Atypical
retinoids are potent inducers of apoptosis, but activation of the apoptotic pathway seems to be independent of
retinoid receptors. Previous studies with a novel adamantyl
retinoid,
ST1926, have shown that apoptosis induction is associated with an early genotoxic stress. To better understand the relevance of these events, we have selected a subline of the H460 lung
carcinoma cell line resistant to
ST1926. Resistant cells exhibited cross-resistance to a related molecule, CD437, but not cross-resistance to agents with different mechanisms of action. In spite of a lack of defects in intracellular
drug accumulation, induction of
DNA strand breaks in resistant cells required exposure to a substantially higher concentration, which was consistent with the degree of resistance. At
drug concentrations causing a similar antiproliferative effect (IC80) and a comparable extent of DNA lesions in sensitive and resistant cells, the apoptotic response was a delayed and less marked event in resistant cells, thus indicating a reduced susceptibility to apoptosis. In spite of recognition of DNA lesions in resistant cells, as supported by phosphorylation of p53 and
histone H2AX, resistant cells exhibited no activation of the mitochondrial pathways of apoptosis. Following exposure to equitoxic
drug concentrations, only sensitive cells exhibited a typical stress/DNA damage response, with activation of the S-phase checkpoint. The cellular resistance to
ST1926 reflects alterations responsible for a reduced generation of DNA lesions and for an enhanced tolerance of the genotoxic stress, resulting in lack of activation of the intrinsic pathway of apoptosis. The defective DNA damage response, accompanied by a reduced susceptibility to apoptosis in resistant cells, provides further support to the involvement of genotoxic stress as a critical event in mediating apoptosis induction by
ST1926.