Abstract:The whole plant of Anisomeles ovata has been widely used in Taiwan for treating inflammation-related skin and liver diseases, however, the detailed pharmacology mechanisms have yet to be elucidated. In the present study, one of the major components, 5,6,4 1 -trihydroxy-7,3 1 -dimethoxyflavone (5-TDMF), was purified from a methanol extract of Anisomeles ovata. A pharmacological study of this compound suggests that 5-TDMF possesses potent free radical scavenging activity both in vitro and ex vivo. Furthermore, 5-TDMF reduces nitric oxide and pro-inflammatory cytokine production in LPC-treated RAW 264.7 cells through the attenuation of nitric oxide synthase and cyclooxygenase-2. Additional experiments suggest that of 5-TDMF interferes with nuclear factor-κB translocation and mitogen-activated protein kinase pathways. These results identify 5-TDMF as an anti-oxidant and anti-inflammatory compound, explain the pharmacologic function of Anisomeles ovata and suggest its great potential as a new anti-inflammatory remedy.
Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death.
Over-activation of ErbB2 highly correlates with tumor progression and chemoresistance and has become an important biomarker and major target of cancer therapy treatments. Although several chemotherapy agents targeting ErbB2 show promising therapeutic effect, additional therapeutic approaches targeting ErbB2 are still urgently needed. Emodin, a major anthraquinone in the rhizome of Rheum palmatum, has been demonstrated to exhibit anticancer effects on several human ErbB2-overexpressing cancers. Computer modeling analysis determined emodin could be a suitable fit for the ErbB2 active pocket site however, the initial binding was unsatisfactory. In order to improve the anti-ErbB2 activity, a series of emodin analogs were synthesized and evaluated against several ErbB2-overexpressing oral cancer cells. Among them, 1,8-dihydroxy-9(10H)-anthraquinone (Em08red), showed potent antiproliferative effect against ErbB2-overexpessing oral cancers. Further studies showed Em08red treatment significantly reduced the levels of ErbB2 phosphorylation, resulting in G2/M arrested and apoptotic cell death. Moreover, treatment with Em08red, significant reduced the levels of anti-apoptosis proteins (Bcl-x and Bcl-2) and activated the caspase-3 and -9, but not caspase-8. Collectively, our results clearly indicate Em08red can down-regulate ErbB2-signaling, induce intrinsic apoptotic cell death and is a promising potent ErbB2-targeted therapeutic.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C116.
Citation Format: Shin-Hun P. Juang, Fong-Pin Liang, Jin-Chern Lien, Yu-Hwa Wu, Chien-Shu Chen. Em08red, an emodin analog, exhibited anti-proliferative activity against oral cancer through down-regulation of ErbB2 signaling pathway and induction of apoptosis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C116.
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