Identification of tumor-suppressor-gene candidates in small cell lung cancer, which combined with a p53 reactivating molecule, can be used for cancer gene therapy

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Abstract:

Small cell lung cancer (SCLC) is a deadly disease with no satisfactory treatments. This necessitates the need to develop more efficient treatment modalities for patients with this cancer type. One intriguing modality is tumor-suppressor-restoration-therapy, involving reintroduction of wild-type tumor-suppressor-gene (TSG) into cancer cells, in which the gene is inactivated. This generally induces apoptosis and/or cell cycle arrest. However, as different types of cancers have different tumor suppressor deficiencies, the strategy must be customized to each cancer type, either by using tumor specific TSG or by combining different TSG.

p53 is mutated in up to 90% of SCLC tumors, and as mutant p53 tend to accumulate in tumor cells, an effective approach would be to reactivate mutant p53 in cancer cells combined with reintroduction of another TSG, frequently inactivated in SCLC. PRIMA-1met (p53-dependent reactivation and induction of massive apoptosis) is a small molecule reported to have the capability of restoring tumor-suppressor function to mutant p53 and hence induce cancer cell death.

We investigated the growth suppression effect of PRIMA-1met on several SCLC cell lines with different p53 mutations using MTT assay. PRIMA-1met inhibited the growth of SCLC cell lines with p53 mutations markedly, but only caused a minor reduction in growth rate in the non-transformed diploid human lung fibroblast cell line CCD32Lu. PRIMA-1met treatment of SCLC cell lines induced caspase-3 activation, PARP cleavage and decrease in total levels of mutant p53, suggesting that PRIMA-1met reactivates mutant p53, resulting in transactivation of target genes, which subsequently leads to apoptosis and p53 downregulation.

Furthermore, two genes (Cyr61 and WISP-2) whose expression were found to be markedly downregulated in SCLC cell lines compared to normal cells and tissues, were tested for their tumor suppressor activity in SCLC cell lines by transient transfection. Neither of the genes had a cytotoxic effect, indicating that the genes are not effective alone in SCLC. Thus, we are currently studying the effect of these genes on cell proliferation in SCLC cells in which p53 has been reactivated by PRIMA-1met. The combination of several TSG in cancer gene therapy might help to open novel avenues for the treatment of SCLC patients.

Document Type: Abstract

DOI: http://dx.doi.org/10.1111/j.1600-0463.2008.001165_49.x

Affiliations: 1: Afdeling for Mikrobiologi, Tumor og Cellebiologi (MTC), Karolinska Instituttet, Nobelsväg 16, SE-17177 Stockholm, Sverige 2: Strålebiologisk Laboratorium afsnit 6321, Finsen centret, Rigshospitalet, Blegdamsvej 9, 2100 København Ø

Publication date: May 1, 2008

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