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Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines

Název česky Kombinovaná terapie perifosinu a ABT-737 u nádorů tlustého střeva vyúsťuje ve vyšší cytotoxický efekt, ale zároveň podněcuje expresi markerů epiteliálně-mesenchymální tranzice


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Popis Colon cancer is the most common type of gastrointestinal cancer with almost 2 million new cases in Western countries in 2018. Both genetic and epigenetic alterations are involved in tumorigenesis. One of the most common aberrations during carcinogenesis is the activating mutation of PI3K/Akt signaling pathway which also modulates tumor resistance to therapy. Therefore, PI3K/Akt pathway was suggested as promising target for anticancer therapy. Perifosine is a synthetic alkyl phospholipid which inhibits Akt recruitment to the cell membrane. Despite promising results in many types of tumors, perifosine failed during clinical studies. In this study, we tested combined therapy of perifosine with ABT-737 (BCL-2 protein family inhibitor) in conditions of specific tumor-like microenvironment, such as hypoxia and acidosis. We found a synergistic cytotoxic effect of perifosine and ABT-737 in colon cancer cells. In 3D models, ABT-737 helps perifosine penetrate deeper into the spheroid and increases its cytotoxicity. Nevertheless, we also observed increased expression of EMT markers Slug/Snail and enhanced cell migration into collagen matrix after simultaneous treatment with perifosine and ABT 737 suggesting that some cells may undergo EMT and became resistant to this combined therapy.
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