Hyperthermic CO2 pneumoperitoneum induces apoptosis in human colon cancer cells through Bax-associated mitochondrial pathway.
Peritoneal carcinomatosis of colorectal cancer is common and associated with poor prognosis, which poses a serious challenge and satisfactory treatments are urgently needed. Hyperthermic CO2 pneumoperitoneum (HT-CO2) is a new strategy. This study was designed to determine the potential of HT-CO2 against colorectal cancer cells. Based on an in vitro HT-CO2 study model, the anti-tumor efficacy of HT-CO2 (42-44 degrees C for 2-4 h) on human colon cancer COLO 205 cells was evaluated and the mechanisms of actions were analyzed. We found that HT-CO2 (43-44 degrees C for 2-4 h) significantly decreased cell viability as determined by WST-8 assay, and the cytotoxicity was attributable to HT-CO2-induced hyperthermia and extracellular acidification. Apoptosis was the major form of cell killing as demonstrated by Annexin-V/PI flow cytometry and morphological analysis (Hoechst/PI fluorescence microscopy and transmission electron microscopy). Further Western blot analysis and flow cytometric analysis of mitochondrial membrane potential showed that Bax-associated mitochondrial apoptotic pathway played critical role in the induction of apoptosis. We conclude that HT-CO2 has significant cytotoxic effect on colon cancer cells through induction of Bax-associated mitochondrial apoptosis, and the cytocidal effect is attributable to HT-CO2-induced hyperthermia and extracellular acidifications. Our data suggest that HT-CO2 may serve as a potential candidate for treating and/or preventing peritoneal carcinomatosis of colorectal cancer and further investigations both in vitro as well as in vivo in animal models are needed.
Peng
Yuanfei
Y
Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
Zheng
Minhua
M
Feng
Bo
B
Chen
Xuehua
X
Yu
Beiqin
B
Lu
Aiguo
A
Wang
Minliang
M
Li
Jianwen
J
Ma
Junjun
J
Xu
Lie
L
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002245:Carbon Dioxide / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000628:therapy*; D005434:Flow Cytometry; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011028:Pneumoperitoneum, Artificial / Q000379:methods*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D051028:bcl-2-Associated X Protein; D002245:Carbon Dioxide