Electromicroscopic observations on gliotoxin-induced apoptosis of cancer cells in culture and human cancer xenografts in transplanted SCID mice.
BACKGROUND
Gliotoxin belongs to a group of compounds produced by fungi, all of them having a bridged polysulfide piperazine ring in their chemical structure. This internal polysulfide bridge enables them to carry out various biofunctions, but so far, the toxicity of these compounds limited them to be used as medicines in clinic. However, the toxicities of these compounds are quite different and determined by their different part of chemical structures. Therefore, it is still possible to find a suitable low toxic compound for drug use. As for anticancer drug developing, the first need is to confirm the anticancer activity in vivo.


METHODS
The morphological changes of human breast cancer MCF-7 cells affected by gliotoxin in culture, and the structural damages of human cancer xenograft tissue in SCID mice after intra-tumor injection of gliotoxin were observed after histological stain and transmission electromicroscopic treatment. The DNA changes of the human colon cancer xenograft were observed in 1.2% agarose gel electrophoresis.


RESULTS
Gliotoxin 1 or 5 microM in medium for 24 hours induced typical apoptotic structural changes to MCF-7 cells, the cell surface membrane showed blebbing clearly. Injection of 1 mg gliotoxin into the tumor tissue directly did not induce noticeable side-effects to the host mice but induced complete damage of the cell structure, the cell surface membran broken down and the components of the nuclei segmented. The whole cancer tissue shrinked and finally formed a dark color scab which came off from the skin few days later. The cured mice showed no tumor recurrence in the six months following observation. The apoptotic DNA damage was also found in human colon cancer xenograft C1-2 tissues after gliotoxin was injected inside the tumor tissue.


CONCLUSIONS
The anticancer activity of gliotoxin is confirmed in vivo.
Pan
Xing Qing
XQ
College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA. pan.67@osu.edu
Harday
John
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D005912:Gliotoxin / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D014183:Transplantation, Heterologous
D005912:Gliotoxin