Impact of the changes in intracellular pH on doxorubicin resistance in different cancer cells. Multidrug resistance in cancer has been associated with the alkalization of the cytosol due to overexpression of proton pumps at the level of the cell membrane and/or expression of drug transporters. In this context it is believed that weak base drugs are protonated and as a result cannot cross the membrane bilayer, a feature that adds to the efficiency of drug transporters. Albeit this model (drug protonation and transporter) has been used over decades, the high pH of the cytosol can drive drug resistance through a different mechanism. The hypothesis made by us was that the change in cytosolic pH makes the membrane less permeable to drugs due to hydrogen-lipid interactions. To test this, a model of hydrogen-lipid interaction was formulated and compared with experimental data. In the figure the X-axis represents the positive increment in the cytosolic pH when cells switch their state from being sensitive to resistant to drugs. The Y-axis represents the ratio of the logarithm values of the concentration of drugs to kill 50% drug resistant vs. sensitive cells. The blank dots represent the experimental data. The black dots show the result expected from the theoretical modelling. The straight line represents the linear trend (best fit) from experimental data. Finally, the best fit passes across all the dots modelled by the theory. For further details see ref. .