Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity.
Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (gamma-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlying the antileukemic activity of RRMs in NB4 and other AML cell lines. In accordance with the S-phase specificity of the cytotoxic and antiproliferative responses of AML cells to RRMs, increases in DSBs are maximal during the S phase of the cell cycle. Induction of DSBs precedes inhibition of DNA replication and is associated with rapid activation of ataxia telangectasia mutated, ataxia telangectasia RAD3-related, and DNA-dependent protein kinases with subsequent stimulation of the p38 mitogen-activated protein kinase. Inhibition of ataxia telangectasia mutated and DNA-dependent protein kinases reduces phosphorylation of H2AX. Cells defective for homologous recombination are particularly sensitive to ST1926, indicating that this process is important for the protection of cells from the RRM-dependent DNA damage and cytotoxicity.
Valli
Claudia
C
Laboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20157 Milan, Italy.
Paroni
Gabriela
G
Di Francesco
Angela Maria
AM
Riccardi
Riccardo
R
Tavecchio
Michele
M
Erba
Eugenio
E
Boldetti
Andrea
A
Gianni'
Maurizio
M
Fratelli
Maddalena
M
Pisano
Claudio
C
Merlini
Lucio
L
Antoccia
Antonio
A
Cenciarelli
Chiara
C
Terao
Mineko
M
Garattini
Enrico
E
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002869:Chromosome Aberrations / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects; D012176:Retinoids / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects*
C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; C099555:CD 437; D002934:Cinnamates; C468783:H2AX protein, human; D006657:Histones; D012176:Retinoids; D011494:Protein Kinases; D000218:Adamantane