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Cancer cells and tissues, regardless of their origin and genetic background, have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the intracellular to extracellular pH gradient (ΔpHi to ΔpHe) in cancer cells and tissue as compared to normal tissue. This perturbation in pH dynamics rises very early in carcinogenesis and is one of the most common patho-physiological hallmarks of tumors. Recently, there has been a very large increase in our knowledge of the importance and roles of pHi and pHe in developing and driving a series of tumor hallmarks. This reversed proton gradient is driven by a series of proton export mechanisms that underlie the initiation and progression of the neoplastic process. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). The NHE1 is an integral membrane transport protein involved in regulating pH and in tumor cells is a major contributor to the production and maintenance of their reversed proton gradient. It is activated during oncogene- dependent transformation resulting in cytosolic alkalinization which then drives subsequent hallmark behaviors including growth factor- and substrate-independent growth, and glycolytic metabolism. It is further activated by various growth factors, hormone, the metabolic microenvironment (low serum, acidic pHe and hypoxia) or by ECM receptor activation. This review will present the recent progress in understanding the role the NHE1 in determining tumor progression and invadopodia- guided invasion/metastasis and recent patents for NHE1 inhibitors and novel therapeutic protocols for anti-NHE1 pharmacological approaches. These may represent a real possibility to open up new avenues for wide-spread and efficient treatments against cancer.

"How do drugs cross the plasma membrane?" this may seem like a trivial question. This question is often over-looked to focus primarily on the different complex macro-molecular aspects involved in drug delivery or drug resistance. However, recent studies have highlighted the theme that to be fully understood, more knowledge of the underlying biology of the most complex biological processes involved in the delivery and resistance to drugs is needed. After all, why would a drug interact with a transporter then subsequently be excluded from P-glycoprotein (P-gp) expressing drug resistant cells? What are the determinants of this transition in behavior? Full consideration of the physical biology of drug delivery has allowed a better understanding of the reasons why specific membrane proteins are upregulated or overexpressed in drug resistant cells. This, in turn, allows us to identify new targets for drug chemicals. Better yet, it increases the significance of recents patents and underlines their importance in multi drug resistance.