Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model.

AIM

The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions.

METHODS

The recombinant virus Ad·sp-E1A(Δ24)-TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A(Δ24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A(Δ24)-TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses.

RESULTS

Infection of A549 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A(Δ24)-TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A(Δ24)-TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A(Δ24)-TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues.

CONCLUSION

The oncolytic adenovirus Ad·sp-E1A(Δ24)-TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.