In Vitro Characterization of the Bacteria-derived Hypoxia-selective Cytotoxin BE-43547.

IF 1.6 4区 医学 Q4 ONCOLOGY Anticancer research Pub Date : 2023-12-01 DOI:10.21873/anticanres.16735
Morten Busk, Peter P Eggertsen, Jens Overgaard, Michael R Horsman, Thomas Tørring, Kristian M Jacobsen, Thomas B Poulsen
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Abstract

Background/aim: Hypoxia-activated pro-drugs, such as TH-302, may kill hypoxic treatment-resistant tumor cells, but have failed in clinical trials. This may be related to variable levels of drug-activating reductases. Compounds such as bacteria-derived BE-43547, which target hypoxic cells independently of reductases, may be beneficial. This study characterized the in vitro potency and hypoxia selectivity of BE-43547 and TH-302.

Materials and methods: Tumor cells were exposed to different oxygenation levels in the presence/absence of drug, and survival was quantified using total cell number (BE-43547) or clonogenic survival (BE-43547 and TH-302) assays. Half-maximal inhibitory concentration (IC50) values and the hypoxia-cytotoxicity-ratio (HCR: normoxic IC50/hypoxic IC50) were determined from dose-response curves. Finally, both drugs were tested in spheroids exposed to 20% or 0% O2 for 24 h followed by assessment of clonogenic survival.

Results: BE-43547 was highly potent and displayed little inter-cell line variability. Strongly enhanced cytotoxicity was observed under oxygen-restricted conditions with HCR's of ~100 and ~20 after 24 h of treatment with 0 or 0.5% O2, respectively. Reducing treatment time somewhat reduced hypoxia selectivity. Hypoxia selectivity was observed regardless of whether the drug was added before or during the hypoxic challenge. TH-302 IC50 values varied 10-fold under oxic conditions, whereas those of the anoxic-to-normoxic HCR varied from 15 to 88. Both BE-43547 and TH-302 were unable to completely sterilize anoxic incubated spheroids.

Conclusion: BE-43547 is highly hypoxia-selective, and unlike TH-302, displayed minimal variability between cell lines, suggesting that BE-43547 targets a fundamental feature/target that is only present, or of survival importance, during hypoxia. Spheroid experiments suggested inadequate tissue penetrability, which may be overcome by designing novel drug analogs.

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细菌来源的低氧选择性细胞毒素BE-43547的体外鉴定。
背景/目的:低氧激活的前药,如TH-302,可能会杀死耐缺氧治疗的肿瘤细胞,但在临床试验中失败。这可能与药物活化还原酶水平的变化有关。细菌衍生的be -43547等化合物可能是有益的,它们独立于还原酶靶向缺氧细胞。研究了BE-43547和TH-302的体外效价和缺氧选择性。材料和方法:将肿瘤细胞暴露于药物存在或不存在的不同氧合水平下,通过总细胞数(BE-43547)或克隆性存活(BE-43547和TH-302)测定存活时间。根据剂量-反应曲线测定半最大抑制浓度(IC50)值和缺氧-细胞毒性比(HCR:常氧IC50/缺氧IC50)。最后,两种药物在暴露于20%或0% O2的球体中测试24小时,然后评估克隆生存。结果:BE-43547毒力强,细胞系间变异性小。在限氧条件下,0或0.5% O2处理24 h后,HCR值分别为~100和~20,细胞毒性明显增强。减少治疗时间在一定程度上降低了缺氧选择性。无论在缺氧刺激之前或期间添加药物,都观察到缺氧选择性。在缺氧条件下,TH-302的IC50值变化了10倍,而在缺氧-常氧条件下,TH-302的IC50值变化在15 - 88之间。BE-43547和TH-302都不能完全灭菌缺氧培养的球体。结论:BE-43547具有高度的缺氧选择性,与TH-302不同,BE-43547在细胞系之间表现出极小的差异性,这表明BE-43547靶向的基本特征/靶标仅在缺氧时存在,或对生存至关重要。球体实验表明组织渗透性不足,这可能通过设计新的药物类似物来克服。
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来源期刊
Anticancer research
Anticancer research 医学-肿瘤学
CiteScore
3.70
自引率
10.00%
发文量
566
审稿时长
2 months
期刊介绍: ANTICANCER RESEARCH is an independent international peer-reviewed journal devoted to the rapid publication of high quality original articles and reviews on all aspects of experimental and clinical oncology. Prompt evaluation of all submitted articles in confidence and rapid publication within 1-2 months of acceptance are guaranteed. ANTICANCER RESEARCH was established in 1981 and is published monthly (bimonthly until the end of 2008). Each annual volume contains twelve issues and index. Each issue may be divided into three parts (A: Reviews, B: Experimental studies, and C: Clinical and Epidemiological studies). Special issues, presenting the proceedings of meetings or groups of papers on topics of significant progress, will also be included in each volume. There is no limitation to the number of pages per issue.
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