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Published on: June 14, 2021
mTOR Pathway Inhibition, Anticancer Activity and In Silico Calculations of Novel Hydrazone Derivatives in Two- and
Muhammet Volkan Bulbul1,2, Arif Mermer3,4,5, Bircan Kolbasi2
1Department of Histology and Embryology, School of Medicine, Agri Ibrahim Cecen University, Agri 04000, Turkey.
Background:
Endometrial cancer remains a significant health concern, with type 1 endometrial cancer characterized by aberrant expression of estrogen-dependent and mTOR pathway proteins. In this study, we evaluated the effects of two novel hydrazone derivatives against the Ishikawa cell line, a model for endometrial cancer.
Methods:
Two novel hydrazone derivatives, MVB1 and MVB2, were synthesized and characterized. The anticancer activity of the compounds in both two- and three-dimensional cultured Ishikawa cells was evaluated by MTT assay. The interaction of the compounds with proteins in the PI3K/AKT/mTOR pathway was evaluated by molecular docking studies and in vitro western blot analyses were performed. Additionally, ADME/T calculations were performed to evaluate the drug-like properties of the compounds.
Results:
MVB1 and MVB2 showed promising anticancer activity with IC50 values of 8.3 ± 0.5 µM and 9.0 ± 1.2 µM in 2D cultures, respectively, and 49.9 ± 2 µM and 20.6 ± 1.9 µM in 3D cultures, respectively. Molecular docking studies revealed significant interactions between these compounds and key proteins in the PI3K/AKT/mTOR pathway, with MVB1 exhibiting the highest mean binding score (-10.5 kcal/mol) among PI3K, AKT1, and mTOR proteins. In vitro studies confirmed that MVB1 effectively suppressed PI3K protein expression in both 2D and 3D cultures (p ≤ 0.0001).
Conclusions:
The findings suggest that MVB1 and MVB2, especially MVB1, are promising candidates for further development as potential therapeutics for endometrial cancer by targeting the PI3K/AKT/mTOR pathway.
Insights
Two novel hydrazone derivatives, MVB1 and MVB2, show potential against endometrial cancer by targeting the PI3K/AKT/mTOR pathway. MVB1 demonstrated significant anticancer activity and suppressed key protein expression in cell line models.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Endometrial cancer, particularly type 1, is linked to estrogen and mTOR pathway dysregulation.
- Novel hydrazone derivatives were investigated for their therapeutic potential.
- The Ishikawa cell line served as a model for endometrial cancer research.
Purpose of the Study:
- To evaluate the anticancer effects of novel hydrazone derivatives MVB1 and MVB2.
- To investigate the mechanism of action involving the PI3K/AKT/mTOR pathway.
- To assess the drug-like properties of these compounds.
Main Methods:
- Synthesis and characterization of hydrazone derivatives MVB1 and MVB2.
- Anticancer activity assessed using MTT assays in 2D and 3D cell cultures.
- Molecular docking and in vitro Western blot analyses to study PI3K/AKT/mTOR pathway interactions.
Main Results:
- MVB1 and MVB2 exhibited significant anticancer activity in both 2D and 3D Ishikawa cell cultures.
- Molecular docking indicated strong interactions with PI3K, AKT1, and mTOR proteins, with MVB1 showing a mean binding score of -10.5 kcal/mol.
- In vitro studies confirmed MVB1's potent suppression of PI3K protein expression (p ≤ 0.0001).
Conclusions:
- MVB1 and MVB2 are promising candidates for endometrial cancer therapy.
- MVB1 shows particular efficacy in targeting the PI3K/AKT/mTOR pathway.
- Further development of these compounds as endometrial cancer therapeutics is warranted.
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