Inducing apoptosis of human colon cancer cells by an IGF-I D domain analogue peptide.
BACKGROUND
The resistance of tumour cells to apoptosis is a major contributor to the limited effectiveness of chemotherapies. Insulin-like growth factor I (IGF-I) has potential to protect cancer cells from variety of apoptotic challenges. This study was carried out to investigate the effect of a novel IGF-I receptor antagonist on apoptosis in colon cancer cells.


RESULTS
We have designed and synthesised a novel antagonist of IGF-I receptor. The effect of this antagonist on human colon cancer cell proliferation was examined by a non-radioactive assay; the apoptosis was revealed by determining the activities of cellular caspases3/7, 8 and 9. The apoptosis pathways were investigated by examining the levels of pro-apoptosis proteins with Western blotting. Following 40 hours treatment with the novel antagonist peptide, colon cancer cell Caspase 3/7 activities increased 2-7 times; Caspase 8 activities increased 2-5 times and Caspase 9 increased 1.2-1.6 times. The proliferation of cancer cell was inhibited by 14-15%. The data showed that the antagonist induced colon cancer cell apoptosis and inhibited cancer cell proliferation. The different changes of Caspase 3/7, 8 and 9 activities suggested that the extrinsic pathways may play a major role in the antagonist peptide-induced apoptosis.


CONCLUSIONS
This is the first report on this novel antagonist to induce human colon cancer cell apoptosis and inhibit cancer cell proliferation. These results suggest that IGF-I receptor antagonists may have the potential to be developed as a novel therapy for colon cancers in the future.
Yang
Shi Yu
SY
University Department of Surgery, Royal Free & University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. shiyu.yang@medsch.ucl.ac.uk
Sales
Kevin M
KM
Fuller
Barry J
BJ
Seifalian
Alexander M
AM
Winslet
Marc C
MC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; C529086:M1557 peptide; D010455:Peptides; D051028:bcl-2-Associated X Protein; C096150:insulin-like growth factor-1 D peptide; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020169:Caspases