Generation of a selectively cytotoxic fusion protein against p53 mutated cancers

BMC Cancer

Research Article

Mahendra P Deonarain¹  Efthymia Yiacoumi²  Agamemnon A Epenetos³  Christina A Kousparou³ 

[1] Imperial College London, Exhibition Road, SW7 2AZ, London, UK;Trojantec Ltd, The Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, 2006, Nicosia, Cyprus;Trojantec Ltd, The Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, 2006, Nicosia, Cyprus;Imperial College London, Exhibition Road, SW7 2AZ, London, UK;

关键词: Cancer therapy;    Antennapedia;    p21;    Trojan;    Recombinant fusion protein;    Cell-penetrating;   

DOI  :  10.1186/1471-2407-12-338

 received in 2011-10-31, accepted in 2012-07-18,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundA significant number of cancers are caused by defects in p21 causing functional defects in p21 or p53 tumour-suppressor proteins. This has led to many therapeutic approaches including restoration by gene therapy with wild-type p53 or p21 using viral or liposomal vectors, which have toxicity or side-effect limitations. We set out to develop a safer, novel fusion protein which has the ability to reconstitute cancer cell lines with active p21 by protein transduction.MethodsThe fusion protein was produced from the cell-translocating peptide Antennapedia (Antp) and wild-type, full-length p21 (Antp-p21). This was expressed and refolded from E. coli and tested on a variety of cell lines and tumours (in a BALB/c nude xenograft model) with differing p21 or p53 status.ResultsAntp-p21 penetrated and killed cancer cells that do not express wild type p53 or p21. This included cells that were matched to cogenic parental cell lines. Antp-p21 killed cancer cells selectively that were malignant as a result of mutations or nuclear exclusion of the p53 and p21 genes and over-expression of MDM2. Non-specific toxicity was excluded by showing that Antp-p21 penetrated but did not kill p53- or p21- wild-type cells. Antp-p21 was not immunogenic in normal New Zealand White rabbits. Recombinant Antp peptide alone was not cytotoxic, showing that killing was due to the transduction of the p21 component of Antp-p21. Antp-p21 was shown to penetrate cancer cells engrafted in vivo and resulted in tumour eradication when administered with conventionally-used chemotherapeutic agents, which alone were unable to produce such an effect.ConclusionsAntp-p21 may represent a new and promising targeted therapy for patients with p53-associated cancers supporting the concept that rational design of therapies directed against specific cancer mutations will play a part in the future of medical oncology.

【 授权许可】

CC BY   
© Kousparou et al.; licensee BioMed Central Ltd. 2012