Abstract
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.
Highlights
Retinoid-related molecules (RRM) are selective antitumor agents with no-cross resistance with other chemotherapeutics [1]
When exposed to a predominantly cytotoxic concentration of ST1926 or CD437 (1 Amol/L), NB4 cells undergo rapid apoptosis [15, 16], which is followed by diminished viability
We evaluated whether ataxia telangectasia mutated (ATM) and/or DNA-PK are involved in ST1926-dependent phosphorylation of histone H2AX, pretreating NB4 cells with the specific inhibitors, IC60211 and KU55933 (Fig. 5C)
Summary
Retinoid-related molecules (RRM) are selective antitumor agents with no-cross resistance with other chemotherapeutics [1]. ST1926, CD437, and congeners are bona fide retinoids activating the classic nuclear retinoic acid receptors with different selectivity and potency [3], there are RRMs that do not bind classic nuclear retinoic acid receptors [5, 6]. The nuclear orphan receptor, Shp/NROB2, binds certain RRMs and plays a major role in the ensuing apoptotic process [11]. There is limited evidence suggesting that ST1926 [12] and possibly CD437 [1, 13, 14] are DNA-damaging agents
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