Chelidonium majus L. extract induces apoptosis through caspase activity via MAPK-independent NF-κB signaling in human epidermoid carcinoma A431 cells

Abstract

Abstract. Chelidonium majus L. (C. majus L.) is known to possess certain biological properties such as anti-inflammatory, antimicrobial, antiviral and antitumor activities. We investigated the effects of C. majus L. extract on human epidermoid carcinoma A431 cells through multiple mechanisms, including induction of cell cycle arrest, activation of the caspase-dependent pathway, blocking of nuclear factor-κB (NF-κB) activation and involvement in the mitogen-activated protein kinase (MAPK) pathway. C. majus L. inhibited the proliferation of A431 cells in a dose-and time-dependent manner, increased the percentage of apoptotic cells, significantly decreased the mRNA levels of cyclin D1, Bcl-2, Mcl-1 and survivin and increased p21 and Bax expression. Exposure of A431 cells to C. majus L. extract enhanced the activities of caspase-3 and caspase-9, while co-treatment with C. majus L., the pancaspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor Z-DEVE-FMK increased the proliferation of A431 cells. C. majus L. extract not only inhibited NF-κB activation, but it also activated p38 MAPK and MEK/ERK signaling. Taken together, these results demonstrate that C. majus L. extract inhibits the proliferation of human epidermoid carcinoma A431 cells by inducing apoptosis through caspase activation and NF-κB inhibition via MAPK-independent pathway. IntroductionChelidonium majus is commonly known as greater celandine. It belongs to the family Papaveraceae and is widely distributed in Europe and western Asia. Extracts of Chelidonium majus L.(C. majus L.) have been shown to exhibit a variety of biological effects including anti-inflammatory, antimicrobial, antiviral and antitumor activities (1,2). The antitumor, antigenotoxic and hepatoprotective effects of C. majus L. extract suggest that it may be potentially useful as an anticancer therapeutic agent (3).Apoptosis is mediated through at least 3 major pathways, which are regulated by death receptors, mitochondria and the endoplasmic reticulum. Activation of the apoptosis pathway is a key mechanism by which cytotoxic drugs kill tumor cells. Defects in apoptosis signaling contribute to the drug resistance of tumor cells (4,5). The Bcl-2 family consists of important apoptotic regulators of programmed cell death. This family of proteins includes both anti-apoptotic molecules such as Bcl-2 and pro-apoptotic molecules such as Bax (6). Bcl-2 and Bcl-X L are members of the Bcl-2 family and are regulated by nuclear factor-(NF)-κB. These proteins can prevent release of cytochrome c and activation of caspases (7).Mitogen-activated protein kinase (MAPK) cascades are involved in the signaling pathways that regulate various cellular responses such as inflammation, proliferation and cell death (8). Three major mammalian MAPK subfamilies have been described: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases and p38 kinases. Each MAPK is activated through a specific phosphorylation cascade (9,10). The ERK cascade is activated through receptor-mediated signaling stimuli and is...

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