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PurposeTamoxifen (TAM) is a non-steroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit cancer cell growth. The study aimed to investigate the effect of the combination of TAM and SIM in the treatment of estrogen receptor positive (ER+) breast cancer cell line, MCF-7, and in mice-bearing Ehrlich solid tumors.MethodsMCF-7 cells were treated with different concentrations of TAM or/and SIM for 72 hours and the effects of the combination treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated using different techniques. In addition, tumor volume, oxidative markers, and inflammatory markers of the combined therapy were explored in mice bearing solid EAC tumors.ResultsThe results showed that treatment of MCF-7 cells with the combination of 10 µM TAM, and 2 µM SIM significantly inhibited the increase in oxidative stress markers, LDH, and NF-kB induced by TAM. In addition, there was a significant decrease in the total apoptotic ratio, caspase-3 activity, and glucose uptake, while there was a non-significant change in Bax/bcl-2 ratio compared to the TAM-treated group. Using the isobologram equation, the drug interaction was antagonistic with combination index, CI=1.18. On the other hand, the combination regimen decreased VEGF, and matrix metalloproteinases, MMP 2&9 compared to TAM-treated cells. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume, decreased oxidative markers, and the protein expression of TNF-α, and NF-κB compared to the TAM treated group.ConclusionAlthough the combination regimen of TAM and SIM showed an antagonistic drug interaction in MCF-7 breast cancer, it displayed favorable antiangiogenic, anti-metastatic, and anti-inflammatory effects.

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The aim of this study was to investigate the protective effect of L-carnitine (L-CAR) in tamoxifen (TAM)-induced toxicity and antitumor activity.Adult female rats were randomly divided into 4 groups. Group I was served as control, groups II and III were injected with (10mg/kg, P.O) TAM and L-CAR (300 mg /kg, i.p.) respectively while, group IV was treated with both compounds.The treatment continued daily for 28 days. Administration of TAM resulted in significant increase in serum lipid profiles, liver enzymes and bilirubin level. In addition, TAM produced significant increase in lipid peroxides (LPO) level accompanied with significant decrease in superoxide dismutase (SOD) activity of hepatic and uterus tissues and significant decrease in glutathione (GSH) content of uterus tissue. Administration of L-CAR prior to TAM treatment decreased significantly serum lipids and liver enzymes and significantly increased SOD activity in liver and uterus tissues compared to TAM treated group. Furthermore, it restored LPO and GSH levels in uterus tissue. On the other hand, the apoptotic markers of caspases 9 and 3 were not detected in liver of all the treated groups. Histopathologically, alterations in the liver and uterus structures after TAM treatment which was attenuated by L-CAR administration. The antitumor effect and survival of the combined treatment of Ehrlich Ascites Carcinoma (EAC)-bearing mice was less than each one alone. In addition, L-CAR interestingly increased survival rate of EAC-bearing mice more than TAM treated group. In conclusion, L-CAR has beneficial effects regarding TAM toxicity; however, it interferes with its antitumor effect.