Auyeung Kathy Ka-Wai, Ko Joshua Ka-Shun
Pharmacology and Toxicology Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, PR China.
Int J Mol Med. 2009 Oct;24(4):571-7. doi: 10.3892/ijmm_00000267.
Conventional chemotherapy of liver cancer fails to provide satisfactory remission and may cause serious side effects, thus it is crucial to derive alternative treatments that effectively inhibit cancer cell growth with known mechanisms of action. In the present study, we investigated the anti-carcinogenic effects of Coptis chinensis and its major constituent, berberine, in HepG2 hepatocellular carcinoma (HCC) cells and attempted to elucidate the underlying mechanism, including involvement of the nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1). Inhibition of cell proliferation, induction of apoptosis and cell cycle arrest at the G2/M phase were observed in HepG2 cells treated with Coptis chinensis or berberine. The pro-apoptotic effects were associated with corresponding down-regulation of Bcl-2, activation of procaspase-3 and -9 as well as cleavage of poly (ADP-ribose) polymerase. We further demonstrated the involvement of NAG-1 in the pro-apoptotic events following prior activation of its upstream transcriptional factor early growth response gene (Egr-1). This was confirmed by increased NAG-1 promoter activity preceded by the elevation of Egr-1/ DNA binding activity. Our results suggest that both Coptis chinensis and berberine are potential anti-carcinogenic agents in treating HCC by inducing cell cycle arrest and promotion of apoptosis, while NAG-1 is a molecular target during the drug-induced pro-apoptotic action in HepG2 cells.
肝癌的传统化疗无法提供令人满意的缓解效果，且可能会引起严重的副作用，因此，研发具有已知作用机制且能有效抑制癌细胞生长的替代治疗方法至关重要。在本研究中，我们调查了黄连及其主要成分黄连素对HepG2肝癌（HCC）细胞的抗癌作用，并试图阐明其潜在机制，包括非甾体抗炎药（NSAID）激活基因（NAG-1）的参与情况。在用黄连或黄连素处理的HepG2细胞中，观察到细胞增殖受到抑制、细胞凋亡被诱导以及细胞周期停滞于G2/M期。促凋亡作用与Bcl-2相应下调、procaspase-3和-9激活以及聚（ADP-核糖）聚合酶的裂解有关。我们进一步证明，在其上游转录因子早期生长反应基因（Egr-1）预先激活后，NAG-1参与了促凋亡事件。Egr-1/DNA结合活性升高之前NAG-1启动子活性增加证实了这一点。我们的结果表明，黄连和黄连素都是通过诱导细胞周期停滞和促进细胞凋亡来治疗肝癌的潜在抗癌药物，而NAG-1是药物诱导HepG2细胞促凋亡作用过程中的分子靶点。
