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

Taylor, Sophie; Spugnini, Enrico P.; Assaraf, Yehuda G.; Azzarito, Tommaso; Rauch, Cyril; Fais, Stefano

doi:10.1016/j.drup.2015.08.004

Cited by 210 publications

(157 citation statements)

References 126 publications

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“…Chemotherapy agents that are weakly basic can also become protonated in an acidic environment, preventing their entry into cells to reach their target sites (70,83). The ability to modulate microenvironmental pH has the potential to curb the development of a metastatic cell phenotype as well as provide a means to avoid the development of multi-drug resistance, at least in the case of weakly basic chemotherapy agents.…”

Section: Nhe1 Inhibition As a Chemotherapy Strategy: The Challenge Ofmentioning

confidence: 99%

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

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Section: Nhe1 Inhibition As a Chemotherapy Strategy: The Challenge Ofmentioning

confidence: 99%

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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“…Lung cancer is the most common cause of cancerrelated death in men and women worldwide (causing 19.4% of all cancer-related death). Chemotherapy is the most widely used method of treating lung cancer followed by radiotherapy and surgery (usually for early stages).…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

et al. 2017

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Paclitaxel (Tx) is one of the first-line chemotherapeutic drugs used against lung cancer, but acquired resistance to this drug is a major challenge against successful chemotherapy. In this work, we have focused on the chronological changes of various cellular parameters and associated effect on Tx (10 nM) resistance development in A549 cell line. It was observed, at initial stage, the cell death percentage due to drug treatment had increased up to 20 days, and thereafter, it started declining and became completely resistant by 40 days. Expressions of βIII tubulin and drug efflux pumps also increased over the period of resistance development. Changes in cellular autophagy and reactive oxygen species generation showed a biphasic pattern and increased gradually over the course of upto 20 days, thereafter declined gradually; however, their levels remained higher than untreated cells when resistance was acquired. Increase in extracellular acidification rates and oxygen consumption rates was found to be directly correlated with acquisition of resistance. The depolarisation of mitochondrial membrane potential was also biphasic; first, it increased with increase of cell death up to 20 days, thereafter, it gradually decreased to normal level along with resistance development. Increase in activity of catalase, glutathione peroxidase and glutathione content over these periods may attribute in bringing down the reactive oxygen species levels and normalisation of mitochondrial membrane potential in spite of comparatively higher reactive oxygen species production by the Tx-resistant cells.

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“…Chemoresistance is one of the biggest challenges in cancer therapy. There are several factors of anti-cancer drug resistance, such as impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis (Taylor et al, 2015). In addition, recent studies showed that another reason of the chemoresistance is the highly acidic microenvironment of tumors.…”

Section: Other Uses Of Ppismentioning

confidence: 99%

“…In addition, recent studies showed that another reason of the chemoresistance is the highly acidic microenvironment of tumors. Almost all anti-cancer drugs are weak bases and they are quickly protonated and neutralized in this acidic environment (Daniel et al, 2013;Taylor et al, 2015;Walsh et al, 2015;Chueca et al, 2016). In this frame, to be provide the increased pH of the tumor microenvironment may be a good strategy and PPIs may be used for buffering the acidic pH and enhancing tumor chemosensitivity (Daniel et al, 2013;Spugnini et al, 2011;Taylor et al, 2015;Walsh et al, 2015;Chueca et al, 2016).…”

Section: Other Uses Of Ppismentioning

confidence: 99%

Proton Pump Inhibitors in Veterinary Medicine

Yavuz

Arslan

2017

American Journal of Animal and Veterinary Sciences

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Inhibition of gastric acid secretion is necessary to treat many gastrointestinal diseases. Proton Pump Inhibitors (PPIs) are very effective drugs, used for gastric acid inhibition and therapy of important erosive and non-erosive gastrointestinal disorders in animals as well as humans. In this review, general properties of PPIs, their mode of action, pharmacokinetics, efficacy, adverse effects, drug interactions and clinical and alternative uses in veterinary medicine were evaluated.

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

Cited by 210 publications

References 126 publications

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

Proton Pump Inhibitors in Veterinary Medicine

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