Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach.

摘要: Despite the major progresses in biomedical research and development of novel therapeutics treatment strategies, cancer is still among dominant causes death worldwide. One crucial challenges clinical management primary (intrinsic) secondary (acquired) resistance to both conventional targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic acquired chemoresistance: these include impaired drug uptake, increased efflux, deletion receptors, altered metabolism, quantitative qualitative alterations targets, DNA damage repair various anti-apoptosis. The fast efflux anticancer drugs mediated by multidrug pumps partial or complete reversibility chemoresistance combined with absence genetic mutations suggests a multifactorial process. However, growing body recent evidence that often triggered highly acidic microenvironment tumors. vast majority drugs, including chemotherapeutics more biological agents, are weak bases quickly protonated neutralized environments, such as extracellular organelles tumor cells. It therefore essential develop new strategies overcome entrapment neutralization base drugs. strategy use proton pump inhibitors which can enhance chemosensitivity increasing pH microenvironment. Recent trials animals spontaneous tumors indicated patient alkalization capable reversing large percentage refractory chemotherapy. Of particular interest was benefit for patients undergoing metronomic regimens becoming widely used veterinary medicine. Overall, results provide substantial altering an effective, well tolerated low cost overcoming resistance.