The phenylhexyl isothiocyanate induces apoptosis and inhibits leukemia cell growth in vivo.
Isothiocyanates are potent chemopreventive agents for carcinogen-induced cancers in rodents. The major mode of action for chemoprevention is cytoprotection i.e. inducing detoxifying enzymes to remove the carcinogens, thus blocking the initiation of carcinogenesis. Analysis has indicated that isothiocyanates also act at the post-initiation levels of carcinogenesis. We have also reported that the phenylhexyl isothiocyanate (PHI) induced growth arrest and apoptosis in human leukemia HL-60 cells in culture. Since then we have investigated the in vivo efficacy of PHI. The effects of PHI were evaluated in immunodeficient mice, with xenografts of human leukemia HL-60 cells. The maximum tolerated dose (MTD) was determined. The experimental mice received 80% of the MTD. Oral feedings of PHI significantly reduced tumor incidence (p<0.05) without overt toxicity. PHI inhibited cell cycle progression through the down-regulation of cyclin expression, Rb phosphorylation and the up-regulation of the cdk-inhibitors. Apoptosis was significantly increased in the treated tumors but not in the normal mouse tissues. In conclusion, PHI induced apoptosis and inhibited the growth of xenografts by targeting the cell cycle regulators. PHI induced selective apoptosis effects in the rapidly growing tumor cells but not in the normal tissues.
Lu
Lulu
L
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Liu
Delong
D
Ma
Xudong
X
Beklemishev
Anastasia
A
Seiter
Karen
K
Ahmed
Tauseef
T
Chiao
J W
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000187:drug effects; D016213:Cyclins / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects
D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D017879:Isothiocyanates; D016160:Retinoblastoma Protein; C073279:6-phenylhexyl isothiocyanate