Antitumor activity of G-quadruplex-interactive agent TMPyP4 in K562 leukemic cells.
The cationic porphyrin TMPyP4 can bind to and stabilize DNA guanine-quadruplexes. We investigated the molecular mechanism of the antitumor activity of TMPyP4 in K562 cells and human telomere reverse transcriptase subunit (hTERT)-transfected K562 cells in which telomerase activity, followed by telomere elongation, was enhanced. Treatment with 100 microM TMPyP4 significantly inhibited the growth of both types of cell, with decreases of cells in the G(1) phase and increases of those in the S and G(2)/M phases after 48 h, preceding cell death after 72 h. cDNA microarray analysis revealed upregulation of 33 genes and downregulation of 54 genes in K562 cells treated with 100 microM TMPyP4 for 48 h. Moreover, TMPyP4 decreased c-Myc protein expression, increased the expression of p21(CIP1) and p57(KIP2) proteins, and activated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-regulated kinase. These findings may provide a rationale for the development of guanine-quadruplex-interactive agents as novel antileukemic therapies.
Mikami-Terao
Yoko
Y
Department of Pediatrics and Institute of DNA Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
Akiyama
Masaharu
M
Yuza
Yuki
Y
Yanagisawa
Takaaki
T
Yamada
Osamu
O
Yamada
Hisashi
H
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015139:Blotting, Southern; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054856:G-Quadruplexes / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011166:Porphyrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000502:physiology*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors; D011166:Porphyrins; D012333:RNA, Messenger; C021096:tetra(4-N-methylpyridyl)porphine; C509186:TERT protein, human; D019098:Telomerase