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  • Title: Knockdown of the Bcl-2 gene increases sensitivity to EGFR tyrosine kinase inhibitors in the H1975 lung cancer cell line harboring T790M mutation.
    Author: Zou M, Xia S, Zhuang L, Han N, Chu Q, Chao T, Peng P, Chen Y, Gui Q, Yu S.
    Journal: Int J Oncol; 2013 Jun; 42(6):2094-102. PubMed ID: 23588221.
    Abstract:
    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are being widely used as targeted therapy in non-small cell lung cancer (NSCLC), but most cases acquire drug-resistance in 9 months. However, the mechanisms of resistance are still not fully understood. Since it has been demonstrated that EGFR-TKI-mediated repression of downstream signaling cascades and apoptosis induction is a key mechanism through which EGFR-TKIs exert their cytotoxic effects, we reasoned that activation of downstream signaling pathways and changes in the expression of apoptosis-related proteins contribute to the acquired resistance to EGFR-TKIs. We analyzed the protein levels of p-Akt, Bcl-2, Bax between gefitinib-sensitive and gefitinib-resistant lung cancer cell lines and evaluated whether targeting the anti-apoptotic protein Bcl-2 induces cell apoptosis and further sensitizes resistant H1975 cells to gefitinib. The data showed that p-Akt was activated and accompanied by substantial Bcl-2 in the H1975 lung cancer cell line, whereas no evidence was observed in HCC827 cells. Using small interfering RNA (siRNA) to silence Bcl-2 in H1975 cells led to significant downregulation of Bcl-2 protein expression, decreased cell viability in vitro and induced intrinsic apoptosis confirmed by flow cytometry and PARP cleavage. In Bcl-2 siRNA-transfected cells, adding gefitinib further reduced the number of viable cells, induced apoptosis to a greater extent compared to either treatment alone. These preclinical data suggested that downregulation of Bcl-2 by RNAi in the gefitinib-resistant H1975 lung cancer cell line with T790M mutation enhanced the effects of gefitinib and may offer a novel therapeutic strategy for the treatment of NSCLC.
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