Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites.
Tumor hypoxia in a solid tumor mass has long been recognized as a cause of resistance to current cancer therapies, and has also been suggested to be a potent driving force towards malignancy. Recent progress in the understanding of the molecular mechanism of the tumor response to hypoxia has increased attention on targeting hypoxia for cancer therapy. We have generated a hypoxia-targeting fusion protein, TOP3, which is composed of a protein transduction domain (PTD) of HIV TAT, an oxygen-dependent degradation domain (ODD) of HIF-1 alpha, and procaspase-3. Here, we examine the effects of TOP3 in a rat ascites model. First, we clarified that the fluid in ascites from MM1 cells, which are derivatives of AH130 rat ascites hepatoma cells, was highly hypoxic. In vitro, MM1 cells retained protein degradation machinery through the ODD domain, and TOP3 effectively impaired MM1 cell growth in culture under hypoxic conditions by inducing apoptosis. Intraperitoneal administration of TOP3 prolonged the life span of rats bearing a significant amount of malignant ascites, and 60% of the treated animals were cured without recurrence of ascites. Thus, TOP3 had a dramatic effect on malignant ascites and, hence, we propose that rodent malignant ascites is an appropriate platform for testing hypoxia-targeted drugs.
Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan. inoue-ma2@mc.pref.osaka.jp
Masahiro
M
Inoue
Mutsuko
M
Mukai
Yukou
Y
Hamanaka
Masaharu
M
Tatsuta
Masahiro
M
Hiraoka
Shinae
S
Kizaka-Kondoh
D000818:Animals; D017209:Apoptosis; D001201:Ascites / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D051272:Glucose Transporter Type 1; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; C498363:TOP3 fusion protein; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004247:DNA; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases