肿瘤多药耐药及其相关机制研究

目前肿瘤的主要治疗方式认为手术配合放化疗，但肿瘤长期的化疗导致肿瘤耐药是限制肿瘤治疗的主要因素之一。肿瘤的耐药产生因素众多，肿瘤代谢异常是导致肿瘤发生发展的重要因素，肿瘤主要利用糖酵解方式供能，称为瓦博格现象；随着研究深入脂肪代谢异常，蛋白质代谢异常均对肿瘤起到重要影响，因此肿瘤的代谢异常是抗肿瘤耐药的一个主要靶点。肿瘤代谢异常对ATP转运蛋白起到调控作用，该蛋白高表达与细胞膜上，在ATP的作用下将药物泵出细胞外降低药物有效浓度，我们发现一些列化合物如黄连素，CTAB等通过调控肿瘤代谢中的关键蛋白对ATP转运蛋白起到明显的抑制作用。肿瘤的能量代谢异常可以导致肿瘤干细胞的异常增殖，肿瘤干细胞具有自我分化和更新的能力，是肿瘤化疗失败的一个主要因素，我们的研究发现非编码RNA中miR-34a以及OLA1等靶点均可通过调控代谢影响肿瘤干细胞的增殖。本课题组以肿瘤代谢异常为主要研究方向，针对代谢异常研究小分子化合物以及非编码RNA等对肿瘤代谢的调控，进一步阐述其调控的代谢的具体机制，为抗肿瘤的临床治疗提供理论基础。

参考文献：

(1)   Pan Yue; Zhang Yunqiu; Chen Qing; Tao Xufeng; Liu Jianzhou; Xiao Gary Guishan^(*). CTAB Enhances Chemo-Sensitivity Through Activation of AMPK Signaling Cascades in Breast Cancer. Frontiers in Pharmacology. 2019, 10, 843.

(2)   Pan Yue; Cao Min; Liu Jianzhou; Yang Qing; Miao Xiaoyu; Go Vay Liang W; Lee Paul W N; Xiao Gary Guishan^(*). Metabolic Regulation in Mitochondria and Drug Resistanice. Advances in Exprimental Medicine and Biology. 2017, 1038

(3)   Pan Yue; Zhang Fan; Zhao Yawei; Shao Dan; Zheng Xiao; Chen Yujing; He Kan; Li Jing^(*); Chen Li^(*). Berberine Enhances Chemosensitivity and Induces Apoptosis Through Dose-orchestrated AMPK Signaling in Breast Cancer, Journal of Cancer, 2017, 8(9): 1679-1689.

(4)   Pan Yue; Shao Dan; Zhao Yawei; Zhang Fan; Zheng Xiao; Tan Yongfei; He Kan; Li Jing^(*); Chen Li^(*). Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK-HIF-1α, International Journal of Biological Sciences, 2017, 13(6): 794-803.

(5)   Pan Y; Wang Z; Shao D; Zheng H; Chen Y; Zheng X; Zhang M; Li J^(*) ; Li F; Chen L^(*), CTAB Induced Mitochondrial Apoptosis by Activating the AMPK–p53 Pathway in Hepatocarcinoma Cells, Toxicology Research, 2015, 4(5):1359~1365.

(6)   Pan Y, Kan M, Xiao X, Wang Y, Guan F, Zhang X, Chen L*. Hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase. Life sciences, 2014, 98(1):24-30. 

抗肿瘤药物活性评价

近年来，随着肿瘤成为威胁人类健康的第一大疾病，抗肿瘤药物开发越来越多。本课题组拟对新的小分子化合物、纳米材料以及脂质体等新剂型进行药理学评价，主要包括其抗肿瘤活性，安全性以及可能的抗肿瘤机制。

参考文献：

(1). Shao D, Li J, Zheng X, Pan Y, Wang Z, Zhang M, Chen Q, Dong W*, Chen L*. Janus “Nano-Bullets” for Magnetic Targeting Chemotherapy of Liver Cancer. Biomaterials. 2016, 100:118-133.

(2). Shao D, Li J, Pan Y, Zhang X, Zheng X, Wang Z, Zhang M, Zhang H*, Chen L*. Noninvasive theranostic imaging of HSV-TK/GCV suicide gene therapy in liver cancer by folate-targeted quantum dot-based liposomes. Biomaterials Science. 2015, 3: 833-841.

(3). Shao D, Li J, Xiao X, Zhang M, Pan Y, Li S, Wang Z, Zhang X, Zheng H, Zhang X*, Chen L*. Real-time visualizing and tracing of HSV-TK/GCV suicide gene therapy by near-infrared fluorescent quantum dots. ACS Applied Materials & Interfaces. 2014, 6: 11082-11090. 

(4). Shao D, Li J, Guan F, Pan Y, Xiao X, Zhang M, Zhang H*, Chen L*. Selective inhibition of liver cancer growth realized by the intrinsic toxicity of a quantum dot-lipid complex. International Journal of Nanomedicine. 2014,9:5753-5769.