Cell Membranes, Cytosolic pH and Drug Transport in Cancer and MDR: Physics, Biochemistry and Molecular Biology

Abstract

Pleiotropic resistance (or multidrug resistance, or MDR) to anticancer drugs in malignant diseases takes place either primarily or secondarily in the treatment of cancer. The first report suggesting that MDR could be the result of active drug extrusion was published in 1973 by Dano [1]. A few years later, P-glycoprotein (Pgp) was identified by Juliano and Ling as a membrane protein that actively extrudes membrane embedded drugs. Biochemistry is a “science of contacts” between at least two biochemical elements (e.g. a drug and a transporter). These elements have to interact in order for a reaction to occur (e.g. drug extrusion). Taking into account that drugs do not necessarily incorporate into the membrane in the vicinity of a drug transporter, these transporters have been thought to exhibit a “vacuum cleaner” like-activity on membrane embedded drugs. Accordingly, understanding this activity is essential; as the movement of membrane embedded drugs, or otherwise, movement of the transporters must occur if extrusion is to take place. These activities should be considered as targets for anticancer drugs. Drug movement occurs by lateral diffusion (Brownian movement) in the membrane and the physical conditions required for drug extrusion by membrane transporters is known as the “2D random walk” theory. A deeper understanding is now possible, because there is enough literature enabling understanding of: (a) why the membrane is central to Pgp* Corresponding author: Email: [e-mail], Tel: [phone], Fax: [phone] 440. Cyril Rauch, Adam Blanchard, Eleanor Wood et al. 2 mediated drug extrusion; (b) why the drug’s molecular weight is an essential determinant in MDR, and; (c) why an alkaline cytosolic pH is essential in MDR. After recalling the importance of pH in many aspects of cancer, including MDR, we will focus on the reason why a better understanding of the “vacuum cleaner” hypothesis is needed to clarify the subsequent processes involved in MDR. This will lead us to consider the cell membrane’s mechanical properties and cytosolic pH alkalinization as important factors in the etiopathogenesis and understanding of MDR.