Hence drugs targeting their function, such as HDAC inhibitors, can also affect nonepigenetic processes

being almost parasitic. Consequently, a nutrient-deprived state can be perceived as a stress signal by tumour cells, which may lead to the activation of stress signalling pathways to support proliferation and survival. Furthermore, the tumour microenvironment is also characterized by hypoxia and poor leaky vasculature and lactic acidosis, which may be associated with extreme metabolic stress, thereby potentiating stress-activated signalling. These stress-related signalling components are intricately linked with survival signalling and are discussed in the following sections. Stress response elements Studies have indicated that many stress response elements are activated as a result of the altered microenvironment associated with the Warburg effect. Heat shock protein 90, a molecular chaperone evoked during stress reactions, has been reported to be activated by hypoglycaemic stress. HSP90 has been found to provide a Aphrodine site cytoprotective response to drug treatment by preventing the degradation of client proteins such as Akt, EGFR, HER2, Kit, METand BcrAbl. Glucose-regulated protein 78, a molecular chaperone in the endoplasmic reticulum, which confers cytoprotective effects from apoptosis signals, has also been known to be activated by hypoglycaemia. Colon carcinoma cells cultured in hypoglycaemic medium were rendered resistant to etoposide treatment and were resensitized by glucose-regulated protein 78 inhibitors. Heat shock factor 1 has been known to regulate heat shock responses, and glucose deprivation has been reported to activate HSF1. HSF1 has also been reported to increase glucose uptake and promote glycolysis, and down-regulation of HSF1 decreases glycolysis and hence may be involved in a feedback loop. HSF1 signalling also promotes cellular adaptation to stress by activating survival signals, which can lead to drug resistance. 974 British Journal of Pharmacology 173 970979 The informativeness of supraphysiological glucose levels in preclinical drug testing Recently, our laboratory tested the hypothesis that a reduced glucose microenvironment can increase chemoresistance due to its activation of survival pathways. The basis for this study was the observation that traditional drug testing was routinely performed on cells grown in glucose-rich medium, a concentration that is approximately five times higher than normal physiological glucose levels . We surmised that culturing cells in conditions closer to its `native’ environment may generate results that would more closely reflect physiological efficacy. We assessed the sensitivity of two PIK3CA mutant and two PIK3CAwild-type gastric PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19822663 cancer cells grown in routine high glucose or low glucose media to two standard-of-care cytotoxic agents, a PI3K/mTOR inhibitor The Warburg effect and drug resistance BJP and a mTOR inhibitor. In support of our hypothesis, resistance to the cytotoxic agents was significantly increased in all cell lines in LG conditions, despite a lack of difference in growth characteristics between HG and LG cells. LG-associated resistance to PI3K/mTOR inhibitors was also observed but only in PIK3CA mutant cells. Further investigation revealed the class-specific resistance to be accompanied by selectively increased GLUT1, mTOR activation, increased lactate and reduced ROS, highlighting increased glycolysis as a feature of cells susceptible to LGassociated chemoresistance. We further demonstrated that this resistance can be selectively attenuated by a combination of PI103 and