Impact of Salinomycin on colorectal cancer in vitro and in vivo.

• Applicant: Privatdozent Dr. Johannes Klose
• Subject Area: General and Visceral Surgery
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275300283

The antibiotic Salinomycin (Sal) raised hope to be a new potent anti-cancer drug due to its effectiveness to kill both cancer stem cells and non-stem cells of several solid and non-solid malignancies. Originally widely used as an anticoccideal and as a dietary supplement in animals breed, the precise mode of action of Sal as an anti-cancer agent remains unclear. Several mechanisms such as blocking the Wingless-type (Wnt) Beta-catenin pathway, activation of apoptosis driven pathways, or inhibition of epithelial-mesenchymal transition (EMT) have been proposed. Lately, a new mechanism responsible for the anti-cancer effect of Sal involving drug-mediated alteration in cancer cell autophagic activity was suggested. Most data of the anti-cancer effects of Sal are obtained from in vitro studies; analyses of the effectiveness of Sal in vivo are rare and only available for some types of cancer, including breast cancer, hepatocellular carcinoma and nasopharyngeal carcinoma. Colorectal cancer (CRC) is the third common malignancy worldwide. Although prognosis in early stages of CRC is promising, patients survival with advanced stages of disease or recurrent CRC ranges within months. Distant metastases in combination with resistance against common chemotherapies are the main cause for cancer-related death. Therefore, new and effective therapies are demanded. Promising reports have demonstrated that Sal affects human CRC cells in vitro. Consequently, in this research project we gain to analyze the impact of Sal on primary human CRC stem cells. The project is divided into three subprojects. (i) First, we want to analyze the impact of Sal on primary human CRC cells in vitro. (ii) In this part of the project, we investigate whether Sal is also feasible to treat CRC in vivo. Therefore, primary human CRC cells will be transplanted in to mice. After tumor growth, the animals will be treated with Sal. (iii) Furthermore, we want to analyze the mode of action of Sal in primary human CRC cells in vitro and in vivo. Gene expression experiments will help to understand the so far unclear mode of action of the drug. Based on our results Sal might be considered as a candidate for pre- and clinical studies to treat patients with advanced or recurrent CRC.

• DFG Programme: Research Grants