Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy

Abstract

Introduction: Cancer is an intricate disorder/dysfunction of cells that can be defined as a genetic heterogeneity in human disease. Therefore, it is characterized by several adaptive complex hallmarks. Among them, the pH dysregulation appears as a symbol of aberrant functions within the tumor microenvironment (TME). In comparison with normal tissues, in the solid tumors, we face with an irregular acidification and alkalinization of the extracellular and intracellular fluids. Methods: In this study, we comprehensively discussed the most recent reports on the hallmarks of solid tumors to provide deep insights upon the molecular machineries involved in the pH dysregulation of solid tumors and their impacts on the initiation and progression of cancer. Results: The dysregulation of pH in solid tumors is fundamentally related to the Warburg effect and hypoxia, leading to expression of a number of molecular machineries, including: NHE1, H+ pump V-ATPase, CA-9, CA-12, MCT-1, GLUT-1. Activation of proton exchangers and transporters (PETs) gives rise to formation of TME. This condition favors the cancer cells to evade from the anoikis and apoptosis, granting them aggressive and metastasis phenotype, as well as resistance to chemotherapy and radiation therapy. This review aimed to discuss the key molecular changes of tumor cells in terms of bio-energetics and cancer metabolism in relation with pH dysregulation. During this phenomenon, the intra- and extracellular metabolites are altered and/or disrupted. Such molecular alterations provide molecular hallmarks for direct targeting of the PETs by potent relevant inhibitors in combination with conventional cancer therapies as ultimate therapy against solid tumors. Conclusion: Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.

Expressional and Functional Characterization of Intracellular pH Regulators and Effects of Ethanol in Human Oral Epidermoid Carcinoma Cells

“…Such acidic steady-state pH i value is not only significantly lower than that of highly proliferated cells, i.e. embryonic stem cells and cancer cells (~7.4) [43,46,47], but also lower than that of normal animal and human mature cells (~7.2) [23-25, 28, 48]. As steady-state pH i is a balance through the combined operation of passive intracellular buffering power and active transmembrane pH i transporters [24][25][26], therefore, the shift of ~0.4 pH i units from alkaline to acidic means a dramatic kinetic change in the pH i regulating mechanism.…”

Advances in redox-responsive drug delivery systems of tumor microenvironment

“…However, the chemical cleavage of a pH-responsive substructure is not fast enough, resulting in slow response speed [ 62 ]. Recent studies have reported that tumor cells not only acidify but also alkalize, in which situation pH-responsive drug delivery systems do not apply [ 65 , 66 ]. Enzyme-responsive drug delivery systems have been recognized as a valuable strategy to achieve efficient intracellular drug delivery [ 67 , 68 ], as there are abundant enzymes including proteases, matrix metalloproteinases and hyaluronidases in the lysosomes [ 62 ].…”

Nanoscale Metal–Organic Frameworks for Therapeutic, Imaging, and Sensing Applications

“…Intracellular pH plays an important role in physiological environments, regulating cellular functions and physiological activities. The pH dysregulation in intracellular fluids is related to tumorigenesis and drug‐resistance . Real‐time sensing and monitoring of pH changes inside live cells are therefore important for probing disease mechanisms and designing pH‐responsive intracellular drug delivery systems.…”