Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Background: Tamoxifen (TAM) is the gold-standard drug therapy for estrogen receptor-positive (ER+) breast cancer, however, its resistance is a challenging in clinical practice. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit several types of cancer cells growth. Aim of the work: The study aimed to investigate the combined anticancer effect of TAM and SIM and to explore the mechanistic pathway in the treatment of two ER+ breast cancer cell lines, MCF-7 and T47D, as well as in mice-bearing Ehrlich solid tumor.Methods: Breast cancer cell lines were treated with different concentrations of TAM or/and SIM for 72 hrs. The combined effect of drug interaction was measured using the isobologram equation. For the mechanistic pathways, oxidative stress, apoptosis, angiogenesis, inflammatory and metastasis markers were investigated. Besides, in vivo, tumor volume, oxidative stress, and inflammatory markers were explored.Results: The results of this study showed that using the combination index, the drug interaction was antagonistic in MCF-7 and synergistic in T47D cells. Besides, there was a significant decrease in apoptotic marker caspase-3 activity and non-significant change in Bax/bcl-2 ratio as well as a significant decrease in NF- mB, compared to the TAM-treated group in MCF-7cells. However, significant increases in caspase 3 activity, Bax/bcl-2 ratio and NF-mB in T47D cells by the combination regimen.On the other hand, treatment of two breast cancer lines with the combination of TAM, and SIM significantly inhibited the increase in oxidative stress markers, LDH, and glucose uptake induced by TAM

Issued also as CD