Synergistic Anti-Breast-Cancer Effects of Combined Treatment With Oleuropein and Doxorubicin In Vivo

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Synergistic Anti-breast Cancer Effect of Oleuropein and Doxorubicin Combined Treatment in vivo
 Background: Breast cancer is the most common cancer and leading cause of cancer deaths among women worldwide. Objective: To investigate the anticancer properties and molecular pathway of oleuropein, doxorubicin alone and in combination in breast tumor xenografts. Methods: Oleuropein was extracted from Manzanillo olive (Olea europaea, L.) trees grown in Tabouk, Saudi Arabia. A reversed phase high performance liquid chromatographic technique was developed to identify and quantify oleuropein obtained in the extract. Female nude mice (BALB/c OlaHsd-foxn1) were injected subcutaneously with MDA-MB-231 human breast cancer cells. After growth of the tumors the animals were randomized into 4 groups to receive intraperitoneal (i.p.) injections of DMSO (Control) (group 1), oleuropein (50 mg/kg) (group 2), doxorubicin (2.5 mg/kg) (group 3), doxorubicin (1.5mg/kg), immediately followed by oleuropein (50 mg/kg) (group 4). Results: The volume of the tumor increased aggressively and reached 173mm3 in the mock-treated animals in a time-dependent manner. On the other hand, a sharp drop in the volume of the tumor (48.7mm3) was observed by using combined treatment of the drugs (more than 3-fold decrease). This effect is mediated through the induction of apoptosis via the mitochondrial pathway. Combined treatment down-regulated the anti-apoptosis and pro-proliferation protein NF-κB and its main oncogenic target Cyclin D1. Furthermore, it inhibited Bcl-2 and Survivin. This inhibition could explain the cooperative suppression of breast tumor xenografts proliferation and the induction of apoptosis by combined drugs. Conclusions: These results indicate the synergistic action of doxorubicin when combined with the natural non toxic oleuropein against breast tumor xenografts.
Key words: Breast cancer – Oleuropein – Doxorubicin – Apoptosis- NF-κB – Cyclin D1

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