A small molecule that disrupts Mdm2-p53 binding activates p53, induces apoptosis and sensitizes lung cancer cells to chemotherapy.
Mdm2 binds to p53 and promotes its degradation. A class of small molecule Mdm2 inhibitors (MI) was recently discovered that binds to Mdm2 and disrupts Mdm2-p53 binding. The efficacy of MI-43 was tested against two pairs of human lung cancer lines differing in p53 status: adenocarcinoma A549 (p53 wild-type, wt) and H522 (p53-null) and non-small cell lung carcinoma H460 (p53wt) and H1299 (p53-null). MI-43 induced the accumulation of p53 and its downstream target genes, Mdm2, p21, Noxa and Puma only in wt p53-containing cells, indicating that disruption of Mdm2-p53 binding increases p53, which is transcriptionally active. MI-43 preferentially inhibited the growth of wt p53-containing cells in a p53 dependent manner, but was much less effective in p53-null cells. Mechanistically, MI-43 induced G(1) or G(2) arrest at low concentration as result of p21 induction, and apoptosis at high concentration due to Puma/Noxa induction. Importantly, MI-43 is much less toxic to normal fetal lung fibroblast, MRC5 cells. Finally, when used in combination, MI-43 sensitized chemo-resistant A549 cells to etoposide-induced apoptosis. Thus, MI-43 or its analogues could be further developed as a novel class of anticancer drug for lung cancer cells harboring wt p53 as a single agent or in combination with chemo-drugs.
Sun
Steven H
SH
Division of Cancer Biology, Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
Zheng
Min
M
Ding
Ke
K
Wang
Shaomeng
S
Sun
Yi
Y
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008956:Models, Chemical; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D007211:Indoles; C530788:MI 43 compound; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D053148:Caspase 3