TCDD as a biological response modifier for Mitomycin C: oxygen tension affects enzyme activation, reactive oxygen species and cell death.
TCDD was assessed as a biological response modifier for increasing MMC cytotoxicity through aryl hydrocarbon receptor (AhR) activation and increasing levels of bioreductive enzymes. Human MCF-7 cells were exposed to TCDD, MMC and combinations thereof under aerobic or hypoxic conditions. Cytotoxicity, enzyme activities (NQO1, XO, XDH, CYPR, CYP1A, GST and UGT) and intracellular reactive oxygen species (ROS) were subsequently measured. Under aerobic conditions, TCDD alone had no significant toxicity but combinations of TCDD and MMC significantly increased cell death. LD50 values were: MMC alone, 0.89 +/- 0.04 microM; TCDD co-treatment, 0.26 +/- 0.007 microM (P = 0.008 vs. MMC alone) and TCDD pre-treatment, 0.04 +/- 0.01 microM (P = 0.003 vs. MMC alone). Under hypoxia, TCDD itself caused significant cell death, likely due to increased ROS, but no combinations of MMC/TCDD altered the LD50 of MMC. Significant changes in enzyme activities were caused by TCDD under aerobic but not hypoxic conditions while MMC decreased the activity of its activating enzymes regardless of oxygen tension. Greater toxicity of MMC/TCDD combinations in aerobic culture, were most likely mediated by increased levels of bioreductive enzymes caused through AhR activation. Data presented herein also demonstrate that low oxygen tension decreases AhR activation and signaling and increases the inherent toxicity of TCDD.
Collier
Abby C
AC
Department of Nutrition, University of Nevada, Reno, 1664 N Virginia Street, Mail Stop 199, Reno, NV 89557, USA.
Pritsos
Karen L
KL
Pritsos
Chris A
CA
D000332:Aerobiosis; D001943:Breast Neoplasms; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000072317:Polychlorinated Dibenzodioxins; D017382:Reactive Oxygen Species; D016685:Mitomycin