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2-(4-Nitrophenyl)isothiazol-3(2H)-one: A Promising Selective Agent against Hepatocellular Carcinoma Cells
Sofia Marka1, Maria-Eleftheria Zografaki2, Georgia Tsolomiti1
1Laboratory of Cell Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece.
Abstract:
Liver cancer ranks among the most prevalent malignancies globally and stands as a leading cause of cancer-related mortality. Numerous isothiazolone derivatives and analogues have been synthesized and investigated for their potential as anticancer agents; however, limited data exist regarding their efficacy against liver cancer. In the present study, two nitrophenyl-isothiazolones, the 5-benzoyl-2-(4-nitrophenyl)isothiazol-3(2H)-one (IsoA) and the 2-(4-nitrophenyl)isothiazol-3(2H)-one (IsoB), were preliminarily investigated for their cytotoxicity against hepatoma human (Huh7) cells as a liver cancer model and Immortalized Human Hepatocytes (IHHs) as a model of non-cancerous hepatocytes. IsoB, derived from IsoA after removal of the benzoyl moiety, demonstrated the highest cytotoxic effect against Huh7 cells with CC50 values of 19.3 μΜ at 24 h, 16.4 μΜ at 48 h, and 16.2 μΜ at 72 h of incubation, respectively. IsoB also exhibited selective toxicity against the liver cancerous Huh7 cells compared to IHH cells, reinforcing its role as a potent and selective anticancer agent. Remarkably, the cytotoxicity of IsoB was higher when compared with the standard chemotherapeutical agent 5-fluorouracil (5-FU), which also failed to exhibit higher toxicity against the liver cancerous cell lines. Moreover, IsoB-treated Huh7 cells presented a noteworthy reduction in mitochondrial membrane potential (ΔΨm) after 48 and 72 h, while mitochondrial superoxide levels showed an increase after 24 h of incubation. The molecular mechanism of the IsoB cytotoxic effect was also investigated using RT-qPCR, revealing an apoptosis-mediated cell death along with tumor suppressor TP53 overexpression and key-oncogene MYCN downregulation.
Insights
A novel compound, IsoB, shows significant potential as a liver cancer treatment. This isothiazolone derivative effectively kills liver cancer cells (Huh7) while sparing normal cells, outperforming 5-fluorouracil.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Liver cancer is a major global health concern with limited effective treatments.
- Isothiazolone derivatives are being explored for anticancer properties, but their efficacy against liver cancer is understudied.
Purpose of the Study:
- To investigate the cytotoxic effects of two nitrophenyl-isothiazolones, IsoA and IsoB, against liver cancer cells.
- To evaluate the selectivity and potential therapeutic mechanisms of IsoB in liver cancer.
Main Methods:
- Cytotoxicity assays were performed on Huh7 liver cancer cells and Immortalized Human Hepatocytes (IHHs).
- IsoB's effects on mitochondrial membrane potential and superoxide levels were assessed.
- RT-qPCR was used to analyze gene expression related to cell death pathways.
Main Results:
- IsoB demonstrated potent and selective cytotoxicity against Huh7 cells, with IC50 values significantly lower than 5-fluorouracil.
- IsoB treatment led to decreased mitochondrial membrane potential and increased mitochondrial superoxide levels in Huh7 cells.
- Molecular analysis revealed IsoB induces apoptosis via TP53 overexpression and MYCN downregulation.
Conclusions:
- IsoB is a promising candidate for liver cancer therapy due to its potent and selective cytotoxic activity.
- The compound's mechanism involves mitochondrial dysfunction and apoptosis induction.
- Further research into IsoB could lead to novel liver cancer treatments.
