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Pharmacology ; 106(11-12): 623-636, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34753130

RESUMEN

INTRODUCTION: 5-Fluorouracil (5-FU) is used to treat various cancers, including non-small-cell lung cancer (NSCLC). It inhibits nucleotide synthesis and induces single- and double-strand DNA breaks. In the homologous recombination pathway, radiation-sensitive 52 (Rad52) plays a crucial role in DNA repair by promoting the annealing of complementary single-stranded DNA and stimulating Rad51 recombinase activity. Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor with clinical activity against NSCLC cells. However, whether the combination of 5-FU and erlotinib has synergistic activity against NSCLC cells is unknown. METHODS: After the 5-FU and/or erlotinib treatment, the expressions of Rad52 mRNA were determined by quantitative real-time polymerase chain reaction analysis. Protein levels of Rad52 and phospho-p38 MAPK were determined by Western blot analysis. We used specific Rad52 or p38 MAPK small interfering RNA and p38 MAPK inhibitor (SB2023580) to examine the role of p38 MAPK-Rad52 signal in regulating the chemosensitivity of 5-FU and/or erlotinib. Cell viability was assessed by MTS assay and trypan blue exclusion assay. RESULTS: In 2 squamous cell carcinoma cell lines, namely, H520 and H1703, 5-FU reduced Rad52 expression in a p38 MAPK inactivation-dependent manner. Enhancement of p38 MAPK activity by transfection with MKK6E (a constitutively active form of MKK6) vector increased the Rad52 protein level and cell survival by 5-FU. However, in human lung bronchioloalveolar cell adenocarcinoma A549 cells, 5-FU reduced Rad52 expression and induced cytotoxicity independent of p38 MAPK. Moreover, 5-FU synergistically enhanced the cytotoxicity and cell growth inhibition of erlotinib in NSCLC cells; these effects were associated with Rad52 downregulation and p38 MAPK inactivation in H520 and H1703 cells. CONCLUSION: The results provide a rationale for combining 5-FU and erlotinib in lung cancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Clorhidrato de Erlotinib/farmacología , Fluorouracilo/farmacología , Neoplasias Pulmonares/patología , Neoplasias de Células Escamosas/patología , Proteína Recombinante y Reparadora de ADN Rad52/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos
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