Investigation of Anticancer Properties of Newly Synthesized Pyridazine-Based Inhibitors in Mouse and Human Breast...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Breast cancer is the most common cancer in women, with doxorubicin (DOX) treatment facing challenges from toxicity and drug resistance.
• Identifying novel anticancer agents with improved efficacy and reduced toxicity is crucial for effective breast cancer therapy.

Purpose of the Study:

• To identify and evaluate novel anticancer agents as potential alternatives to doxorubicin (DOX) for breast cancer treatment.
• To assess the efficacy, selectivity, and molecular mechanisms of 2S-series molecules against triple-negative breast cancer (TNBC) cell lines.

Main Methods:

• Cytotoxic effects of DOX and 2S-series molecules were evaluated on human (MDA-MB-231) and mouse (4T1) TNBC cells and healthy hTERT cells using MTT assays.
• Apoptosis, cell cycle, and gene expression profiles were analyzed via flow cytometry and qPCR, respectively.
• Molecular docking was used to examine binding interactions with Hsp90.

Main Results:

• Compounds 2S-5 and 2S-13 demonstrated selective cytotoxicity against TNBC cell lines, with 2S-13 showing IC50 values of 7.73 µM (MDA-MB-231) and 8.21 µM (4T1).
• 2S-13 modulated critical cancer-related pathways, including PI3K-Akt, MAPK, apoptosis, and HIF-1, indicating broader activity than DOX.
• Both 2S-5 and 2S-13 showed selective toxicity towards cancer cells over healthy breast epithelial cells.

Conclusions:

• The compound 2S-13 shows significant potential as a drug candidate for breast cancer, particularly against the MDA-MB-231 cell line.
• Current findings are based on in vitro models; further in vivo studies are necessary to validate therapeutic potential, efficacy, and safety.
• Additional research should focus on pharmacokinetic analyses, long-term efficacy, safety assessment, and detailed exploration of resistance mechanisms and molecular targets of 2S-13.