Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo

International Journal of Nanomedicine, May 2016

Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo Yan He,1,* Zhiyun Du,1,* Shijing Ma,1 Yue Liu,2 Dongli Li,1 Huarong Huang,1 Sen Jiang,1 Shupeng Cheng,1 Wenjing Wu,1 Kun Zhang,1 Xi Zheng1,2 1Allan H Conney Laboratory for Anticancer Drug Research, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, People’s Republic of China; 2Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA *These authors contributed equally to this work Abstract: Silver nanoparticles (AgNPs) have now been recognized as promising therapeutic molecules and are extending their use in cancer diagnosis and therapy. This study demonstrates for the first time the antitumor activity of green-synthesized AgNPs against lung cancer in vitro and in vivo. Cytotoxicity effect was explored on human lung cancer H1299 cells in vitro by MTT and trypan blue assays. Apoptosis was measured by morphological assessment, and nuclear factor-κB (NF-κB) transcriptional activity was determined by a luciferase reporter gene assay. The expressions of phosphorylated stat3, bcl-2, survivin, and caspase-3 were examined by Western blot analysis. AgNPs showed dose-dependent cytotoxicity and stimulation of apoptosis in H1299 cells. The effects on H1299 cells correlated well with the inhibition of NF-κB activity, a decrease in bcl-2, and an increase in caspase-3 and survivin expression. AgNPs significantly suppressed the H1299 tumor growth in a xenograft severe combined immunodeficient (SCID) mouse model. The results demonstrate the anticancer activities of AgNPs, suggesting that they may act as potential beneficial molecules in lung cancer chemoprevention and chemotherapy, especially for early-stage intervention. Keywords: silver nanoparticles, antitumor, lung cancer, cytotoxicity, H1299

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Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo

International Journal of Nanomedicine effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo Yan he 0 2 Zhiyun Du 0 2 Wenjing Wu 0 2 Kun Zhang 0 2 Xi Zheng 0 1 2 0 Kun Zhang allan h conney laboratory for anticancer research, school of chemical engineering and light Industry, guangdong University of Technology , 100 Wai huan West road, guangzhou higher education Mega center, guangzhou 510006, People's republic of china Tel 1 s usan l ehman c ullman l aboratory for c ancer r esearch, Department of c hemical Biology, ernest Mario s chool of Pharmacy, rutgers, The state University of New Jersey , Piscataway, NJ, Usa , USA 2 a llan h c onney l aboratory for a nticancer Drug r esearch, s chool of chemical engineering and light Industry, g uandong University of Technology , g uangzhou, People's republic of china Silver nanoparticles (AgNPs) have now been recognized as promising therapeutic molecules and are extending their use in cancer diagnosis and therapy. This study demonstrates for the first time the antitumor activity of green-synthesized AgNPs against lung cancer in vitro and in vivo. Cytotoxicity effect was explored on human lung cancer H1299 cells in vitro by MTT and trypan blue assays. Apoptosis was measured by morphological assessment, and nuclear factor-κB (NF-κB) transcriptional activity was determined by a luciferase reporter gene assay. The expressions of phosphorylated stat3, bcl-2, survivin, and caspase-3 were examined by Western blot analysis. AgNPs showed dose-dependent cytotoxicity and stimulation of apoptosis in H1299 cells. The effects on H1299 cells correlated well with the inhibition of NF-κB activity, a decrease in bcl-2, and an increase in caspase-3 and survivin expression. AgNPs significantly suppressed the H1299 tumor growth in a xenograft severe combined immunodeficient (SCID) mouse model. The results demonstrate the anticancer activities of AgNPs, suggesting that they may act as potential beneficial molecules in lung cancer chemoprevention and chemotherapy, especially for early-stage intervention. silver nanoparticles; antitumor; lung cancer; cytotoxicity; H1299 - a o l n w o d e n i c i d e m o n a N f o l a n r u o J l a n o it a n r e t n I open access to scientific and medical research Introduction Pharmaceutical application of nanomaterial is the most promising way for the generation of new fields in biomedical sciences. Among the silver nanoparticles (AgNPs), nanorization of silver is essentially one of the significant features for good conductivity, chemical stability, relative lower toxicity, and outstanding therapeutic potential, such as anti-inflammatory, antimicrobial, antifungal, anti-angiogenesis, antiplatelet, and anticancer activities.1–4 A number of AgNPs have been developed by chemical, physical, and, recently improved, biological methods, among which green synthesis using plants or microorganisms is easier, more efficient, and ecofriendly.5,6 Many plant extracts have been regarded as potent natural reducing agents because of the presence of rich functional molecules, such as phenolic compounds with high antioxidant activity.7,8 Unlike other metal nanoparticles, AgNPs are nontoxic to human body at a lower dosage.9 Green synthesis of nanoparticles, with low range of toxicity, has become an attractive research area for increasing biomedical applications, such as in preparation of implantable biomaterial, molecular imaging, wound healing, and drug delivery.10–13 Especially, the applications of AgNPs have risen up in cancer diagnosis and treatment,14 not only as attractive targeted drug delivery vehicles or probes for early cancer screening15,16 but also as a promising therapeutic molecule by itself. AgNPs showed potential cytotoxicity against various cancer cells such as lung cancer A549 cells,17 breast cancer MCF-7 cells,18 colon cancer HT29 cells,19 cervical cancer HeLa cells,20 and Dalton’s lymphoma ascites tumor.21 Hsin et al provided evidence for the mitochondrial pathway of apoptosis of AgNPs in NIH3T3 cells, which is mediated by a ROS- and JNK-dependent mechanism.22 The previous study also showed that AgNPs possess anti-angiogenic effects due to the activation of PI3K/Akt signaling pathways.23 AgNPs can selectively inhibit HeLa cells by caspase-3-mediated cell death and DNA damage.20 Yet, neither the underlying biochemical mechanisms nor the molecular triggers have been revealed.24 In general, the toxicity of AgNPs appears to be driven by the release of silver ions. AgNPs have a slower dissolution rate, leading to a continuous release of silver ions. It was reported that although AgNPs exhibited significant cytotoxicity against NSCLC A549 cells, they showed no cytotoxicity toward normal healthy peripheral lymphocytes (PLs).17 Greulich et al reported silver ions were more cytotoxic toward bacteria and human cells 8 1 0 2 l u J 3 1 n o 1 2 2 . 8 9 . 2 3 . 3 1 2 y b / m o c . s s e r p e v .do (...truncated)


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Yan He, Zhiyun Du, Shijing Ma, Yue Liu, Dongli Li, Huarong Huang, Sen Jiang, Shupeng Cheng, Wenjing Wu, Kun Zhang, Xi Zheng. Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo, International Journal of Nanomedicine, 2016, pp. 1879-1887, DOI: 10.2147/IJN.S103695