Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway

Abstract

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC. Methods:The NSCLCs were cultured and treated with various doses (40, 80, 120 µg/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis.Results: BBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and timedependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction. Conclusions:The results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/ JNK activation and the mitochondrial pathway.

Remodeling tumor microenvironment with natural products to overcome drug resistance

“…In clinical trials of natural products combined with cisplatin for the treatment of melanoma, berberine acted more like a chemosensitizer, effectively activating the ROS/p38/caspase cascade that stimulates melanoma cell death ( 83 ). Moreover, berberine triggers apoptosis-related responses such as cleavage of caspase-3, release of cytochrome c and depolarization of the mitochondrial membrane in non-small cell lung cancer through activation of apoptosis signal-regulated kinase 1 (ASK1) and c-jun NH2 kinase (JNK) via the ROS pathway ( 84 ). Natural products further enhance the therapeutic efficacy of cancer treatment through regulating intracellular ROS levels via multiple signal pathways, to switch on the cell death cascade.…”

Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review

“…Furthermore, berberine promoted NSCLC cell apoptosis through the miR19a/TF/MAPK signaling pathway [ 58 ]. Berberine could also induce NSCLC cell apoptosis via activating the ROS-mediated apoptosis signal-regulating kinase 1/JNK and mitochondrial apoptotic pathways [ 59 ].…”

“…Arrest cell cycle at G 1 phase via Akt/CREB signaling axis Suppress cell proliferation via inhibiting proliferative kinase signaling [56] In vivo Athymic nude mice Berberine: 1000 or 1800 ppm; P. amurense extract: 3000 or 5400 ppm Inhibit tumor growth [56] In vitro A549 and PC9 cells 0, 40, and 80 µM Induce cell apoptosis via activation of the ROS/ASK1/JNK pathway [59] Table 1. Cont.…”

Multi-Target Potential of Berberine as an Antineoplastic and Antimetastatic Agent: A Special Focus on Lung Cancer Treatment

“…Berberine has been shown to induce apoptosis in NSCLC by inducing ROS augmentation or oxidative stress and subsequent activation of Apoptosis Signal-regulating Kinase 1 (ASK1)/JNK signaling as well as the mitochondrial apoptotic pathway [ 86 ]. ASK1, a member of the mitogen-activated protein kinase (MAPK) family, regulates cell differentiation and apoptosis [ 66 ].…”

“…Upon activation, ASK1 dissociates from thioredoxin-1 to activate c-jun-NH2-kinase (JNK) and p38 MAPK pathways, which further induces cell death [ 100 ]. Berberine-induced ROS generation promotes ASK1/JNK phosphorylation, which in turn suppresses Bcl-2 family proteins, driving a loss of MMP, the release of mitochondrial cytochrome c, and the consequent caspase-dependent apoptosis pathway [ 86 ]. A different mechanism of action of Berberine was elucidated by Chen et al, whereby Berberine induces cell apoptosis and suppresses NSCLC cell proliferation and growth both in vitro and in vivo models by modulating the miR-19a/TF/MAPK signaling pathway induced by Berberine-mediated upregulation of miR-19a and downregulation of tissue factor (TF) expression [ 90 ].…”