Erianin inhibits indoleamine 2, 3-dioxygenase –induced tumor angiogenesis
Introduction
There are few obvious early symptoms of lung cancer, so the patients are diagnosed at middle and late stage, leading to the poor prognosis with low quality of life [1]. With platinum-based chemotherapy is the standard first-line treatment of advanced non-small cell lung cancer. Angiogenesis is a very important biological processes. Many studies found that angiogenesis has a close relationship with non-small cell lung cancer development, metastasis and prognosis [2].
Erianin is natural products of low molecular extracted from the Dendrobium Chrysostom [3]. In traditional Chinese medicine, Erianin is often used as antipyretic and analgesic agent. Erianin belongs to bibenzyl derivatives in structure, with the activity of anti-virus [3], anti-bacterial [4], as well as anti-benign prostatic hyperplasia [5].
Angiogenesis is the process of formation of new blood vessels, is a sign of tumor processes. Angiogenesis plays an important role in many physiological processes, including embryonic development, tissue repair of postoperative and Posttraumatic. It can also be used as a marker in wound healing, cancer, ischemic and inflammatory diseases [6], [7], [8].
Indole amine 2,3-dioxygenase(IDO)is the rate-limiting enzyme in the pathway of tryptophan (TRP) along the dog urine ammonia acid (KYN) in the metabolic process. Almost 99% TRP metabolizes through dog urine acid pathway [9]. Li, etc. [10] co-cultured fibroblast cells of overexpression of IDO and vascular endothelial cells in vitro, and found micro-vascular endothelial cells, and untreated fibroblasts do not encourage micro-vascular endothelial cells, indicating that IDO can directly cause the endothelial cells of the blood vessel formation. Dog Urine ammonia acid was added to reverse the IDO-mediated angiogenesis, suggesting that tryptophan depletion may be one of the mechanisms of stimulating angiogenesis [11]. The overexpression of IDO in ovarian cancer cells can result in a significant increase in the number of new blood vessels, confirmed that immune tolerance is not the only function of IDO, IDO is also able to induce tumor angiogenesis [12], playing a non-immunological role, providing new targets for therapeutic angiogenesis.
Erianin can has the anti-angiogenic effect by inducing apoptosis of vascular endothelial cells [13]. IDO is involved in various stages of cancer development, and the current research on IDO focuses on its immunological function. Recently, it is found that the immune regulation function is not the only function of IDO, and IDO plays an important role in the invasion, metastasis and angiogenesis.
So we use the application of in vitro experiment methods to study whether Erianin can inhibit lung cancer cell invasion, metastasis and angiogenesis by the regulation of IDO expression, and provide a theoretical basis for lung cancer anti-angiogenesis therapy.
Section snippets
Reagents
The powder of Erianin was dissolved in dimethyl sulfoxide (DMSO), with a concentration of 1 mM solution. 1-Methyl-d-tryptophan (1-d-MT)(Sigma-Aldrich)was prepared into 200 mM solution under alkaline conditions, and then adjusted pH to 7.4 by HCl. They were all stored at −20 °C.The blue MTT formazan precipitate was dissolved in 100 μl of DMSO.
Cell culture
The mouse Lewis lung cancer cell lines(2LL)was generously donated by Longhua hospital (Shanghai, China) and 2LL-IDO cells which express human IDO gene were
Statistical analysis
Statistical analyses were performed using GraphPad Prism 5.0 software (GraphPad Software Inc, USA)with the two-tailed Student’s t-test. Significance was determined at the 95% confidence interval. All data were expressed as the mean ± standard deviation (SD) from a representative experiment.
Verification of overexpression of IDO in lewis lung cancer cells in mice
Firstly, in order to use the 2LL-IDO cells in the following experiments, we verified the expression of IDO gene in 2LL-IDO cells. Because 2LL-EGFP-IDO cells with green fluorescent protein, the fluorescence of the cells was observed under fluorescence microscope. As shown in Fig. 1A, 2LL-EGFP-IDO cells can emit green fluorescence under blue excitation light. Next, we used Western blot and qPCR to detect the expression of IDO in 2LL-IDO cells at the protein and mRNA levels, respectively. The
Discussion
The study of tumor angiogenesis is of great value in the early diagnosis, treatment and prognosis of tumor [16]. Dendrobium has high medicinal value, and its efficacy has been the focus of attention over the world [17]. As one of the effective components of Dendrobium, Erianin has great anti-tumor and anti-angiogenesis effect in vitro and in vivo [3]. We studied the effect of IDO on the angiogenesis of Lewis lung cancer in mice with IDO as the breakthrough point, and expounds the Erianin can
Conflicts of interest
The authors have declared that no competing interests exist.
Funding
The authors have no support or funding to report.
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These authors contributed equally to this article and should be considered as co-first authors.