Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

摘要: New targeted agents like antibodies or small molecules against tyrosine and lipid kinases clearly expand the standard therapy options in oncology. However, tumour resistance is still a challenge, often induced by mutations growth-related signalling cascades. Twenty ten percentage of all patients with colorectal gastric cancers, respectively, carry phosphatidyl-3-kinase (PI3K) do not respond to receptor-blocking therapies. Recently, selective kinase inhibitors have been generated, which block PI3K pathway cells. So far, their therapeutic role for treatment mutated versus wild-type human gastrointestinal cancers has clarified detail. To define inhibitory pro-apoptotic effects two BEZ235 BKM120 three colon cancer (HT-29, HCT-116 DLD-1) (NCI-n87, AGS MKN-45), cell lines different PIK3CA gene mutation status were used. Firstly, viability, apoptosis caspase assays performed during incubation either alone combined cytotoxic agents. Secondly, molecular consequences cycle pathways analysed defining protein levels FACS Western blot analysis. Both clear concentration-dependent reduction viability an increase apoptotic death, cells being more sensitive treatment. single-agent caused G1 arrest cells, whilst G2 shift half lines. There was downregulation PI3K–AKT at concentrations 100nM both additional inhibition mTOR pathway. Furthermore, synergistic induction when irinotecan Human less BKM120. especially increased response PI3KCA Our data support clinical development these cancers.