequent release of Smac and AIF indicative of intrinsic apoptosis pathway. Blockage of casapse-8 and -9 did not show any inhibitory effect on the ART-induced apoptosis, but which was remarkably prevented by silencing AIF. Of the utmost importance, ART treatment induced the activation of Bak but not Bax, and silencing Bak but not Bax remarkably inhibited ART-induced apoptosis and AIF release. Furthermore, although ART treatment did not induced a significant down-regulation of voltage-dependent anion channel 2 (VDAC2) expression and up-regulation of Bim expression, silencing VDAC2 potently enhanced the ART-induced Bak activation and apoptosis which were significantly prevented by silencing Bim. Collectively, our data firstly demonstrate that ART induces Bak-mediated caspase-independent intrinsic apoptosis in which Bim and VDAC2 as well as AIF play important roles in both ASTC-a-1 and A549 cell lines, indicating a potential therapeutic effect of ART for lung cancer.

Artemisinin induces A549 cell apoptosis dominantly via a reactive oxygen species-mediated amplification activation loop among caspase-9, -8 and -3

“…Similar to DHA, ARTS induces caspase-dependent intrinsic apoptosis in many cancer cell lines such as Leukemic T cells, Neuroblastoma and Pancreatic cancer cells [2,[33][34][35]. However, we recently found that caspase-independent intrinsic pathway played an important role in ARTSinduced apoptosis of both A549 and ASTC-a-1 cell lines [36]. NF-jB pathway may be involved in ARTS-induced multiple myeloma cell apoptosis [37].…”

“…Caspase-dependent intrinsic pathway [2,[33][34][35] NSCLC (A549, ASTC-a-1) Caspase-independent intrinsic pathway [36] Breast cancer (MCF-7, T47D) Lysosome-dependent intrinsic pathway [35] Multiple myeloma (SP2/0) Decreased NF-jB pathway [37] ARTE Hepatoma (HepG2, Hep3B)…”

The Synergistic Anticancer Effect of Artesunate Combined with Allicin in Osteosarcoma Cell Line in Vitro and in Vivo

“…Artesunate, is a derivative of artemisinin isolated from Artemisia annua L, has been used to treat malaria, especially against cerebral malaria (Padilla-Camberos et al, 2010;Bachmeier et al, 2011;Berdelle et al, 2011;Jin et al, 2011;Mota et al, 2011;Jiang et al, 2012;Zhou et al, 2012), new report shown that it has a variety of biological activities, such as hepatoprotective, antioxidative, antiinflammatory, antidiabetic, antiallergic, and antibacterial effects (Li et al, 2009;Bat-Chen et al, 2010;Du et al,…”

Artesunate Induces Cell Death in Human Cancer Cells via Enhancing Lysosomal Function and Lysosomal Degradation of Ferritin

“…At present, there is an increasing amount of evidence suggesting that ART has an anti-cancer function (3). For instance, ART has been shown to induce apoptosis and necrosis in multiple human cancer cells (4,5). The anti-cancer effects of ART also include the following: cell cycle arrest (6), inhibition of angiogenesis (7), and reduction of cell invasion and metastasis (8).…”