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苯乙双胍和草氨酸的协同抗癌作用。

Synergistic anti-cancer effect of phenformin and oxamate.

机构信息

Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America ; Department of Obstetrics and Gynecology and Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Sioux Falls, South Dakota, United States of America.

Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

出版信息

PLoS One. 2014 Jan 21;9(1):e85576. doi: 10.1371/journal.pone.0085576. eCollection 2014.

DOI:10.1371/journal.pone.0085576
PMID:24465604
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3897486/
Abstract

Phenformin (phenethylbiguanide; an anti-diabetic agent) plus oxamate [lactate dehydrogenase (LDH) inhibitor] was tested as a potential anti-cancer therapeutic combination. In in vitro studies, phenformin was more potent than metformin, another biguanide, recently recognized to have anti-cancer effects, in promoting cancer cell death in the range of 25 times to 15 million times in various cancer cell lines. The anti-cancer effect of phenformin was related to complex I inhibition in the mitochondria and subsequent overproduction of reactive oxygen species (ROS). Addition of oxamate inhibited LDH activity and lactate production by cells, which is a major side effect of biguanides, and induced more rapid cancer cell death by decreasing ATP production and accelerating ROS production. Phenformin plus oxamate was more effective than phenformin combined with LDH knockdown. In a syngeneic mouse model, phenformin with oxamate increased tumor apoptosis, reduced tumor size and (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography compared to control. We conclude that phenformin is more cytotoxic towards cancer cells than metformin. Furthermore, phenformin and oxamate have synergistic anti-cancer effects through simultaneous inhibition of complex I in the mitochondria and LDH in the cytosol, respectively.

摘要

苯乙双胍（苯乙基双胍；一种抗糖尿病药物）加草氨酸 [乳酸脱氢酶 (LDH) 抑制剂] 被测试为一种有潜力的抗癌治疗联合用药。在体外研究中，苯乙双胍比二甲双胍（另一种最近被认为具有抗癌作用的双胍类药物）更有效，在各种癌细胞系中，其促进癌细胞死亡的效力范围为 25 倍至 1500 万倍。苯乙双胍的抗癌作用与线粒体中复合物 I 的抑制以及随后活性氧 (ROS) 的过度产生有关。草氨酸的添加抑制了细胞中 LDH 活性和乳酸的产生，这是双胍类药物的一个主要副作用，并通过减少 ATP 产生和加速 ROS 产生来诱导更快的癌细胞死亡。苯乙双胍加草氨酸比苯乙双胍联合 LDH 敲低更有效。在同基因小鼠模型中，与对照组相比，苯乙双胍加草氨酸增加了肿瘤细胞凋亡，减少了肿瘤大小和正电子发射断层扫描/计算机断层扫描 (PET/CT) 上的 (18)F-氟脱氧葡萄糖 (FDG) 摄取。我们得出的结论是，苯乙双胍对癌细胞的细胞毒性比二甲双胍更强。此外，苯乙双胍和草氨酸通过分别抑制线粒体中的复合物 I 和细胞质中的 LDH 具有协同的抗癌作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/e38485a6a2fa/pone.0085576.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/ad3602f0a925/pone.0085576.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/e68edaec7ddc/pone.0085576.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/66dde07f35af/pone.0085576.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/e8ce30ae9914/pone.0085576.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/e38485a6a2fa/pone.0085576.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/ad3602f0a925/pone.0085576.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/f8fe40c25044/pone.0085576.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/30d5de95e073/pone.0085576.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/ddb48cc6c9c4/pone.0085576.g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/66dde07f35af/pone.0085576.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/369d/3897486/e38485a6a2fa/pone.0085576.g009.jpg

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