title: MDDD, a 4,9-diazapyrenium derivative, is selectively toxic to glioma cells by inducing growth arrest at G0/G1 independently of p53.
abstract: 4-Methyl-2,7-diamino-5,10-diphenyl-4,9-diaz-apyrenium chloride (MDDD), a stable and water soluble nucleic acid-intercalating agent, was shown to be toxic to cancer cells with IC50 around 10 microM. IC(50) We tested MDDD for its potential antitumor activities and found it inhibited cancer cell growth with IC(50) in the micromolar range for the majority of cancer cells tested, with the exception of glioma cells, for which the IC(50) is in the submicromolar range. This unique selectivity of MDDD to glioma cells can potentially be exploited for anti-glioma therapeutics. Although the underlying mechanisms for the apparent glioma specificity remain to be elucidated, our analysis indicates that MDDD significantly reduces cell clonogenicity and blockes cell proliferation at the G1 phase. MDDD treatment also triggers induction of p53 and p21 at the protein levels, suggesting the activation of DNA damage response. However, MDDD mediated growth inhibition does not require the p53 pathway since p53+/- isogenic cell pairs display the same sensitivity. These properties of MDDD favor its candidacy for evaluation as a new anti-tumor agent, particularly for glioma.
authors.affiliation: Immusol Inc., 10790 Roselle Street, San Diego, CA 92121, USA.
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Yu
authors.forename: James
authors.initials: J
authors.lastname: Macdonald
authors.forename: Steve
authors.initials: S
authors.lastname: Josephs
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Vivian
authors.initials: V
authors.lastname: Nguy
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Tor
authors.forename: Flossie
authors.initials: F
authors.lastname: Wong-Staal
authors.forename: Qi-Xiang
authors.initials: QX
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D016193:G1 Phase; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011726:Pyridinium Compounds / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D016192:Resting Phase, Cell Cycle; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C523256:4-methyl-2,7-diamino-5,10-diphenyl-4,9-diaz-apyrenium chloride; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011726:Pyridinium Compounds; D016159:Tumor Suppressor Protein p53; D004247:DNA