Abstract
Lung cancer is a leading cause of cancer death worldwide, and non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer, which is highly metastatic, leading to the poor survival rate of patients. We recently reported that 4-[4-(4-hydroxyphenoxy)phenoxy]phenol (4-HPPP), a phenoxyphenol, exerts antihepatoma effects by inducing apoptosis and autophagy. In this study, we further examined the effect of 4-HPPP and its analogs on NSCLC cells. Colony formation assays showed that 4-HPPP exerts selective cytotoxicity against NSCLC H1299 cells; furthermore, the inhibitory effect of 4-HPPP on the proliferation and migration of NSCLC cells was validated using an in vivo zebrafish-based tumor xenograft assay. The flow cytometry-based dichlorofluorescein diacetate (DCF-DA) assays indicated that 4-HPPP caused an increase in reactive oxygen species (ROS) in NSCLC cells, and Western blot assays showed that the major ROS scavenging enzymes superoxide dismutases- (SODs-) 1/2 were upregulated, whereas peroxidase (PRX) was downregulated. Furthermore, 4-HPPP caused both aneuploidization and the accumulation of γH2AX, a sensor of DNA damage, as well as the activation of double-strand break (DSB) markers, especially Ataxia-telangiectasia-mutated and Rad3-related (ATR) in NSCLC cells. Our present work suggests that the antiproliferative effects of 4-HPPP on lung cancer cells could be due to its phenoxyphenol structure, and 4-HPPP could be a candidate molecule for treating NSCLC by modulating ROS levels and lowering the threshold of polyploidy-specific cell death in the future.
Highlights
Lung cancer has a high incidence and is the leading cause of cancer-associated deaths in both males and females [1,2,3]
The human Non-small-cell lung carcinoma (NSCLC) cell line H1299 was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA), and the human bronchial epithelium cell line BEAS-2B was kindly provided by Dr Poling-Kuo (Kaohsiung Medical University, Taiwan)
We examined whether 4-HPPP reduced the clonogenicity of NSCLC cells, and a colony formation assay was conducted (Figure 1(b))
Summary
Lung cancer has a high incidence and is the leading cause of cancer-associated deaths in both males and females [1,2,3]. Non-small-cell lung carcinoma (NSCLC) is the most common type of lung cancer, accounting for 80% to 85% of lung cancer, and it shows a low proliferation rate and metastatic ability. Large-cell lung carcinoma accounts for 10% to 15% of NSCLC and is poorly differentiated [4, 5]. These tumors are large peripheral masses associated with early metastases. Chemotherapy is the most common treatment for NSCLC [2,3,4, 6], NSCLC usually develops acquired resistance to chemotherapy and is associated with poor prognosis and low survival rates; continued efforts are still needed to overcome these difficulties [7, 8]
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