A transition state analogue of 5'-methylthioadenosine phosphorylase induces apoptosis in head and neck cancers.
Methylthio-DADMe-immucillin-A (MT-DADMe-ImmA) is an 86-pm inhibitor of human 5'-methylthioadenosine phosphorylase (MTAP). The sole function of MTAP is to recycle 5'-methylthioadenosine (MTA) to S-adenosylmethionine. Treatment of cultured cells with MT-DADMe-ImmA and MTA inhibited MTAP, increased cellular MTA concentrations, decreased polyamines, and induced apoptosis in FaDu and Cal27, two head and neck squamous cell carcinoma cell lines. The same treatment did not induce apoptosis in normal human fibroblast cell lines (CRL2522 and GM02037) or in MCF7, a breast cancer cell line with an MTAP gene deletion. MT-DADMe-ImmA alone did not induce apoptosis in any cell line, implicating MTA as the active agent. Treatment of sensitive cells caused loss of mitochondrial inner membrane potential, G(2)/M arrest, activation of mitochondria-dependent caspases, and apoptosis. Changes in cellular polyamines and MTA levels occurred in both responsive and nonresponsive cells, suggesting cell-specific epigenetic effects. A survey of aberrant DNA methylation in genomic DNA using a microarray of 12,288 CpG island clones revealed decreased CpG island methylation in treated FaDu cells compared with untreated cells. FaDu tumors in a mouse xenograft model were treated with MT-DADMe-ImmA, resulting in tumor remission. The selective action of MT-DADMe-ImmA on head and neck squamous cell carcinoma cells suggests potential as an agent for treatment of cancers sensitive to reduced CpG island methylation.
Basu
Indranil
I
Biochemistry, Pathology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
Cordovano
Grace
G
Das
Ishita
I
Belbin
Thomas J
TJ
Guha
Chandan
C
Schramm
Vern L
VL
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D018899:CpG Islands; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry* / Q000494:pharmacology
D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase