Synergistic cytotoxicity of perifosine and ABT-737 to colon cancer cells

An acidic environment and hypoxia within the tumour are hallmarks of Cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon Cancer. Numerous Akt-targeted therapies are being developed, the activity of Akt-inhibitors is, however, strongly pH-dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt Inhibitor perifosine and the Bcl-2/Bcl-xL Inhibitor ABT-737 was tested in colon Cancer HT-29 and HCT-116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour-specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced Apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon Cancer.

ABT-737; colon cancer; combined treatment; peeling analysis; perifosine; spheroids; synergism; tumour microenvironment.