Silencing of X-Linked Inhibitor of Apoptosis Decreases Resistance to Cisplatin and Paclitaxel but Not Gemcitabine in Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) is a highly lethal malignancy that often becomes resistant to chemotherapy. The effect of silencing the X-linked inhibitor of apoptosis gene (XIAP) on resistance to cisplatin, paclitaxel and gemcitabine was studied in the NSCLC cell lines A549 and H460. Transfection of these cells with small interfering RNA (siRNA) for XIAP blocked overexpression of the gene, suppressed cell proliferation, increased apoptosis and increased the cells' sensitivity to cisplatin and paclitaxel by preventing the binding of XIAP to caspase3 and increasing the activity of this enzyme. There was no significant difference in resistance to gemcitabine between XIAP-silenced cells and non-transfected cells. Changes in chemoresistance were independent of the activity of caspase-9. Silencing XIAP with siRNA can decrease chemoresistance in NSCLC and may have a potential role in the treatment of this disease.

The Chinese Herb Isolate Isorhapontigenin Induces Apoptosis in Human Cancer Cells by Down-regulating Overexpression of Antiapoptotic Protein XIAP

“…There is abundant research focusing on XIAP depletion or knockdown in cancer cells leading to reduction in cell migration and invasion (7,29). Molecular approaches for targeting XIAP expression include phosphorothioate antisense oligonucleotide (AEG-35156)-targeted XIAP mRNA (30), small interfering RNA (siRNA) (31), and a small molecule inhibitor of XIAP (32). However, safety is the major limitation of the aforementioned approaches, along with other concerns such as poor stability, membrane penetration, and transfection efficiency (33).…”

Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly

“…Western blot analysis was conducted as previously study [16,17]. Briefly, 50 mg total proteins from samples was separated on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis gels and transferred to PVDF membranes (Millipore Corp., USA).…”

“…The sequences of XIAP siRNA were described previously [16]. The transfection was performed using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol.…”

Enhanced Inhibition of Bladder Cancer Cell Growth by Simultaneous Knockdown of Antiapoptotic Bcl-xL and Survivin in Combination with Chemotherapy

“…For example, the antiapoptotic proteins BCL2 and XIAP are of minor importance in EJ28 and J82 BCa cells, while Bcl-xL and survivin seem to be most important [6]. However, in other tumor entities, such as gastric cancer and non-small cell lung cancer, siRNA-mediated knockdown of BCL2 and XIAP, respectively, induced apoptosis and reduced tumor growth [24,25]. Likewise, even though the phosphatidylinositol 3-kinase (PI3K) p110 isoforms α and β are both upregulated in paclitaxel-resistant ovarian cancer cells only the siRNA-mediated knockdown of PI3K p110β resensitized these cells towards paclitaxel [26].…”