Research Article: Therapeutic potential of CPI-613 for targeting tumorous mitochondrial energy metabolism and inhibiting autophagy in clear cell sarcoma

Date Published: June 7, 2018

Publisher: Public Library of Science

Author(s): Yuki Egawa, Chiemi Saigo, Yusuke Kito, Toshiaki Moriki, Tamotsu Takeuchi, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0198940

Abstract

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.

Partial Text

Clear cell sarcoma (CCS) affects the deep soft tissues of young adults and is known to have high rates of metastasis [1, 2]. Lymphatic metastasis is rare in other malignant soft tissue tumors but is commonly detected in CCS [3, 4]. Radical surgical resection is the first line of treatment of CCS. However, the rate of local recurrence can reach as high as 84% and the rate of late metastases can be as high as 63%, and these are associated with the 5–20-year survival rate of 67–10% [5]. Considering that CCS is relatively resistant to conventional soft tissue sarcoma chemotherapy regimens, there is an urgent need to develop therapies that also control metastasis.

CPI-613 is an analog of lipoic acid, which strongly disrupts mitochondrial metabolism through inhibiting the TCA cycle [6]. Despite the early dogma that cancer cells bypass the TCA cycle and solely use anaerobic glycolysis, recent advances demonstrate that certain cancer cells still utilize the TCA cycle for energy production and macromolecule synthesis [17]. Furthermore, CPI-613 disrupts the redox balance in cancer cell mitochondria [7].

 

Source:

http://doi.org/10.1371/journal.pone.0198940

 

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