Anti-Melanoma Activity of Indomethacin Incorporated into Mesoporous Silica Nanoparticles
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RESEARCH PAPER
Anti-Melanoma Activity of Indomethacin Incorporated into Mesoporous Silica Nanoparticles Natália Helen Ferreira 1 & Arthur Barcelos Ribeiro 1 & Francisco Rinaldi-Neto 1 & Fernanda Santos Fernandes 1 & Samuel do Nascimento 1 & Wilson Rodrigues Braz 1 & Eduardo José Nassar 1 & Denise Crispim Tavares 1
Received: 5 May 2020 / Accepted: 5 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Melanoma is the deadliest type of skin cancer. Treatments that directly address tumor survival are required. Indomethacin (IND) is a well-known drug used worldwide. Although widely used as a therapeutic agent, IND has undesirable gastrointestinal effects. PURPOSE To investigate the antitumor efficacy of IND incorporated into mesoporous silica nanoparticles (MSNPs+IND), as well as its toxic potential in a syngeneic murine B16 melanoma model. METHODS Antitumor activity was evaluated by measuring tumor size and weight and by histopathological analysis. Possible molecular signaling pathways involved in the antitumor activity were analyzed by Western blot in liver tissue and by immunohistochemistry in tumor tissue. The potential toxicity was evaluated by determining body and organ weights and by biochemical and genotoxic analysis. RESULTS MSNPs+IND treatments inhibited tumor growth by up to 70.09% and decreased the frequency of mitosis in tumor tissues, which was up to 37.95% lower compared to the IND groups. In hepatic tissue, COX-2 levels decreased significantly after treatment with MSNPs+IND and IND. Additionally, MSNPs+IND and IND increased the levels of cleaved caspase-3 (156.25% and 137.50%, respectively), inducing tumor cell apoptosis. Genotoxicity was limited to the group treated with the higher concentration of IND, while MSNPs prevented IND-induced genotoxicity.
* Natália Helen Ferreira [email protected]
1
Universidade de Franca, Avenida Dr. Armando Salles Oliveira, 201 – Parque Universitário, Franca, São Paulo 14404-600, Brazil
CONCLUSIONS MSNPs may be promising for future applications in cancer therapy.
KEY WORDS apoptosis . cleaved caspase-3 . COX-2 inhibition . inhibition of tumor growth
ABBREVIATIONS APTES B16F10 BRAF b.w. Ca2+ COX COX-1 COX-2 DAMPs DMEM DMSO DNA EDTA FDA HAM F10 HIF-1 IAP INCA IND MEK MN MNPCE MSNP MSNP+IND
3-Aminopropyltriethoxysilane alkoxide Murine melanoma cells Human oncogene Body weight Calcium Cyclooxygenase Cyclooxygenase, isoform 1 Cyclooxygenase, isoform 2 Damage-associated molecular patterns Dulbecco’s Modified Eagle’s Medium Dimethylsulfoxide Deoxyribonucleic acid Ethylenediamine tetraacetic acid Food and Drug Administration Nutrient Mixture F-10 Ham Hypoxia-inducible fator-1 Inhibitors of apoptosis proteins Brazilian National Cancer Institute (Instituto Nacional do Câncer) Indomethacin Human oncogene Micronucleus Micronucleated polychromatic erythrocytes Mesoporous silica nanoparticles Indomethacin incorporated into mesoporous silica nanoparticles
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NCE NDI NF-κB NK NM NO NP NSAIDs O2 OECD PBS PGE2 pH RNA ROS
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