Antibodies to prion protein inhibit human colon cancer cell growth.
A putative role for prion protein (PrP) in apoptosis has been implicated. This function was investigated to test whether antibodies to PrP could induce apoptosis and be utilised in the treatment of cancers. Various antibodies to PrP were screened in MTT proliferation assays with HCT 116 colon cancer cells. Antibodies were shown to have varying degrees of anti-proliferative activity, with 3F4 and 6D11 essentially inactive, compared to other highly active antibodies. Surprisingly, BAR221 and F89/160.1.5 antibodies were particularly potent and afforded >40% reduction in proliferation at 50 microg/ml. In combination therapy experiments, antibodies to PrP enhanced the effect of irinotecan, 5-FU, cisplatin and doxorubicin to varying degrees. Use of PrP antibody in vitro resulted in increased apoptosis as measured by reduced Bcl-2 expression. In different colon cancer cell lines, antibody effectiveness correlated with tumour aggressiveness. Remarkably, in an in vivo nude mouse bearing human HCT 116 xenografts, tumour growth was inhibited by treatment with PrP antibody. Forty-seven days after treatment, at 9 mg/kg antibody in combination with irinotecan, tumour sizes were approximately 33% smaller compared to animals receiving irinotecan alone. The data suggest a potential pharmacological application for PrP antibodies in combination chemotherapy.
McEwan
J F
JF
Sylvan Pharmaceuticals, Bondi Junction, NSW 2022, Australia. arthro@ozemail.com.au
Windsor
M L
ML
Cullis-Hill
S D
SD
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D011328:Prions / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000970:Antineoplastic Agents; D011328:Prions