Inhibition of GSK-3 beta activity attenuates proliferation of human colon cancer cells in rodents.
The authors' recent discovery that glycogen synthase kinase-3beta (GSK-3beta) participates in colon cancer cells' survival and proliferation prompted us to investigate whether GSK-3beta inhibition alters proliferation of colon cancer cells in vivo. Groups of four or five athymic mice (Balb/c, nu/nu) with subcutaneous xenografts of SW480 human colon cancer cells were treated with dimethyl sulfoxide (DMSO) or different doses (1, 2 and 5 mg/kg body weight) of either small-molecule GSK-3beta inhibitor (SB-216763 and AR-A014418) by intraperitoneal injection three times per week for 5 weeks. Compared with DMSO (a diluent of the GSK-3beta inhibitors) as a control, either GSK-3beta inhibitor significantly inhibited proliferation of cancer cell xenografts in the rodents in a dose-dependent manner. Histochemical and immunohistochemical analysis of tumor xenografts demonstrated a significant, dose-dependent decrease in fractions of proliferating cells and an increase in the incidence of apoptosis of cancer cells in mice treated with either GSK-3beta inhibitor. No adverse events or effects were observed in the rodents during the course of treatment, except for rare lethal accidents due to intraperitoneal injection. Morphological examination showed no apparent pathologic changes in major organs including the lungs, liver, pancreas, kidneys, spleen and large bowel of rodents treated with DMSO and the GSK-3beta inhibitors. The results indicate that the GSK-3beta inhibitors would be a novel class of therapeutic agent for colon cancer.
Shakoori
Abbas
A
Division of Translational and Clinical Oncology, Molecular and Cellular Targeting Translational Oncology Center, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-0934, Japan.
Mai
Wei
W
Miyashita
Katsuyoshi
K
Yasumoto
Kazuo
K
Takahashi
Yutaka
Y
Ooi
Akishi
A
Kawakami
Kazuyuki
K
Minamoto
Toshinari
T
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006131:Growth Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D011897:Random Allocation; D014183:Transplantation, Heterologous
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004121:Dimethyl Sulfoxide