Introduction of hypoxia-targeting p53 fusion protein for the selective therapy of non-small cell lung cancer.
Non-small cell lung cancer (NSCLC), which accounts for ~85% of lung cancer, is the major cause of malignancy mortality around the world. TP53 dysfunction and hypoxia are the typical biological features of the diverse solid tumors, including NSCLC. To develop an effective and low cytotoxic biological agent for targeted therapy, a p53 fusion protein, which was conjugated with the minimum motif of oxygen-dependent degradation domain (ODD) and the basic domain of TAT of HIV-1 named as TAT-ODD-p53, was evaluated for the treatment of NSCLC established by grafting H1299 cell line in which TP53 is homozygously deleted. We provide the evidence that this p53 fusion protein could significantly induce the cell-cycle arrest and/or apoptosis to inhibit H1299 cells' growth via p53-dependent pathways, including up-regulation of p21 expression and activation of pro-caspase-3, especially under hypoxia in vitro. The results in vivo indicated that this protein could selectively accumulate in the low oxygen tension areas of solid tumor tissues, inhibiting tumor growth via a similar mechanism to that in vitro. No obvious side effects were observed. Therefore, this recombinant p53 protein is likely to become a good candidate for targeted therapy of NSCLC.
Beijing Institute of Pharmacology and Toxicology, China.
Yu
Y
Zhao
Shaoping
S
Wu
Junhua
J
Wu
Peiyuan
P
Jia
Shan
S
Gao
Xiangdong
X
Yan
Yuxia
Y
Wang
D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054322:tat Gene Products, Human Immunodeficiency Virus; D053148:Caspase 3