二甲双胍与氧光动力疗法作为三阴性乳腺癌的一种新型治疗方法。

Metformin and oxyphotodynamic therapy as a novel treatment approach for triple-negative breast cancer.

作者信息

Pei Xiaofeng, Wang Xiaojin, Xian Jianzhong, Mi Jiaoping, Gao Jiebing, Li Xinglin, Li Zhijun, Yang Min, Bi Lei, Yan Yan, Lv Weize, Jin Hongjun

机构信息

Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.

Molecular Imaging Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.

出版信息

Ann Transl Med. 2020 Sep;8(18):1138. doi: 10.21037/atm-20-5704.

DOI:10.21037/atm-20-5704

PMID:33240987

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7576064/

Abstract

BACKGROUND

Treatment for triple-negative breast cancer (TNBC) remains a significant challenge due to a lack of targeted therapies. While photodynamic therapy (PDT) has been utilized as a treatment approach for several types of cancer, oxyphotodynamic therapy (OPDT) is a novel method that improves treatment efficacy by increasing local oxygen concentration. Metformin (MET) has been demonstrated utility as an anti-tumor agent by acting through the adenosine monophosphate-activated protein kinase (AMPK) pathway. We hypothesized that MET in combination with heme, a byproduct of 5-aminolevulinic acid (ALA), may increase cytotoxicity for cancer treatment. This study aimed to investigate the synergistic effect of MET and ALA with PDT or OPDT on TNBC tumorigenic cells.

METHODS

The treatment efficacy and phototoxicity of PDT or OPDT were determined using a cell viability assay. PDT/OPDT experiments were carried out in nine groups based on different combinations and concentrations of ALA and/or MET. To calculate the synergistic effect by compuSyn soft for different groups, cells were incubated with ALA and/or MET at the following concentrations (0, 0.25, 0.5,1, 2, 4, 8, 16, 24, and 32 mM). The fluorescence of ALA-induced protoporphyrin IX (PpIX) and MitoTracker Green were observed under a confocal microscope.

RESULTS

The optimized therapeutic concentration ratio of ALA and MET was determined to be 1:1. The inhibition of cancer growth (IC) for each group was 14.03, 10.62, 7.71, 18.27, 22.09, 23.96, 4.57, 10.20, and 8.18 mM, respectively. The combination index (CI) values (fa =0.5) of the last three combination groups (groups 7, 8, and 9) were 0.44, 1.70, and 1.47, respectively. PpIX fluorescence intensity of group 9 (ALA-MET-OPDT group) remained the highest among all groups, indicating an enhanced therapeutic effect.

CONCLUSIONS

This study introduces OPDT as a novel anti-tumor therapy for TNBC. Furthermore, the combined use of ALA and MET had a synergistic anti-tumor effect in TNBC cells when combined with OPDT.

摘要

背景

由于缺乏靶向治疗方法，三阴性乳腺癌（TNBC）的治疗仍然是一项重大挑战。虽然光动力疗法（PDT）已被用作多种癌症的治疗方法，但氧光动力疗法（OPDT）是一种通过提高局部氧浓度来提高治疗效果的新方法。二甲双胍（MET）已被证明可通过单磷酸腺苷激活蛋白激酶（AMPK）途径发挥抗肿瘤作用。我们假设MET与5-氨基酮戊酸（ALA）的副产物血红素联合使用可能会增加癌症治疗的细胞毒性。本研究旨在探讨MET和ALA与PDT或OPDT联合应用对TNBC致瘤细胞的协同作用。

方法

采用细胞活力测定法测定PDT或OPDT的治疗效果和光毒性。根据ALA和/或MET的不同组合和浓度，将PDT/OPDT实验分为九组。为了使用compuSyn软件计算不同组的协同效应，将细胞与以下浓度（0、0.25、0.5、1、2、4、8、16、24和32 mM）的ALA和/或MET孵育。在共聚焦显微镜下观察ALA诱导的原卟啉IX（PpIX）和线粒体Tracker Green的荧光。

结果

确定ALA和MET的最佳治疗浓度比为1:1。每组对癌症生长的抑制率（IC）分别为14.03、10.62、7.71、18.27、22.09、23.96、4.57、10.20和8.18 mM。最后三个组合组（第7、8和9组）的联合指数（CI）值（fa =0.5）分别为：0.44、1.70和1.47。第9组（ALA-MET-OPDT组）的PpIX荧光强度在所有组中保持最高，表明治疗效果增强。