Abstract
Cancer is the second leading cause of death worldwide. Chemotherapy has shown reasonable success in treating cancer. However, multidrug resistance (MDR), a phenomenon by which cancerous cells become resistant to a broad range of functionally and structurally unrelated chemotherapeutic agents, is a major drawback in the effective use of chemotherapeutic agents in the clinic. Overexpression of P-glycoprotein (Pgp) is a major cause of MDR in cancer as it actively effluxes a wide range of structurally and chemically unrelated substrates, including chemotherapeutic agents. Interestingly, Pgp is also overexpressed in the endothelial cells of blood–brain barrier (BBB) restricting the entry of 98% small molecule drugs to the brain. The efficacy of Pgp is sensitive to any impairment of the membrane structure. A small increase of 2% in the membrane surface tension, which can be caused by a very low drug concentration, is enough to block the Pgp function. We demonstrate in this work by mathematical equations that the incorporation of drugs does increase the surface tension as expected, and the mechanism of endocytosis dissipates any increase in surface tension by augmenting the internalisation of membrane per unit of time, such that an increase in the surface tension of about 2% can be dissipated within only 4.5 s.
Highlights
Cancer is the second leading cause of death worldwide [1]
multidrug resistance (MDR) is a phenomenon by which cancerous cells become resistant to a broad range of functionally and structurally unrelated chemotherapeutic agents [6]
We demonstrate here that a key element protecting Pgp function is pinocytosis, which is known as fluid phase endocytosis [21]
Summary
Cancer is the second leading cause of death worldwide [1]. It is a major health problem worldwide with more than 18 million patients diagnosed with cancer in 2018, and a death toll of around 9.5 million. It has been deduced that changes in surface tension of the cell membrane induced by the incorporation of drugs are enough to impede Pgp function [20] Experimental results confirming this theory suggest that a small increase in the membrane surface, of about 2%, is enough to block the effect of Pgp [20]. We demonstrate that the incorporation of drugs does increase the surface tension as expected, but that the mechanism of endocytosis dissipates any increase in surface tension by augmenting the internalisation of membrane per unit of time, such that an increase in the surface tension of about 2% can be dissipated within 4.5 s
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