Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy

Abstract

Background Silver nanoparticles (AgNPs) exhibit strong antibacterial and anticancer activity owing to their large surface-to-volume ratios and crystallographic surface structure. Owing to their various applications, understanding the mechanisms of action, biological interactions, potential toxicity, and beneficial effects of AgNPs is important. Here, we investigated the toxicity and differentiation-inducing effects of AgNPs in teratocarcinoma stem cells. Materials and methods AgNPs were synthesized and characterized using various analytical techniques such as UV–visible spectroscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, and transmission electron microscopy. The cellular responses of AgNPs were analyzed by a series of cellular and biochemical assays. Gene and protein expressions were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Results The AgNPs showed typical crystalline structures and spherical shapes (average size =20 nm). High concentration of AgNPs induced cytotoxicity in a dose-dependent manner by increasing lactate dehydrogenase leakage and reactive oxygen species. Furthermore, AgNPs caused mitochondrial dysfunction, DNA fragmentation, increased expression of apoptotic genes, and decreased expression of antiapoptotic genes. Lower concentrations of AgNPs induced neuronal differentiation by increasing the expression of differentiation markers and decreasing the expression of stem cell markers. Cisplatin reduced the viability of F9 cells that underwent AgNPs-induced differentiation. Conclusion The results showed that AgNPs caused differentially regulated cytotoxicity and induced neuronal differentiation of F9 cells in a concentration-dependent manner. Therefore, AgNPs can be used for differentiation therapy, along with chemotherapeutic agents, for improving cancer treatment by targeting specific chemotherapy-resistant cells within a tumor. Furthermore, understanding the molecular mechanisms of apoptosis and differentiation in stem cells could also help in developing new strategies for cancer stem cell (CSC) therapies. The findings of this study could significantly contribute to the nanomedicine because this study is the first of its kind, and our results will lead to new strategies for cancer and CSC therapies.

Utilização de Nanopartículas no Tratamento do Câncer: Aspectos Gerais, Mecanismos de Ação Antineoplásicos e Aplicabilidades Tumorais

“…A morte celular causada pela geração de ERO é específica das NP de metais. O excesso de produção de ERO pode ser maléfico para a célula, sendo responsável também por danos à dupla-fita de DNA 19 .…”

“…A principal fonte produtora de ERO dentro da célula é a mitocôndria, em razão dos seus processos químicos de geração de energia. Quando as ERO se excedem ou escapam da mitocôndria, essas moléculas invadem o citosol conseguindo destruir estruturas moleculares maiores, como o DNA, ou causam estresse oxidativo por lesão da membrana plasmática 16 , tornando as ERO um importante mecanismo contra células neoplásicas 19 . Após a lesão genética, os genes pró--apoptóticos são ativados, induzindo a célula à morte pelas vias apoptóticas ou pela autofagia 16 .…”

“…Os íons de prata são capazes de induzir citotoxicidade celular por intermédio do aumento da instabilidade de sódio e potássio nos canais iônicos da membrana celular, que desestabiliza a mitocôndria e libera ERO, levando a célula à morte 19 . Apesar da sua eficiência em geração de ERO e morte tumoral, no estudo feito por Bhanumathi et al 26 , foram observados leves efeitos citotóxicos em tecidos saudáveis de camundongos que teriam sido expostos à NP de prata no coração, rim, cérebro e pulmão.…”

“…Estudos mostram que células tumorais de células epiteliais alveolares humanas (A549), células neuroendócrinas e células de ovário já foram encontradas em experimentos com prata 19 , além de já ter sido comprovada sua efetividade contra células de leucemia mieloide e câncer de mama 27 . Na Tabela 1, são apresentados alguns experimentos envolvendo NP de prata e seus respectivos índices de diminuição tumoral.…”

Non-cytotoxic, temperature-responsive and antibacterial POEGMA based nanocomposite coatings with silver nanoparticles

“…31,32 Numerous research show, that in cancer chemotherapeutic regimes, AgNPs can promote apoptosis and tumor cell differentiation. 49,50 To minimalize the risks of negative effects towards human health, the materials with prolonged release of silver ions from permanently bonded AgNPs are highly demanded. XPS results (Fig.…”