title: Development of resistance to the atypical retinoid, ST1926, in the lung carcinoma cell line H460 is associated with reduced formation of DNA strand breaks and a defective DNA damage response.
abstract: 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.
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan 20133, Italy.
authors: Valentina
authors: V
authors: Zuco
authors: Chiara
authors: C
authors: Zanchi
authors: Cinzia
authors: C
authors: Lanzi
authors: Giovanni L
authors: GL
authors: Beretta
authors: Rosanna
authors: R
authors: Supino
authors: Claudio
authors: C
authors: Pisano
authors: Marcella
authors: M
authors: Barbarino
authors: Romina
authors: R
authors: Zanier
authors: Federica
authors: F
authors: Bucci
authors: Concetta
authors: C
authors: Aulicino
authors: Paolo
authors: P
authors: Carminati
authors: Franco
authors: F
authors: Zunino
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002934:Cinnamates / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000737:chemistry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D012176:Retinoids / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; C099555:CD 437; D002934:Cinnamates; D006657:Histones; D012176:Retinoids; D045304:Cytochromes c; D004247:DNA; D020169:Caspases; D000218:Adamantane