Therapeutic potential of CPI-613 for targeting tumorous mitochondrial energy metabolism and inhibiting autophagy in clear cell sarcoma.
Therapeutic potential of CPI-613 for targeting tumorous mitochondrial energy metabolism and inhibiting autophagy in clear cell sarcoma.
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DOI：
10.1371/journal.pone.0198940
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Takeuchi T
中科院分区：
文献类型：
--
作者：
Egawa Y;Saigo C;Kito Y;Moriki T;Takeuchi T
透明细胞肉瘤(CCS)是一种侵袭性的软组织肿瘤，转移率高。在本研究中，我们发现针对肿瘤线粒体能量代谢的CPI-613在体外诱导HS-MM CCS细胞自噬小体形成和溶酶体融合。有趣的是，CPI-613和抑制自噬小体与溶酶体融合的氯喹在体外显著诱导HS-MM CCS细胞生长坏死。随后，我们建立了CCS的小鼠正交异性转移模型，并评估了CPI-613和氯喹联合使用对CCS进展的可能抑制作用。将HS-MM注射到CCS最常见的部位大腿的腱膜内，导致SCID-beige小鼠的大量转移。相比之下，CPI-613(25 mg/kg)和氯喹(50 mg/kg)每周两天连续两周的腹腔注射，显著抑制了注射部位的肿瘤生长，并阻止了转移。目前的结果提示CPI-613和氯喹联合应用对CCS的进展有抑制作用。
Clear cell sarcoma (CCS) is an aggressive type of soft tissue tumor that is associated with high rates of metastasis. In the present study, we found that CPI-613, which targets tumorous mitochondrial energy metabolism, induced autophagosome formation followed by lysosome fusion in HS-MM CCS cells in vitro. Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro. Subsequently, we established a murine orthotropic metastatic model of CCS and evaluated the putative suppressive effect of a combination of CPI-613 and chloroquine on CCS progression. Injection of HS-MM into the aponeuroses of the thigh, the most frequently affected site in CCS, resulted in massive metastasis in SCID-beige mice. By contrast, intraperitoneal administration of CPI-613 (25 mg/kg) and chloroquine (50 mg/kg), two days a week for two weeks, significantly decreased tumor growth at the injection site and abolished metastasis. The present results imply the inhibitory effects of a combination of CPI-613 and chloroquine on the progression of CCS.
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影响因子：
4.7
作者：
Takeuchi, T;Misaki, A;Ohtsuki, Y
通讯作者：
Ohtsuki, Y
影响因子：
3.5
作者：
Iwashita H;Sakurai HT;Nagahora N;Ishiyama M;Shioji K;Sasamoto K;Okuma K;Shimizu S;Ueno Y
通讯作者：
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影响因子：
78.5
作者：
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通讯作者：
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影响因子：
21.1
作者：
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通讯作者：
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影响因子：
5.9
作者：
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通讯作者：
Zachar Z