The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo.
Cationic porphyrins are being studied as possible anticancer agents because of their ability to bind to and stabilize DNA guanine quadruplexes (G-quadruplexes). We have shown previously that the cationic porphyrin TMPyP4 is able to bind to and stabilize G-quadruplexes in human telomere sequences, resulting in inhibition of telomerase activity. To better understand the mechanism of action behind telomerase inhibition by TMPyP4, we performed a cDNA microarray analysis on cells treated with TMPyP4 and TMPyP2, a positional isomer of TMPyP4 that has low affinity for G-quadruplexes. Analysis of time course data from the microarray experiments revealed that TMPyP4 and TMPyP2 treatment altered the expression of several gene clusters. We found that c-MYC, an oncogene nearly ubiquitous in human tumors that bears the potential in its promoter to form a G-quadruplex, was among the genes specifically down-regulated by TMPyP4, but not by TMPyP2. The hTERT gene, which encodes the catalytic subunit of telomerase, is transcriptionally regulated by c-MYC, and we have found that TMPyP4 also causes a decrease in human telomerase reverse transcriptase transcripts, suggesting two possible mechanisms for the effect of TMPyP4 on telomerase activity. We also show that TMPyP4, but not TMPyP2, is able to prolong survival and decrease tumor growth rates in two xenograft tumor models. We believe that, because of the actions of TMPyP4 in decreasing both c-MYC protein levels and telomerase activity, as well as its anticancer effects in vivo, it is a worthwhile agent to pursue and develop further.
Grand
Cory L
CL
Arizona Cancer Center, Tucson, Arizona 85724, USA.
Han
Haiyong
H
Muñoz
Rubén M
RM
Weitman
Steve
S
Von Hoff
Daniel D
DD
Hurley
Laurence H
LH
Bearss
David J
DJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011166:Porphyrins / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000378:metabolism*; D013997:Time Factors
D020533:Angiogenesis Inhibitors; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D011166:Porphyrins; D016271:Proto-Oncogene Proteins c-myc; C021096:tetra(4-N-methylpyridyl)porphine; D012313:RNA; D004247:DNA; D019098:Telomerase