Figure 6.

The mechanism of action of gemcitabine is by competing with deoxycytidine. Incorporation of gemcitabine into the DNA strand introduces an irreparable error that the cell cannot circumvent. This faulty DNA unleashes apoptotic mechanisms. A high level of deoxycytidine may prevail over gemcitabine, reducing its effects. The DNA synthesis mechanism is over-simplified in the diagram, the objective of which is to show how an increased glycolytic flux participates in resistance to gemcitabine. Lonidamine, which significantly decreases glycolysis, is probably good to associate with gemcitabine to prevent resistance, although this has not been tested. Increased expression of ribonucleotide reductase, specifically the M1 isoform, is also an important participant in resistance.