86 P = 0.021 CoCl2 + glibenclamide 10 0.481 ± 0.0685   paclitaxel 10 0.424 ± 0.0517   Discussion Breast cancer

is one of the most common malignancies in women. With morbidity increasing worldwide, breast cancer has become a significant threat to human life [16]. In China, the incidence is now 21 cases per million women [17, 18]. Breast cancer survival rates indicate that this cancer is one of the most malignant tumors in major metropolitan areas in China [19]. Surgery accompanied with chemotherapy is currently the main treatment strategy for breast cancer [20]. TA2 mice have a high incidence of spontaneous breast cancer without chemical stimulus. The morbidity of spontaneous breast cancer in parous female TA2 mice is 84.1% within an average of 280 days after birth [21]. Previous studies confirmed that TA2 spontaneous breast cancer is associated with MMTV infection and pregnancy-associated hormones, a combination that BAY 11-7082 order induces p53 gene mutation and results in the initiation and development of breast cancer [22]. Here normal TA2 mice injected with TA2 spontaneous breast cancer cells were used to AZD8931 mw find more compare the efficacy of combined treatment with CoCl2 + glibenclamide, agents that simultaneously cut off nutrition and oxygen. Tumor hypoxia is well recognized

as a major driving force behind many tumor biological behaviors including growth, metabolism, angiogenesis, metastasis, invasion and apoptosis [23, 24]. In some advanced tumors, hypoxia can be used as a tool to decrease tumor growth. Pilati and Guadagni et al. [2, 3] reported a type of therapy called hypoxic antiblastic stop-flow perfusion (SFP) that can be used as a treatment option for patients with locally advanced tumors [25, 26]. CoCl2 has been used in the treatment of anemia and it is known to activate hypoxic signaling by stabilizing HIF1α. CoCl2 can also activate hypoxia-mediated

signaling PDK4 pathways aberrantly under normoxic conditions by stabilizing cytosolic HIF1α [27]. This type of deviation effects long-term hypoxia because cobalt is a metal ion that is not easily cleared from tumor tissue. Glibenclamide is a drug widely used in clinics for the treatment of type 2-diabetes that specifically blocks KATP channels [28]. Different subtypes of potassium channels have been shown to be involved in normal and malignant cell proliferation [29]. Some of these potassium channels are overexpressed in tumors. Other reports have described the antiproliferative effect of glibenclamide in different neoplastic cell lines through the blocking of the KATP channels [30, 31]. Furthermore, Glibenclamide can bind to the sulphonylurea receptor (SUR1), a member of the ATP-binding cassette (ABC) protein superfamily, and block the activity of numerous ABC transporters including the P-gp multidrug transporter involved in anticancer drug resistance [32]. TA2 mice with tumor xenografts were treated with CoCl2 and glibenclamide to study the combined effect of blocking both nutrition and oxygen.