Lee Jae-Seon, Choi Jiwon, Lee Seon-Hyeong, Kang Joon Hee, Ha Ji Sun, Kim Hee Yeon, Jang Hyonchol, Yook Jong In, Kim Soo-Youl
Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea.
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Pharmaceutics. 2020 Nov 23;12(11):1128. doi: 10.3390/pharmaceutics12111128.
Recent findings indicate that (a) mitochondria in proliferating cancer cells are functional, (b) cancer cells use more oxygen than normal cells for oxidative phosphorylation, and (c) cancer cells critically rely on cytosolic NADH transported into mitochondria via the malate-aspartate shuttle (MAS) for ATP production. In a spontaneous lung cancer model, tumor growth was reduced by 50% in heterozygous oxoglutarate carrier (OGC) knock-out mice compared with wild-type counterparts. To determine the mechanism through which OGC promotes tumor growth, the effects of the OGC inhibitor -phenylmaleimide (NPM) on mitochondrial activity, oxygen consumption, and ATP production were evaluated in melanoma cell lines. NPM suppressed oxygen consumption and decreased ATP production in melanoma cells in a dose-dependent manner. NPM also reduced the proliferation of melanoma cells. To test the effects of NPM on tumor growth and metastasis in vivo, NPM was administered in a human melanoma xenograft model. NPM reduced tumor growth by approximately 50% and reduced melanoma invasion by 70% at a dose of 20 mg/kg. Therefore, blocking OGC activity may be a useful approach for cancer therapy.
(a) 增殖癌细胞中的线粒体具有功能；(b) 癌细胞在氧化磷酸化过程中比正常细胞消耗更多的氧气；(c) 癌细胞严重依赖通过苹果酸-天冬氨酸穿梭（MAS）转运到线粒体中的胞质NADH来产生ATP。在一个自发性肺癌模型中，与野生型对照相比，杂合型氧代戊二酸载体（OGC）敲除小鼠的肿瘤生长减少了50%。为了确定OGC促进肿瘤生长的机制，在黑色素瘤细胞系中评估了OGC抑制剂N-苯基马来酰亚胺（NPM）对线粒体活性、耗氧量和ATP产生的影响。NPM以剂量依赖性方式抑制黑色素瘤细胞的耗氧量并降低ATP产生。NPM还降低了黑色素瘤细胞的增殖。为了测试NPM对体内肿瘤生长和转移的影响，在人黑色素瘤异种移植模型中给予NPM。在剂量为20 mg/kg时，NPM使肿瘤生长减少了约50%，并使黑色素瘤侵袭减少了70%。因此，阻断OGC活性可能是一种有用的癌症治疗方法。
