Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53

Abstract

Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a cytoprotective agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21 WAF1 , Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.

Overexpression of SUMO-1 in hepatocellular carcinoma: a latent target for diagnosis and therapy of hepatoma

“…There are a variety of tumor suppressors or oncogenes according to their different potencies to suppress or promote cancer cell proliferation. The tumor suppressor, wild-type p53, could inhibit the growth of cancer cell after being transfected into tumor cell (Pataer et al 2006;Xu et al 1996). While Bcl-2 and c-Myc, which are two dominant oncogenes, could promote the cancer development and growing, the inhibition of expression and function of Bcl-2 and c-Myc would inhibit tumor growth and induce apoptosis of malignant cells (Brunelle et al 2004;Duan et al 2005;Sutter et al 2004).…”

Thyroid transcription factor 1 represses the expression of Ki-67 and induces apoptosis in non-small cell lung cancer

“…Several studies have shown that transfection with wild-type p53 alone or a combination of wild-type p53 with exposure to amifostine, a cytoprotective agent can directly promote cells into apoptosis and/or growth arrest when p53 was overexpressed (19,20). To our knowledge, direct induction of apoptosis by TTF-1 overexpression has not been reported previously.…”

Smad-Signaling in Mammary Gland Development and Tumorigenesis

“…Of these two drugs, amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion [136]. However, their practical use in Smad-targeted therapy remains to be determined.…”