High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo
High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo
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DOI：
10.3390/cancers11020156
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发表时间：
2019-02-01
期刊：
影响因子：
5.2
通讯作者：
Rotblat, Barak
中科院分区：
文献类型：
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作者：
Marciano, Ran;Prasad, Manu;Rotblat, Barak
肿瘤细胞利用葡萄糖来满足其合成代谢需求，包括快速增殖。然而，由于血管缺陷和葡萄糖摄取增加，肿瘤细胞必须克服葡萄糖剥夺。因此，肿瘤细胞依赖于在这种条件下促进存活的细胞途径。因此，靶向这些生存机制可以作为肿瘤学的新治疗策略。因此，我们试图通过体外高通量药物筛选来鉴定使肿瘤细胞对葡萄糖饥饿敏感的小分子抑制剂。具体来说，我们寻找抑制剂，选择性地杀死肿瘤细胞生长在无葡萄糖，但不是在正常培养基。用MCF7细胞对7000种药物进行表型药物筛选，鉴定出67种潜在候选药物，其中31种单独验证。在鉴定的化合物中，我们发现了大量已知靶向线粒体的化合物。在四种不同的肿瘤细胞系中验证了两种鉴定的化合物QNZ（EVP 4593）和罂粟碱的功效。我们发现，这些药物抑制mTOR（雷帕霉素的Mammilian靶标）途径在肿瘤细胞生长的葡萄糖饥饿下，但在正常条件下。结果在体内得到验证和证实，当与VEGF抑制剂贝伐单抗（avastin）组合时，QNZ和罂粟碱在肿瘤异种移植模型中表现出上级抗肿瘤活性。施用这些药物组合（即，阿瓦斯丁和罂粟碱，以及阿瓦斯丁和QNZ）导致小鼠中侵袭性DLD 1结肠细胞系的增殖和mTOR活性显著降低。鉴于我们的研究结果，我们建议将靶向代谢挑战肿瘤的化合物，如线粒体活性抑制剂，作为癌症的治疗策略。
Tumor cells utilize glucose to fuel their anabolic needs, including rapid proliferation. However, due to defective vasculature and increased glucose uptake, tumor cells must overcome glucose deprivation. Accordingly, tumor cells depend on cellular pathways promoting survival under such conditions. Targeting these survival mechanisms can thus serve as a new therapeutic strategy in oncology. As such, we sought to identify small-molecule inhibitors which sensitize tumor cells to glucose starvation by high-throughput drug screening in vitro. Specifically, we searched for inhibitors that selectively killed tumor cells growing in glucose-free but not in normal medium. This phenotypic drug screen of 7000 agents with MCF7 cells led to the identification of 67 potential candidates, 31 of which were validated individually. Among the identified compounds, we found a high number of compounds known to target mitochondria. The efficacies of two of the identified compounds, QNZ (EVP4593) and papaverine, were validated in four different tumor cell lines. We found that these agents inhibited the mTOR(Mechamistic\Mammilian Target of Rapamycin) pathway in tumor cells growing under glucose starvation, but not under normal conditions. The results were validated and confirmed in vivo, with QNZ and papaverine exhibiting superior antitumor activity in a tumor xenograft model when combined with the VEGF inhibitor bevacizumab (avastin). Administering these drug combinations (i.e., avastin and papaverine, and avastin and QNZ) led to significant reductions in proliferation and mTOR activity of the aggressive DLD1 colon cell line in mice. Given our findings, we propose that compounds targeting metabolically challenged tumors, such as inhibitors of mitochondrial activity, be considered as a therapeutic strategy in cancer.