Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells
Despite the use of sorafenib as one of the most effective drugs for the treatment of liver cancer, its significant limitations remain—poor solubility, the need to use high doses with the ensuing complications on healthy tissues and organs, and the formation of cell resistance to the drug. At the sam...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/12/6641 |
| _version_ | 1797486471545880576 |
|---|---|
| author | Elena G. Varlamova Mikhail V. Goltyaev Aleksander V. Simakin Sergey V. Gudkov Egor A. Turovsky |
| author_facet | Elena G. Varlamova Mikhail V. Goltyaev Aleksander V. Simakin Sergey V. Gudkov Egor A. Turovsky |
| author_sort | Elena G. Varlamova |
| collection | DOAJ |
| description | Despite the use of sorafenib as one of the most effective drugs for the treatment of liver cancer, its significant limitations remain—poor solubility, the need to use high doses with the ensuing complications on healthy tissues and organs, and the formation of cell resistance to the drug. At the same time, there is more and more convincing evidence of the anticancer effect of selenium-containing compounds and nanoparticles. The aim of this work was to develop a selenium–sorafenib nanocomplex and study the molecular mechanisms of its anticancer effect on human hepatocyte carcinoma cells, where nanoselenium is not only a sorafenib transporter, but also an active compound. We have created a selenium–sorafenib nanocomplex based on selenium nanoparticles with size 100 nm. Using vitality tests, fluorescence microscopy, and PCR analysis, it was possible to show that selenium nanoparticles, both by themselves and doped with sorafenib, have a pronounced pro-apoptotic effect on HepG2 cells with an efficiency many times greater than that of sorafenib (So). “Naked” selenium nanoparticles (SeNPs) and the selenium–sorafenib nanocomplex (SeSo), already after 24 h of exposure, lead to the induction of the early stages of apoptosis with the transition to the later stages with an increase in the incubation time up to 48 h. At the same time, sorafenib, at the studied concentrations, began to exert a proapoptotic effect only after 48 h. Under the action of SeNPs and SeSo, both classical pathways of apoptosis induction and ER-stress-dependent pathways involving Ca<sup>2+</sup> ions are activated. Thus, sorafenib did not cause the generation of Ca<sup>2+</sup> signals by HepG2 cells, while SeNPs and SeSo led to the activation of the Ca<sup>2+</sup> signaling system of cells. At the same time, the selenium–sorafenib nanocomplex turned out to be more effective in activating the Ca<sup>2+</sup> signaling system of cells, inducing apoptosis and ER stress by an average of 20–25% compared to “naked” selenium nanoparticles. Our data on the mechanisms of action and the created nanocomplex are promising as a platform for the creation of highly selective and effective drugs with targeted delivery to tumors. |
| first_indexed | 2024-03-09T23:33:44Z |
| format | Article |
| id | doaj.art-0f4b9c7001e9426ea0ca580f308350dc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:33:44Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0f4b9c7001e9426ea0ca580f308350dc2023-11-23T17:04:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312664110.3390/ijms23126641Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 CellsElena G. Varlamova0Mikhail V. Goltyaev1Aleksander V. Simakin2Sergey V. Gudkov3Egor A. Turovsky4Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, RussiaInstitute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, RussiaProkhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilove St., 119991 Moscow, RussiaProkhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilove St., 119991 Moscow, RussiaInstitute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, RussiaDespite the use of sorafenib as one of the most effective drugs for the treatment of liver cancer, its significant limitations remain—poor solubility, the need to use high doses with the ensuing complications on healthy tissues and organs, and the formation of cell resistance to the drug. At the same time, there is more and more convincing evidence of the anticancer effect of selenium-containing compounds and nanoparticles. The aim of this work was to develop a selenium–sorafenib nanocomplex and study the molecular mechanisms of its anticancer effect on human hepatocyte carcinoma cells, where nanoselenium is not only a sorafenib transporter, but also an active compound. We have created a selenium–sorafenib nanocomplex based on selenium nanoparticles with size 100 nm. Using vitality tests, fluorescence microscopy, and PCR analysis, it was possible to show that selenium nanoparticles, both by themselves and doped with sorafenib, have a pronounced pro-apoptotic effect on HepG2 cells with an efficiency many times greater than that of sorafenib (So). “Naked” selenium nanoparticles (SeNPs) and the selenium–sorafenib nanocomplex (SeSo), already after 24 h of exposure, lead to the induction of the early stages of apoptosis with the transition to the later stages with an increase in the incubation time up to 48 h. At the same time, sorafenib, at the studied concentrations, began to exert a proapoptotic effect only after 48 h. Under the action of SeNPs and SeSo, both classical pathways of apoptosis induction and ER-stress-dependent pathways involving Ca<sup>2+</sup> ions are activated. Thus, sorafenib did not cause the generation of Ca<sup>2+</sup> signals by HepG2 cells, while SeNPs and SeSo led to the activation of the Ca<sup>2+</sup> signaling system of cells. At the same time, the selenium–sorafenib nanocomplex turned out to be more effective in activating the Ca<sup>2+</sup> signaling system of cells, inducing apoptosis and ER stress by an average of 20–25% compared to “naked” selenium nanoparticles. Our data on the mechanisms of action and the created nanocomplex are promising as a platform for the creation of highly selective and effective drugs with targeted delivery to tumors.https://www.mdpi.com/1422-0067/23/12/6641cancerapoptosisnecrosisselenium nanoparticlessorafenibselenium–sorafenib nanocomplex |
| spellingShingle | Elena G. Varlamova Mikhail V. Goltyaev Aleksander V. Simakin Sergey V. Gudkov Egor A. Turovsky Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells International Journal of Molecular Sciences cancer apoptosis necrosis selenium nanoparticles sorafenib selenium–sorafenib nanocomplex |
| title | Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells |
| title_full | Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells |
| title_fullStr | Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells |
| title_full_unstemmed | Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells |
| title_short | Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells |
| title_sort | comparative analysis of the cytotoxic effect of a complex of selenium nanoparticles doped with sorafenib naked selenium nanoparticles and sorafenib on human hepatocyte carcinoma hepg2 cells |
| topic | cancer apoptosis necrosis selenium nanoparticles sorafenib selenium–sorafenib nanocomplex |
| url | https://www.mdpi.com/1422-0067/23/12/6641 |
| work_keys_str_mv | AT elenagvarlamova comparativeanalysisofthecytotoxiceffectofacomplexofseleniumnanoparticlesdopedwithsorafenibnakedseleniumnanoparticlesandsorafenibonhumanhepatocytecarcinomahepg2cells AT mikhailvgoltyaev comparativeanalysisofthecytotoxiceffectofacomplexofseleniumnanoparticlesdopedwithsorafenibnakedseleniumnanoparticlesandsorafenibonhumanhepatocytecarcinomahepg2cells AT aleksandervsimakin comparativeanalysisofthecytotoxiceffectofacomplexofseleniumnanoparticlesdopedwithsorafenibnakedseleniumnanoparticlesandsorafenibonhumanhepatocytecarcinomahepg2cells AT sergeyvgudkov comparativeanalysisofthecytotoxiceffectofacomplexofseleniumnanoparticlesdopedwithsorafenibnakedseleniumnanoparticlesandsorafenibonhumanhepatocytecarcinomahepg2cells AT egoraturovsky comparativeanalysisofthecytotoxiceffectofacomplexofseleniumnanoparticlesdopedwithsorafenibnakedseleniumnanoparticlesandsorafenibonhumanhepatocytecarcinomahepg2cells |