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.