Stable XIAP knockdown clones of HCT116 colon cancer cells are more sensitive to TRAIL, taxanes and irradiation in vitro

• Published in: Cancer chemotherapy and pharmacology Vol. 64; no. 2; pp. 307 - 316
• Main Authors: Connolly, Kate, Mitter, Richard, Muir, Morwenna, Jodrell, Duncan, Guichard, Sylvie
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.07.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cancer Research; Caspases - metabolism; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - radiotherapy; Flow Cytometry; Gamma Rays; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Immunoblotting; In Vitro Techniques; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Nude; Oligonucleotide Array Sequence Analysis; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Taxoids - pharmacology; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Tumor Cells, Cultured; Tumors; X-Linked Inhibitor of Apoptosis Protein - genetics; Xenograft Model Antitumor Assays; TRAIL; Paclitaxel; Docetaxel; XIAP; HCT116; Radiotherapy; Microarray; Antineoplastic agent; Clonality; Colon cancer; Taxane derivatives; Intestinal disease; Antimitotic; Tumor cell; Clone; Cytokine; Malignant tumor; In vitro; X linked inhibitor of apoptosis protein; Colonic disease; Treatment; Apoptosis inhibitory protein; Tumor necrosis factor; Irradiation; Digestive diseases; TNF related apoptosis inducing ligand; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-008-0872-x

Purpose To develop a model of X-linked inhibitor of apoptosis (XIAP) down regulation in colorectal cancer cell lines. This may be used to determine whether combination strategies have clinical potential. Methods A series of clones were developed using short hairpin RNA (shRNA) against XIAP stably expressed in HCT116 cells. XIAP mRNA and protein levels were established by RT-PCR and Immunoblot, respectively. GeneChip microarrays confirmed XIAP knockdown and absence of compensation by other IAP members. Results Four XIAP knockdown cell lines show 82-93% reduction in XIAP mRNA and 67-89% reduction in protein when compared to four luciferase control cell lines. XIAP knockdown sensitises cells to rhTRAIL by a factor of 3, to paclitaxel and docetaxel by a factor of >2 and, to a lesser extent, radiotherapy (20% enhancement). Conclusions Clinical trials with XIAP antisense continue, and these data suggest combination studies with agents such as rhTRAIL and taxanes should be undertaken.