Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma
Hepatocellular carcinoma is the seventh most common type of cancer in the world, with limited treatment options. A promising strategy to treat cancer is to associate chemotherapeutics and plant bioactive compounds. Here, we examined whether diallyl disulfide (DADS; 50–200 μM) and sorafenib (SORA; 8...
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MDPI AG
2022-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2582 |
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| author | Ana Rita Thomazela Machado Katiuska Tuttis Patrick Wellington da Silva Santos Alexandre Ferro Aissa Lusânia Maria Greggi Antunes |
| author_facet | Ana Rita Thomazela Machado Katiuska Tuttis Patrick Wellington da Silva Santos Alexandre Ferro Aissa Lusânia Maria Greggi Antunes |
| author_sort | Ana Rita Thomazela Machado |
| collection | DOAJ |
| description | Hepatocellular carcinoma is the seventh most common type of cancer in the world, with limited treatment options. A promising strategy to treat cancer is to associate chemotherapeutics and plant bioactive compounds. Here, we examined whether diallyl disulfide (DADS; 50–200 μM) and sorafenib (SORA; 8 μM), either alone or in combination, were toxic to hepatocellular carcinoma cells (HepG2) in vitro. We assessed whether DADS and/or SORA induced cell death (LIVE/DEAD assay and autophagy) and cell cycle changes (flow cytometry), altered expression of key genes and proteins (RT-qPCR and Western blot), and modulated tumorigenesis signatures, such as proliferation (clonogenic assay), migration (wound healing), and invasion (inserts). The DADS + SORA combination elicited autophagic cell death by upregulating LC3 and NRF2 expression and downregulating <i>FOS</i> and <i>TNF</i> expression; induced the accumulation of cells in the G1 phase which thereby upregulated the <i>CHEK2</i> expression; and inhibited invasion by downregulating the <i>MMP2</i> expression. Predictive analysis indicated the participation of the MAPK pathway in the reported results. The DADS + SORA combination suppressed both cell invasion and clonogenic survival, which indicated that it dampened tumor growth, proliferation, invasion, and metastatic potential. Therefore, the DADS + SORA combination is a promising therapy to develop new clinical protocols. |
| first_indexed | 2024-03-09T15:58:41Z |
| format | Article |
| id | doaj.art-bf113671e3364b42ab81f8fd7e2327a4 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:41Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-bf113671e3364b42ab81f8fd7e2327a42023-11-24T17:18:26ZengMDPI AGPharmaceutics1999-49232022-11-011412258210.3390/pharmaceutics14122582Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular CarcinomaAna Rita Thomazela Machado0Katiuska Tuttis1Patrick Wellington da Silva Santos2Alexandre Ferro Aissa3Lusânia Maria Greggi Antunes4Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-904, SP, BrazilDepartment of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-904, SP, BrazilDepartment of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-904, SP, BrazilInstitute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, BrazilDepartment of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-904, SP, BrazilHepatocellular carcinoma is the seventh most common type of cancer in the world, with limited treatment options. A promising strategy to treat cancer is to associate chemotherapeutics and plant bioactive compounds. Here, we examined whether diallyl disulfide (DADS; 50–200 μM) and sorafenib (SORA; 8 μM), either alone or in combination, were toxic to hepatocellular carcinoma cells (HepG2) in vitro. We assessed whether DADS and/or SORA induced cell death (LIVE/DEAD assay and autophagy) and cell cycle changes (flow cytometry), altered expression of key genes and proteins (RT-qPCR and Western blot), and modulated tumorigenesis signatures, such as proliferation (clonogenic assay), migration (wound healing), and invasion (inserts). The DADS + SORA combination elicited autophagic cell death by upregulating LC3 and NRF2 expression and downregulating <i>FOS</i> and <i>TNF</i> expression; induced the accumulation of cells in the G1 phase which thereby upregulated the <i>CHEK2</i> expression; and inhibited invasion by downregulating the <i>MMP2</i> expression. Predictive analysis indicated the participation of the MAPK pathway in the reported results. The DADS + SORA combination suppressed both cell invasion and clonogenic survival, which indicated that it dampened tumor growth, proliferation, invasion, and metastatic potential. Therefore, the DADS + SORA combination is a promising therapy to develop new clinical protocols.https://www.mdpi.com/1999-4923/14/12/2582liver cancernutraceutical<i>Allium sativum</i> L.DNA damagenutrigenomics |
| spellingShingle | Ana Rita Thomazela Machado Katiuska Tuttis Patrick Wellington da Silva Santos Alexandre Ferro Aissa Lusânia Maria Greggi Antunes Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma Pharmaceutics liver cancer nutraceutical <i>Allium sativum</i> L. DNA damage nutrigenomics |
| title | Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma |
| title_full | Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma |
| title_fullStr | Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma |
| title_full_unstemmed | Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma |
| title_short | Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma |
| title_sort | diallyl disulfide induces chemosensitization to sorafenib autophagy and cell cycle arrest and inhibits invasion in hepatocellular carcinoma |
| topic | liver cancer nutraceutical <i>Allium sativum</i> L. DNA damage nutrigenomics |
| url | https://www.mdpi.com/1999-4923/14/12/2582 |
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