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Use of a Genetically Engineered E. coli Overexpressing β-glucuronidase Accompanied by Glycyrrhizic Acid, A Natural and Anti-inflammatory Agent, for Directed Treatment of Colon Carcinoma in a Mouse Model.
使用过表达 β-葡萄糖醛酸酶的基因工程大肠杆菌,并伴有天然和抗炎剂甘草酸,用于小鼠模型结肠癌的定向治疗。
- 影响因子:4.35
- DOI:10.1016/j.ijpharm.2020.119159
- 作者列表:"Afkhami-Poostchi A","Mashreghi M","Iranshahi M","Matin MM
- 发表时间:2020-02-17
Abstract
:Bacteria-directed enzyme prodrug therapy (BDEPT), is an emerging alternative directed and tumor-specific approach. The basis of this method is the conversion of a non-toxic prodrug by a bacterial enzyme to a toxic drug within the tumor-microenvironment (TME). In the present study, the therapeutic efficacy of BDEPT was investigated based on the ability of Escherichia coli DH5α-lux/βG in activation of glycyrrhizic acid (GL), a natural and non-toxic compound purified from licorice, to glycyrrhetinic acid (GA) only in TME. To do so, the anti-bacterial effects of GL on bacteria and the cytotoxic effects of the produced GA on survival rate of CT26 mouse colon carcinoma cells were evaluated. The IC50 values of the produced GA and cisplatin were determined as 210 μM and 100 μM, respectively. Comparing these values to GL treatment (1305 μM) indicates that bacteria could have efficiently activated GL to GA to inhibit the growth of tumor cells. Afterward, the anti-cancer effects of bacteria used in combination with GL was investigated in a mouse model of colon carcinoma. Results were indicative of targeted homing and even proliferation of luminescent bacteria in TME. Moreover, combined treatment greatly inhibited tumor growth. Histopathological analysis of dissected tissues also demonstrated increased apoptosis rate in tumor cells after combined treatment and interestingly, showed no obvious damage to the spleen and liver of treated mice. Accordingly, this BDEPT approach could be considered as an effective alternative tumor-specific therapy utilizing prodrug-activating enzymes expressing from tumor-targeting bacteria to allow the development of new tumor-specific pharmacotherapy protocols.
摘要
: 细菌导向的酶前体药物治疗 (brept),是一种新兴的替代导向和肿瘤特异性方法。该方法的基础是在肿瘤微环境 (TME) 内通过细菌酶将无毒前药转化为有毒药物。在本研究中,基于大肠杆菌 dh5 α-lux/β g 对甘草酸 (GL) 的活化能力研究了 BDEPT 的治疗效果, 一种从甘草中纯化的天然无毒化合物,仅在 TME 中为甘草次酸 (GA)。为此,评价了 GL 对细菌的抗菌作用和产生的 GA 对 CT26 小鼠结肠癌细胞存活率的细胞毒作用。所产生的 GA 和顺铂的 IC50 值分别测定为 210 μ m 和 100 μ m。将这些值与 GL 处理 (1305 μ m) 进行比较表明,细菌可以有效激活 GL 到 GA 来抑制肿瘤细胞的生长。随后,在结肠癌小鼠模型中研究了细菌与 GL 联合使用的抗癌作用。结果表明 TME 中发光细菌的靶向归巢甚至增殖。此外,联合治疗大大抑制了肿瘤的生长。解剖组织的组织病理学分析也显示联合治疗后肿瘤细胞凋亡率增加,有趣的是,对治疗小鼠的脾脏和肝脏无明显损伤。因此,这种 BDEPT 方法可以被认为是一种有效的替代肿瘤特异性疗法,利用肿瘤靶向细菌表达的前体药物激活酶,以允许开发新的肿瘤特异性药物治疗方案。
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