Antitumor activity of actinonin in vitro and in vivo.
Actinonin, an antibiotic and CD13/aminopeptidase N (APN) inhibitor, has been shown to be cytotoxic to tumor cell lines in vitro. We investigated the antiproliferative effects of actinonin on human and murine leukemia and lymphoma cells. Actinonin inhibited growth of NB4 and HL60 human cell lines and AKR mouse leukemia cells in vitro with an IC50 of about 2-5 micrograms/ml. The inhibitory effect on CD13-positive cells was not blocked by pretreatment with the anti-CD13/APN monoclonal antibody F23, which binds with high affinity to the active site of CD13/APN and blocks its enzymatic activity. Moreover, F23 alone was not inhibitory to CD13-positive cells. Furthermore, a similar inhibitory IC50 of actinonin was seen in the CD13-negative cell lines RAJI and DAUDI human lymphoma. These data suggest that the inhibitory effect of actinonin is not mediated by inhibition of CD13/APN. Cell cycle analysis showed that actinonin induces a G1 arrest in HL60 and NB4 cells; apoptosis was observed in 20-35% of the cells as measured by intracellular flow cytometry. To assess whether these effects could be seen in vivo, the effect of actinonin on the syngeneic AKR mouse leukemia model was evaluated. Actinonin showed dose-dependent antitumor effects on AKR leukemia in vivo, resulting in a survival advantage. In conclusion, apoptosis, growth inhibition, and therapeutic effects in vivo are induced by actinonin and are not likely to be mediated by CD13/APN.
Xu
Y
Y
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Lai
L T
LT
Gabrilove
J L
JL
Scheinberg
D A
DA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008806:Mice, Inbred AKR; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D006877:Hydroxamic Acids; C010531:actinonin