Lung cancer is the leading cause of
cancer-related death in developed countries.
Non-small cell lung cancer (NSCLC) represents 80% of the total
lung cancer cases and is comprised of
adenocarcinoma,
adenosquamous carcinoma,
squamous cell carcinoma and
large cell carcinoma (LCC) subtypes. The ability of LCC to metastasize earlier than the other forms of
lung cancer suggests
anti-angiogenic drugs as effective agents to combat this
cancer.
Thalidomide is an
anti-angiogenic drug that has shown promise in multiple
hematological diseases, and myeloma and other
cancers. However, the molecular mechanism by which
thalidomide exerts its effects is poorly understood. Therefore, we evaluated the effectiveness of
thalidomide on NSCLC cell growth, and found that LCC cells were growth inhibited by 40-60%. This effect seemed specific to LCC
cancer cells, since other forms of NSCLC were only mildly affected by
thalidomide. At the molecular level,
thalidomide increased
peroxisome proliferator-activated receptor gamma (
PPARgamma)
protein dose-dependently, and peroxisome proliferator response element activity. Further,
thalidomide treatment of LCC cells decreased
nuclear factor kappa B activity in a dose-dependent fashion, increased apoptosis and decreased the expression of
angiogenic proteins. In our mouse xenograft model of
lung cancer, we found that intratumoral
thalidomide caused a 64% decrease in
tumor growth; moreover,
tumors from the
thalidomide-treated mice expressed higher
PPARgamma, than
tumors from control mice. This study shows the antitumor activity of
thalidomide against LCC
tumors and suggests a model in which
thalidomide exerts its antitumor effects on LCC cells through the induction of
PPARgamma and subsequent downstream signaling. To our knowledge, this is the first study to show a link between
thalidomide and
PPARgamma.