The phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 is effective in inhibiting regrowth of tumour cells after cytotoxic therapy
| Autor: | Slavica Brnjic, Angelo De Milito, Karolina Lesiak-Mieczkowska, Mårten Fryknäs, Rolf Larsson, Vivien Schmidt, Emma Hernlund, Padraig D'Arcy, Walid Fayad, Maria Hägg Olofsson, Tobias Sjöblom, Xiaonan Zhang, Stig Linder |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Colorectal cancer Cell Survival Blotting Western Antineoplastic Agents Apoptosis medicine Tumor Cells Cultured Cytotoxic T cell Humans PI3K/AKT/mTOR pathway Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Phosphoinositide 3-kinase biology Cell growth Bortezomib Carcinoma Imidazoles medicine.disease Flow Cytometry Immunohistochemistry In vitro Cell biology Oncology Colonic Neoplasms biology.protein Cancer research Quinolines medicine.drug |
| Zdroj: | European journal of cancer (Oxford, England : 1990). 48(3) |
| ISSN: | 1879-0852 |
| Popis: | PURPOSE:Regrowth of tumour cells between cycles of chemotherapy is a significant clinical problem. Treatment strategies where antiproliferative agents are used to inhibit tumour regrowth between chemotherapy cycles are attractive, but such strategies are difficult to test using conventional monolayer culture systems.METHODS:We used the in vitro tumour spheroid model to study regrowth of 3-D colon carcinoma tissue after cytotoxic therapy. Colon carcinoma cells with wild-type or mutant phosphatidyl inositol 3-kinase catalytic subunit (PI3KCA) or KRAS alleles were allowed to form multicellular spheroids and the effects of different pharmacological compounds were studied after sectioning and staining for relevant markers of cell proliferation and apoptosis.RESULTS:Studies using colon cancer cells with gene disruptions suggested that the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway was essential for proliferation in 3-D culture. The dual PI3K-mTOR inhibitor NVP-BEZ235, currently in clinical trials, was found to inhibit phosphorylation of the mTOR target 4EBP1 in 3-D cultured cells. The ability of NVP-BEZ235 to inhibit tumour cell proliferation and to induce apoptosis was markedly more pronounced in 3-D cultures compared to monolayer cultures. It was subsequently found that NVP-BEZ235 was effective in inhibiting regrowth of 3-D cultured cells after treatment with two cytotoxic inhibitors of the ubiquitin-proteasome system (UPS), methyl-13-hydroxy-15-oxokaurenoate (MHOK) and bortezomib (Velcade®).CONCLUSIONS:The dual PI3K-mTOR inhibitor NVP-BEZ235 was found to reduce cell proliferation and to induce apoptosis in 3-D cultured colon carcinoma cells, NVP-BEZ235 is a promising candidate for use in sequential treatment modalities together with cytotoxic drugs to reduce the cell mass of solid tumours. |
| Databáze: | OpenAIRE |
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