Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 Bishoy El-Aarag a,b, *, Tomonari Kasai b , Junko Masuda b , Hussein Agwa c , Magdy Zahran c , Masaharu Seno b a Biochemistry Division, Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koom, Egypt b Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan c Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koom, Egypt A R T I C L E I N F O Article history: Received 7 May 2016 Received in revised form 4 October 2016 Accepted 14 November 2016 Keywords: A549 cancer cells VEGF Thalidomide analogs Anticancer MMP-2 A B S T R A C T Lung cancer is one of the major causes of cancer-related mortality worldwide, and non-small-cell lung cancer is the most common form of lung cancer. Several studies had shown that thalidomide has potential for prevention and therapy of cancer. Therefore, the current study aimed to investigate the antitumor effects of two novel thalidomide analogs in human lung cancer A549 cells. The antiproliferative, antimigratory, and apoptotic effects in A549 cells induced by thalidomide analogs were examined. In addition, their effects on the expression of mRNAs encoding vascular endothelial growth factor165 (VEGF165) and matrix metalloproteinase-2 (MMP-2) were evaluated. Their influence on the tumor volume in nude mice was also determined. Results revealed that thalidomide analogs exhibited antiproliferative, antimigratory, and apoptotic activities with more pronounced effect than thalidomide drug. Furthermore, analogs 1 and 2 suppressed the expression levels of VEGF165 by 42% and 53.2% and those of MMP-2 by 45% and 52%, respectively. Thalidomide analogs 1 and 2 also reduced the tumor volume by 30.11% and 53.52%, respectively. Therefore, this study provides evidence that thalidomide analogs may serve as a new therapeutic option for treating lung cancer. ã 2016 Elsevier Masson SAS. All rights reserved. 1. Introduction Lung cancer is generally divided into small-cell lung cancer (SCLC), representing approximately 15% of cases, and non-small- cell lung cancer (NSCLC), representing 85% of cases and including several histological types, such as adenocarcinoma, large-cell carcinoma, and squamous-cell carcinoma [1]. Regardless of the subtype, the 5-year survival rate for lung cancer is among the lowest of all cancers (approximately 15%) [2,3]. SCLC is highly responsive to chemotherapy and radiation therapy, but it is often widely disseminated by the time of diagnosis, rendering the cure difficult. In contrast, NSCLC shows a strong primary resistance to anticancer drugs. The high mortality resulting from lung cancer is due not only to the late stage diagnosis but also to the lack of effective treatments even for patients diagnosed with stage I lung cancer [2]. The development of new molecules to fight cancer is urgently required because most anticancer drugs are ineffective owing to drug resistance. Molecular hybridization, which covalently com- bines two or more drug pharmacophores into a single molecule, is an effective tool to design highly active novel entities [4]. These merged pharmacophores may act on multiple therapeutic targets and offer the possibility of circumventing drug resistance. In addition, the hybrids also minimize unwanted side effects and enable synergic action [5]. The molecular hybridization approach has already been applied to the development of novel antimalarial agents for overcoming drug resistance [6]. Thalidomide is an immunomodulatory and antiangiogenic drug [7–9]. Several studies have shown that thalidomide has antitu- moral properties, and promising results have been reported after thalidomide treatment in patients with myeloma, myelodysplastic syndrome, and a variety of solid tumors [10,11]. Due to the anti-inflammatory and antiangiogenic properties of thalidomide [12,13] as well as the numerous biological activities of * Corresponding author at: Biochemistry Division, Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koom, Egypt. E-mail address: bishoy.yousef@gmail.com (B. El-Aarag). http://dx.doi.org/10.1016/j.biopha.2016.11.063 0753-3322/ã 2016 Elsevier Masson SAS. All rights reserved. Biomedicine & Pharmacotherapy xxx (2016) xxx–xxx G Model BIOPHA 4573 No. of Pages 7 Please cite this article in press as: B. El-Aarag, et al., Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2, Biomed Pharmacother (2016), http://dx.doi.org/10.1016/j.biopha.2016.11.063 Available online at ScienceDirect www.sciencedirect.com