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Identification of a Small-Molecule Glucose Transporter Inhibitor, Glutipyran, That Inhibits Cancer Cell Growth
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-07-23 , DOI: 10.1021/acschembio.1c00480 Makoto Kawatani 1 , Harumi Aono 1 , Sayoko Hiranuma 1 , Takeshi Shimizu 1 , Makoto Muroi 1 , Naoko Ogawa 1 , Tomokazu Ohishi 2 , Shun-Ichi Ohba 2 , Manabu Kawada 2 , Toshihiko Nogawa 1 , Akiko Okano 1 , Daisuke Hashizume 3 , Hiroyuki Osada 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-07-23 , DOI: 10.1021/acschembio.1c00480 Makoto Kawatani 1 , Harumi Aono 1 , Sayoko Hiranuma 1 , Takeshi Shimizu 1 , Makoto Muroi 1 , Naoko Ogawa 1 , Tomokazu Ohishi 2 , Shun-Ichi Ohba 2 , Manabu Kawada 2 , Toshihiko Nogawa 1 , Akiko Okano 1 , Daisuke Hashizume 3 , Hiroyuki Osada 1
Affiliation
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Cancer cells reprogram their metabolism to survive and grow. Small-molecule inhibitors targeting cancer are useful for studying its metabolic pathways and functions and for developing anticancer drugs. Here, we discovered that glutipyran and its derivatives inhibit glycolytic activity and cell growth in human pancreatic cancer cells. According to proteomic profiling of glutipyran-treated cells using our ChemProteoBase, glutipyran was clustered within the group of endoplasmic reticulum (ER) stress inducers that included glycolysis inhibitors. Glutipyran inhibited glucose uptake and suppressed the growth of various cancer cells, including A431 cells that express glucose transporter class I (GLUT1) and DLD-1 GLUT1 knockout cells. When cotreated with the mitochondrial respiration inhibitor metformin, glutipyran exhibited a synergistic antiproliferative effect. Metabolome analysis revealed that glutipyran markedly decreased most metabolites of the glycolytic pathway and the pentose phosphate pathway. Glutipyran significantly suppressed tumor growth in a xenograft mouse model of pancreatic cancer. These results suggest that glutipyran acts as a broad-spectrum GLUT inhibitor and reduces cancer cell growth.
中文翻译：
鉴定可抑制癌细胞生长的小分子葡萄糖转运蛋白抑制剂谷吡喃
癌细胞重新编程其新陈代谢以生存和生长。针对癌症的小分子抑制剂可用于研究其代谢途径和功能以及开发抗癌药物。在这里，我们发现谷吡喃及其衍生物抑制人胰腺癌细胞的糖酵解活性和细胞生长。根据使用我们的 ChemProteoBase 对谷吡喃处理的细胞进行的蛋白质组学分析，谷吡喃聚集在包括糖酵解抑制剂在内的内质网 (ER) 应激诱导剂组中。谷吡喃抑制葡萄糖摄取并抑制多种癌细胞的生长，包括表达 I 类葡萄糖转运蛋白 (GLUT1) 的 A431 细胞和 DLD-1 GLUT1 敲除细胞。当与线粒体呼吸抑制剂二甲双胍共同治疗时，谷吡喃表现出协同抗增殖作用。代谢组分析显示，谷吡喃显着降低糖酵解途径和磷酸戊糖途径的大多数代谢物。谷吡喃显着抑制胰腺癌异种移植小鼠模型中的肿瘤生长。这些结果表明谷吡喃充当广谱 GLUT 抑制剂并减少癌细胞生长。
更新日期：2021-08-20
中文翻译：
鉴定可抑制癌细胞生长的小分子葡萄糖转运蛋白抑制剂谷吡喃
癌细胞重新编程其新陈代谢以生存和生长。针对癌症的小分子抑制剂可用于研究其代谢途径和功能以及开发抗癌药物。在这里，我们发现谷吡喃及其衍生物抑制人胰腺癌细胞的糖酵解活性和细胞生长。根据使用我们的 ChemProteoBase 对谷吡喃处理的细胞进行的蛋白质组学分析，谷吡喃聚集在包括糖酵解抑制剂在内的内质网 (ER) 应激诱导剂组中。谷吡喃抑制葡萄糖摄取并抑制多种癌细胞的生长，包括表达 I 类葡萄糖转运蛋白 (GLUT1) 的 A431 细胞和 DLD-1 GLUT1 敲除细胞。当与线粒体呼吸抑制剂二甲双胍共同治疗时，谷吡喃表现出协同抗增殖作用。代谢组分析显示，谷吡喃显着降低糖酵解途径和磷酸戊糖途径的大多数代谢物。谷吡喃显着抑制胰腺癌异种移植小鼠模型中的肿瘤生长。这些结果表明谷吡喃充当广谱 GLUT 抑制剂并减少癌细胞生长。
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