Acta Pharm. 67 (2017) 35-52
Original research paper
Hydrazinyldiene-chroman-2,4-diones
in inducing growth arrest and apoptosis in breast cancer cells: Synergism with
doxorubicin and correlation with physicochemical properties
LULZIME
BALLAZHI, FAIK IMERI, AHMED JASHARI, EMIL POPOVSKI, GORAN STOJKOVIÆ, ALEKSANDAR
J. DIMOVSKI, BOZHANA MIKHOVA and KRISTINA MLADENOVSKA
krml@ff.ukim.edu.mk; kmladenovska@yahoo.com
1 Faculty of Pharmacy,
Center of Biomolecular Pharmaceutical Analyses, University
“Ss Cyril and Methodius”, 1000 Skopje, Republic of Macedonia
2 Institute of Physiology, University of Zürich,
CH-8057, Zürich, Switzerland
3 Faculty of Natural Sciences & Mathematics, State University of Tetovo, 1200 Tetovo, Republic of
Macedonia
4 Institute of Chemistry, Faculty of Natural Sciences and Mathematics, University
“Ss. Cyril and Methodius”, PO Box 162, 1000 Skopje, Republic of Macedonia
5 Bulgarian Academy of Sciences, Institute of Organic Chemistry with
Centre of Phytochemistry,
1113 Sofia, Bulgaria
Accepted September 21, 2016
Published online September
28, 2016
This study evaluates the effects of previously synthesized hydrazinyldiene-chroman-2,4-diones on cell proliferation and apoptosis, cell cycle distribution and migration capacity of MCF-7 breast cancer cells in synergy with doxorubicin. Physicochemical properties of the synthesized compounds were correlated with their structure and activity. Significant cell viability decrease in comparison with the effect of doxorubicin alone and the reference 4-hydroxycoumarin was observed when combination treatment comprising doxorubicin and the title compounds was applied. Synergistic effect with doxorubicin was also observed in down-regulation of phospho-Thr308Akt levels, confirming reduced proliferation and increased apoptosis. Combined treatment increased the percentage of cells arrested at the G2/M stage. Additive inhibition of cell migration was also observed, pointing to the possibility of reducing the risk of metastases. With their solubility profile and log D7.4, all the synthesized compounds follow Lipinski’s rule of five for good permeability (absorption) potential.
Keywords: hydrazinyldiene-chroman-2,4-diones,
physicochemical properties, doxorubicin, cytotoxicity,
breast cancer cells