ArticleOncotarget2016
Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.
- Effects of extracellular acidity on resistance to chemotherapy treatment: a systematic review.Medical oncology (Northwood, London, England) · 2018Pooled it
- Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis.Acta physiologica (Oxford, England) · 2026Article
- Resistance to neoadjuvant chemotherapy in breast cancers: a metabolic perspective.Journal of experimental & clinical cancer research : CR · 2025Review
- Antagonizing the S1P-S1P3 Axis as a Promising Anti-Angiogenic Strategy.Metabolites · 2025Article
- A 10-year bibliometric analysis in the field of osteosarcoma treatment from 2014 to 2023.Discover oncology · 2025Article
- Review
- Article
- Article
- Review
- Cellular and Genetic Background of Osteosarcoma.Current issues in molecular biology · 2023Review
- Contribution of Mitochondrial Activity to Doxorubicin-Resistance in Osteosarcoma Cells.Cancers · 2023Article
- Endogenous Extracellular Matrix Regulates the Response of Osteosarcoma 3D Spheroids to Doxorubicin.Cancers · 2023Article
- Craft of Co-encapsulation in Nanomedicine: A Struggle To Achieve Synergy through Reciprocity.ACS pharmacology & translational science · 2022Review
- Proton Pump Inhibitors Enhance the Antitumor Effect of Chemotherapy for Esophageal Squamous Cell Carcinoma.Cancers · 2022Article
- Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer.Reviews of physiology, biochemistry and pharmacology · 2022Article
- An overview of resistance to chemotherapy in osteosarcoma and future perspectives.Cancer drug resistance (Alhambra, Calif.) · 2022Review
- Article
- Acid Microenvironment in Bone Sarcomas.Cancers · 2021Review
- A Quantitative Pharmacology Model of Exosome-Mediated Drug Efflux and Perturbation-Induced Synergy.Pharmaceutics · 2021Article
- Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Current therapy of osteosarcoma (OS), the most common primary bone malignancy, is based on a combination of surgery and chemotherapy. Multidrug resistance mediated by P-glycoprotein (P-gp) overexpression has been previously associated with treatment failure and progression of OS, although other mechanisms may also play a role. We considered the typical acidic extracellular pH (pHe) of sarcomas, and found that doxorubicin (DXR) cytotoxicity is reduced in P-gp negative OS cells cultured at pHe 6.5 compared to standard 7.4. Short-time (24-48 hours) exposure to low pHe significantly increased the number and acidity of lysosomes, and the combination of DXR with omeprazole, a proton pump inhibitor targeting lysosomal acidity, significantly enhanced DXR cytotoxicity. In OS xenografts, the combination treatment of DXR and omeprazole significantly reduced tumor volume and body weight loss. The impaired toxicity of DXR at low pHe was not associated with increased autophagy or lysosomal acidification, but rather, as shown by SNARF staining, with a reversal of the pH gradient at the plasma membrane (ΔpHcm), eventually leading to a reduced DXR intracellular accumulation. Finally, the reversal of ΔpHcm in OS cells promoted resistance not only to DXR, but also to cisplatin and methotrexate, and, to a lesser extent, to vincristine. Altogether, our findings show that, in OS cells, short-term acidosis induces resistance to different chemotherapeutic drugs by a reversal of ΔpHcm, suggesting that buffer therapies or regimens including proton pump inhibitors in combination to low concentrations of conventional anticancer agents may offer novel solutions to overcome drug resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.