Resistance to gemcitabine in the pancreatic cancer cell line KLM1-R reversed by metformin action
Abstract
BACKGROUND/AIM: The pancreatic cancer cell line KLM1 can gain chemoresistance following gemcitabine (GEM) treatment. Metformin was found to be a useful sensitising agent towards GEM treatment following gain of chemoresistance.
MATERIALS AND METHODS: The proliferation of GEM-sensitive and -resistant cells was investigated over a range of metformin concentrations from 0.005 to 5 mM. The intra- and extra-cellular energetic profiles of these two cell types under metformin exposure were investigated through adenosine triphosphate (ATP) and L-lactate assays.
RESULTS: There was an unexpected decrease in intracellular L-lactate following gain of chemoresistance, despite observable medium acidification. At the biochemical level, a marked effect on phosphorylated proteins upstream of Akt, along the mTOR pathway, was observed at 6 h. These changes followed a time-dependent pattern linked closely to the changes in the energetic profile.
CONCLUSION: Together, these results indicate that metformin indirectly blocks protein phosphorylation, including that of heat shock protein 27 (HSP27).
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