4-Nitrochalcone as a potential drug in non-clinical breast cancer studies
Claudia Martins Galindo1, Letícia Milani1, Lucas Trevisan França de Lima2
1Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil.
Abstract:
Breast cancer is a high-magnitude public health problem, continually challenging physicians and scientists worldwide in the field of drug therapy. 4-nitrochalcone (4NC) is a phenolic compound that has promising antitumor activity in vitro, but its application in breast cancer treatment is still poorly explored. This study aimed to evaluate the action of 4NC in vitro and in vivo breast cancer models. The cytotoxic potential of 4NC was tested towards MCF-7 and MDA-MD-231 breast cancer cells, with a lower impact in the non-tumor lineage HB4a. For in vivo studies, solid Ehrlich carcinoma (SEC) was used, a syngeneic mouse model with non-nuclear estrogen and progesterone positivity, characterized by immunohistochemistry. Daily oral administration of 4NC (25 mg kg-1) for 21 days led to a consistent reduction in tumor growth compared to the vehicle group. No signs of toxicity evaluated by hematological, biochemical, histological, and oxidative stress parameters were observed in mice, and the DL50 was >2000 mg kg-1. The effectors Raptor and S6K1 showed decreased activation, with a consequent reduction in protein synthesis; concomitantly, there was an increase in LC3-II levels, but the protective autophagic response was not completed, with the maintenance of p62 levels and cell death. These results open new possibilities for the use of 4NC as a tumor cell metabolism modulating agent.
Insights
4-nitrochalcone (4NC) effectively reduced breast cancer tumor growth in vivo without toxicity. This phenolic compound modulated tumor cell metabolism, showing potential for new breast cancer therapies.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Breast cancer presents a significant global health challenge, with ongoing research into novel drug therapies.
- 4-nitrochalcone (4NC), a phenolic compound, exhibits promising in vitro antitumor activity, yet its therapeutic potential in breast cancer remains underexplored.
Purpose of the Study:
- To investigate the efficacy and safety of 4-nitrochalcone (4NC) in preclinical models of breast cancer.
- To evaluate the effects of 4NC on breast cancer cell lines and in a solid Ehrlich carcinoma (SEC) mouse model.
Main Methods:
- Cytotoxicity of 4NC was assessed against MCF-7 and MDA-MD-231 breast cancer cells and the non-tumor HB4a cell line.
- In vivo studies involved daily oral administration of 4NC (25 mg/kg) to mice with solid Ehrlich carcinoma (SEC) for 21 days.
- Tumor growth, toxicity (hematological, biochemical, histological, oxidative stress), and molecular markers (Raptor, S6K1, LC3-II, p62) were analyzed.
Main Results:
- 4NC demonstrated selective cytotoxicity against breast cancer cells with minimal impact on normal cells.
- Oral administration of 4NC significantly reduced tumor growth in the SEC mouse model without observable toxicity (DL50 > 2000 mg/kg).
- 4NC treatment led to decreased activation of Raptor and S6K1, reduced protein synthesis, increased LC3-II, but incomplete autophagy, indicated by sustained p62 levels and cell death.
Conclusions:
- 4-nitrochalcone (4NC) exhibits significant antitumor activity and a favorable safety profile in preclinical breast cancer models.
- 4NC acts as a modulator of tumor cell metabolism, impacting protein synthesis and autophagy pathways.
- These findings suggest 4NC holds potential as a novel therapeutic agent for breast cancer treatment by targeting tumor cell metabolism.
