Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype. (July 2014)

• Record Type: Journal Article
• Authors: Bhattacharya, B; Low, S H H; Soh, C; Kamal Mustapa, N; Beloueche‐Babari, M; Koh, K X; Loh, J; Soong, R
• Is Part Of: British journal of pharmacology. Volume 171:Number 13(2014:Jul.)
• Page Start: 3255
• Page End: 3267
• Publication Date: 2014-07
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12668
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12668-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The testing of anticancer compounds <italic>in vitro</italic> is usually performed in hyperglycaemic cell cultures, although many tumours and their <italic>in vivo</italic> microenvironments are hypoglycaemic. Here, we have assessed, in cultures of tumour cells, the effects of reduced glucose levels on resistance to anticancer drugs and investigated the underlying cellular mechanisms.</p> </sec> <sec id="bph12668-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p> <italic>PIK3CA</italic> mutant (AGS, HGC27), and wild‐type (MKN45, NUGC4) gastric cancer cells were cultured in high‐glucose (HG, 25 mM) or low‐glucose (LG, 5 mM) media and tested for sensitivity to two cytotoxic compounds, 5‐fluorouracil (5‐FU) and carboplatin, the PI3K/mTOR inhibitor, PI103 and the mTOR inhibitor, Ku‐0063794.</p> </sec> <sec id="bph12668-sec-0003" sec-type="section"> <title>Key Results</title> <p>All cells had increased resistance to 5‐FU and carboplatin when cultured in LG compared with HG conditions despite having similar growth and cell cycle characteristics. On treatment with PI103 or Ku‐0063794, only the <italic>PIK3CA</italic> mutant cells displayed increased resistance in LG conditions. The <italic>PIK3CA</italic> mutant LG cells had selectively increased p‐mTOR, p‐S6, p‐4EBP1, GLUT1 and lactate production, and reduced reactive oxygen species, consistent with increased glycolysis. Combination analysis indicated PI103 and Ku‐0063794 were synergistic in <italic>PIK3CA</italic> mutant LG cells only. Synergism was accompanied by reduced mTOR signalling and increased autophagy.</p> </sec> <sec id="bph12668-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Hypoglycaemia increased resistance to cytotoxic agents, especially in tumour cells with a high dependence on glycolysis. Dual inhibition of the PI3K/mTOR pathway may be able to attenuate such hypoglycaemia‐associated resistance.</p> </sec> </abstract>