Motexafin gadolinium enhances p53-Mdm2 interactions, reducing p53 and downstream targets in lymphoma cell lines.
BACKGROUND
Loss of p53 renders cells more susceptible to acute oxidant stress induced by oxidant-generating agents such as motexafin gadolinium (MGd). We hypothesized that reactive oxygen species (ROS)-generating MGd results in low-level p53 expression, making cells more susceptible to oxidant stress.


METHODS
Lymphoma cells were incubated with different concentrations of MGd with or without zinc (Zn) and ascorbate, and ROS, apoptosis, proteins, and oxidant genes were measured.


RESULTS
MGd, with ascorbate and Zn, induced apoptosis in lymphoma cells. This was accompanied by reduction of p53 protein but not message, and by reduction of p53 downstream targets p21, glutathione peroxidase 1 (GPx1), and p53 up-regulated modulator of apoptosis (PUMA). p53 protein reduction was reversed by MG132, and nutlin-3.


CONCLUSIONS
Our data are consistent with a pathway of cell death that is independent of p53-mediated induction of PUMA; the cellular response to reduce p53 represents a cell survival adjustment to ROS-mediated stress.
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA. a-singh@northwestern.edu
Amareshwar T K
AT
Singh
Andrew M
AM
Evens
Sheila N
SN
Prachand
Leo I
LI
Gordon
D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008665:Metalloporphyrins / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
D007093:Imidazoles; D007976:Leupeptins; D008665:Metalloporphyrins; D010879:Piperazines; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C437683:motexafin gadolinium; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D015032:Zinc; D001205:Ascorbic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde