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

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.

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

“…Moreover, a novel mitochondrial inhibitor named CPI-613 has been approved for a phase I clinical study with pancreatic cancer patients. This compound blocks two enzymes, pyruvate dehydrogenase and a-ketoglutarate dehydrogenase [162,163], and was administered in combination with modified FOLFIRINOX; the combination has given improved outcomes [164,165].…”

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

“…Apoptosis was elicited in a ROS-dependent manner as shown using N -acetyl cysteine as an antioxidant in the pancreatic cancer cell lines AsPC-1 and PANC-1 [ 211 ]. Partially contradicting, Egawa et al failed to detect apoptotic features, such as DNA fragmentation, in fibroblasts, which suggests a cell type-dependent mode of action [ 219 ]. Hence, more detailed studies on cell death mechanisms triggered by CPI-613 are required.…”

“…The activation of the AMPK–ACC axis was in turn observed to be crucial for the induction of apoptosis in pancreatic cancer cell lines [ 211 ]. Ambiguously, CPI-613 in combination with chloroquine, but not CPI-613 alone, caused autophagosome formation followed by lysosome fusion in clear cell sarcoma cells [ 219 ]. CPI-613 in combination with PS48 increased autolysosome formation in porcine fibroblasts, however without elevating LC3B levels [ 220 ].…”

“…Using positron emission tomography (PET) scanning, Sai et al indirectly monitored the delivery of CPI-613 into BxPC3 xenografts [ 230 ]. A combination of 25 mg/kg BW CPI-613 and chloroquine (50 mg/kg BW) once per week abolished the spread of clear cell sarcoma cells to the mesenteries [ 219 ]. However, CPI-613 and chloroquine alone failed to show this anti-metastatic effect or at least a reduction in xenograft tumor growth [ 219 ].…”

“…A combination of 25 mg/kg BW CPI-613 and chloroquine (50 mg/kg BW) once per week abolished the spread of clear cell sarcoma cells to the mesenteries [ 219 ]. However, CPI-613 and chloroquine alone failed to show this anti-metastatic effect or at least a reduction in xenograft tumor growth [ 219 ]. None of the studies described reported severe side effects or hematologic alterations [ 194 ].…”