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真菌来源的环五肽马拉弗菌素C作为抗癌药物的研究。

Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug.

作者信息

Wang Jing, Jiang Zaoli, Lam Wing, Gullen Elizabeth A, Yu Zhe, Wei Ying, Wang Lihui, Zeiss Caroline, Beck Amanda, Cheng Ee-Chun, Wu Chunfu, Cheng Yung-Chi, Zhang Yixuan

机构信息

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Department of Oncology and Hematology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China.

出版信息

PLoS One. 2015 Nov 5;10(11):e0140069. doi: 10.1371/journal.pone.0140069. eCollection 2015.

Abstract

Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C's effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.

摘要

马尔弗菌素C是一种真菌环五肽,据称具有抗癌潜力,但尚无体内研究来证实这一特性。因此,我们进行了体外和体内实验,以研究其抗癌作用和毒性。我们的研究表明,马尔弗菌素C剂量依赖性地抑制结肠38细胞和HCT 116细胞的生长,IC50分别为0.27±0.07μM和0.18±0.023μM。这种抑制作用是由马尔弗菌素C对G2/M期阻滞的作用所解释的。此外,我们观察到马尔弗菌素C处理后磷酸化组蛋白H2A.X、p53、裂解的半胱天冬酶3和LC3的表达上调,而凋亡检测表明坏死和晚期凋亡细胞的数量增加。在体内,病理研究显示,马尔弗菌素C在BDF1小鼠中的致死剂量下的急性毒性可能是由急性但细微的炎症反应引起的,这与血浆细胞因子检测中IL-6升高一致。进一步的抗肿瘤和毒性实验证明,每周注射0.3mg/kg是马尔弗菌素C在BDF1小鼠结肠38异种移植模型中的最佳治疗剂量,而每隔一天注射0.1mg/kg则没有效果且耐药性更高,每周注射0.9mg/kg要么导致7周龄小鼠死亡,要么在9周龄小鼠中与0.3mg/kg组相比没有优势。总体而言,我们得出结论,马尔弗菌素C使结肠38细胞停滞在G2/M期,并通过坏死、凋亡和自噬诱导多种形式的细胞死亡。马尔弗菌素C具有强大的细胞生长抑制活性,但治疗指数过低,不能成为一种抗癌药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/858f/4635020/87b3a7121073/pone.0140069.g001.jpg

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