RESUMO
BACKGROUND: Gefitinib (Iressa, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor. E2F-1 is a critical determinant in cell cycle. Growth signals up-regulate telomerase activity. The effects of gefitinib on E2F-1 and telomerase in A549, H23 and A431 cells were examined. MATERIALS AND METHODS: Cell proliferation and cell cycle progression were measured by the WST-1 assay and flow cytometry. The expression of E2F-1 and cyclin-dependent kinase inhibitors was evaluated, and hTERT mRNA expression and telomerase activity were analyzed. RESULTS: In the A431 and A549 cells, treatment with gefitinib inhibited cell proliferation and was associated with an increase in G1-phase. In both cell types, gefitinib decreased the expression of E2F-1 mRNA and protein, followed by the suppression of hTERT mRNA and telomerase activity. In the H23 cells, gefitinib did not affect cell proliferation. CONCLUSION: The antiproliferative effects of gefitinib may be, at least in part, due to the inhibition of E2F-1 expression and telomerase activity.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Fator de Transcrição E2F1/antagonistas & inibidores , Fase G1/efeitos dos fármacos , Quinazolinas/farmacologia , Telomerase/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Regulação para Baixo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Telomerase/genética , Telomerase/metabolismo , Células Tumorais Cultivadas , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/metabolismo , Neoplasias Vulvares/patologiaRESUMO
OBJECTIVE: We examined the significance of human T-cell lymphotropic virus type I (HTLV-I) Tax protein-induced resistance to anticancer drugs and the relationship between Tax and multidrug resistance proteins. MATERIALS AND METHODS: S1T cell, a leukemic non-Tax-producing T-cell clone established from an adult T-cell leukemia (ATL) patient, S1TcTax05 and S1TcTax10 clones, transfected with Tax stably expressing cDNA, and S1Tneo, transfected with a neomycin-resistant gene, were examined for Tax-related anticancer drug resistance. Resistance of those cells to the anticancer drugs doxorubicin, etoposide, cisplatin, and vindesine was tested with the MTT method. Expression of multidrug resistance protein mRNAs (MDR1, MRP1, cMOAT/MRP2, and LRP) was analyzed with reverse transcriptase polymerase chain reaction (RT-PCR). Doxorubicin subcellular distribution in those cells was examined by fluorescence microscopy. RESULTS: S1TcTax05 and S1TcTax10 showed resistance to doxorubicin, etoposide, and vindesine, but not to cisplatin as compared with S1T or S1Tneo. RT-PCR demonstrated that MRP1 mRNA was expressed, but MDR1, cMOAT, and LRP mRNAs were not in S1T or S1Tneo. Marked expression of LRP mRNA was detected, but no change of MDR1, MRP1, or cMOAT mRNA expression in Tax-expressing S1TcTax05 and S1TcTax10. Fluorescence microscopy demonstrated that doxorubicin was distributed mainly in the cytoplasm of S1TcTax05 and S1TcTax10, and in the nucleus of S1T and S1Tneo. CONCLUSIONS: These findings suggest that Tax-related drug resistance of ATL cells is due to LRP and not MDR1, as reported previously. These findings in cells derived from an ATL patient suggest a novel mechanism for drug resistance in Tax-expressing ATL cells.