Drug Resistance and Cellular Adaptation to Tumor Acidic pH Microenvironment
| Autor: | Robert J. Gillies, Daniel Verduzco, Jonathan W. Wojtkowiak, Karla J. Schramm |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Drug
Cellular adaptation media_common.quotation_subject Pharmaceutical Science Drug resistance Hydrogen-Ion Concentration Pharmacology Biology Models Biological Article Cell biology Drug Resistance Neoplasm Apoptosis Drug Discovery Tumor Microenvironment medicine Extracellular Humans Molecular Medicine Glycolysis medicine.symptom Flux (metabolism) media_common Acidosis |
| Zdroj: | Molecular Pharmaceutics. 8:2032-2038 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp200292c |
| Popis: | Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to biochemical resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be physiological, emerging as a consequence of the tumor's physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an "ion trapping" phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed. |
| Databáze: | OpenAIRE |
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