Hypoxia‐Induced Acidification Causes Mitoxantrone Resistance Not Mediated by Drug Transporters in Human Breast Cancer Cells

Hypoxia has clinically been associated with resistance to chemotherapy. The aim of this study was to investigate whether hypoxia induces resistance to doxorubicin and mitoxantrone, two common drugs in cancer treatment, in MCF‐7 breast cancer cells, and SW1573 non‐small lung cancer cells. In addition, the role of drug transporters P‐gp, BCRP and MRP1 was analysed. Hypoxia induced resistance in MCF‐7 cells to mitoxantrone shifted the IC50 value from 0.09 μM (±0.01) to 0.54 μM (±0.06) under hypoxia, whereas survival of MCF‐7 and SW1573 cells in the presence of doxorubicin was not altered. Accumulation of mitoxantrone and daunorubicin, a doxorubicin fluorescent homologue, appeared to be 5.3 and 3.2 times lower in MCF‐7 cells, respectively. Cytotoxicity assays showed no increased functionality of the drug transporters P‐gp, BCRP and MRP1 under hypoxia. In addition, protein levels of these drug transporters were not changed. Medium of the MCF‐7 cells became more acidic under hypoxia thereby causing a decreased uptake of mitoxantrone. Hypoxia induces mitoxantrone resistance in MCF‐7 cells not mediated by the three major MDR transporters. Hypoxia‐induced acidification may cause this resistance by decreased cellular uptake together with a lowered cytotoxicity due to pH‐dependent topoisomerase type II activity.

• Publication year

  2005

• Venue

  Cellular Oncology

• Publication date

  2005-02-28

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1155/2005/236045PMID 15750206PMCID 4617579
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular tumor spheroids by hypoxia‐inducible factor‐1 and reactive oxygen species

  2003cited by this paper
• Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

  2003cited by this paper
• Prognostic significance of tumor oxygenation in humans.

  2003cited by this paper
• Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

  2003cited by this paper
• Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro.

  2003cited by this paper
• Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.

  2002influential reference
• Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C.

  2002cited by this paper
• Peptide transport by the multidrug resistance protein MRP1.

  2001cited by this paper
• Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

  2001cited by this paper
• The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics.

  2001cited by this paper
• Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues.

  2001cited by this paper
• Specific detection of multidrug resistance proteins MRP1, MRP2, MRP3, MRP5, and MDR3 P-glycoprotein with a panel of monoclonal antibodies.

  2000cited by this paper
• pH and drug resistance in tumors.

  2000cited by this paper
• The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture.

  1999cited by this paper
• Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines.

  1999cited by this paper
• Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.

  1998cited by this paper
• Topoisomerase II activities in AML and their correlation with cellular sensitivity to anthracyclines and epipodophyllotoxines.

  1996cited by this paper
• Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours

  1996cited by this paper
• Acid-catalyzed oxidation of the anticancer agent mitoxantrone by nitrite ions.

  1996cited by this paper
• Topoisomerase II activities in AML blasts and their correlation with cellular sensitivity to anthracyclines and epipodophyllotoxines.

  1996cited by this paper
• Hypoxia and drug resistance

  1994cited by this paper
• Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia.

  1993cited by this paper
• Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

  1991influential reference
• Mechanisms of drug resistance in breast cancer.

  1990cited by this paper
• Protection of cultured malignant cells from mitoxantrone cytotoxicity by low extracellular pH: a possible mechanism for chemoresistance in vivo.

  1990cited by this paper
• Monoclonal antibody JSB‐1 detects a highly conserved epitope on the P‐glycoprotein associated with multi‐drug‐resistance

  1988cited by this paper
• THE METABOLISM OF TUMORS IN THE BODY

  1927cited by this paper

• Role of EMT in drug resistance of breast cancer: molecular mechanisms and therapeutic strategies

  2025cites this paper
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  2024cites this paper
• Spatial transcriptomics in breast cancer reveals tumour microenvironment-driven drug responses and clonal therapeutic heterogeneity

  2024cites this paper
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  2023cites this paper
• A comprehensive review on the composition, biogenesis, purification, and multifunctional role of exosome as delivery vehicles for cancer therapy.

  2023cites this paper
• Oxidative Stress

  2022cites this paper
• Cathepsin G-Induced Cell Aggregation of Breast Cancer MCF-7 Decreases Doxorubicin Sensitivity in a Hypoxia-Inducible Factor-Independent Mechanism.

  2022cites this paper
• Isovitexin Suppresses Stemness of Lung Cancer Stem-Like Cells through Blockage of MnSOD/CaMKII/AMPK Signaling and Glycolysis Inhibition

  2021cites this paper
• Oxidative Stress

  2021cites this paper
• Glycolysis-induced drug resistance in tumors—A response to danger signals?

  2021cites this paper
• Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway

  2020cites this paper
• Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance.

  2020cites this paper
• Acidity is one of the main mechanism for hypoxia triggering chemoresistance to mitoxanthrone (MX) in the human breast cancer MCF-7 cell line

  2019cites this paper
• Epigallocatechin-3-gallate-induced vascular normalization in A549-cell xenograft-bearing nude mice: therapeutic efficacy in combination with chemotherapy

  2019cites this paper
• Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review

  2019cites this paper
• The Clinical Impact of Hypoxia in Head and Neck Squamous Cell Carcinoma

  2018cites this paper
• Conditioned medium mimicking the tumor microenvironment augments chemotherapeutic resistance via ataxia‑telangiectasia mutated and nuclear factor‑κB pathways in gastric cancer cells.

  2018cites this paper
• 6 Anticancer Drug Metabolism : Chemotherapy Resistance and New Therapeutic Approaches

  2018cites this paper
• Using LC–MS/MS-based targeted proteomics to monitor the pattern of ABC transporters expression in the development of drug resistance

  2018cites this paper
• Metastasis-Associated Protein 1 Deficiency Results in Compromised Pulmonary Alveolar Capillary Angiogenesis in Mice

  2017cites this paper
• Upregulation of ABCG2 via the PI3K-Akt pathway contributes to acidic microenvironment-induced cisplatin resistance in A549 and LTEP-a-2 lung cancer cells.

  2016cites this paper
• Cancer stem cell metabolism: a potential target for cancer therapy

  2016cites this paper
• Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression.

  2016cites this paper
• The anticancer agent ellipticine binds to glycosaminoglycans at mildly acidic pH characteristic of the extracellular matrix of tumor tissues

  2016cites this paper
• Inhalational Anesthetic Agents and Their Effects on Cancer Cell Biology

  2015cites this paper
• Inhibitory effects of indirubin derivative PHII-7 on invasion and migration in metastatic cancer.

  2015cites this paper
• Role of hypoxia-inducible factor-1α, carbonic anhydrase-IX, glucose transporter-1 and vascular endothelial growth factor associated with lymph node metastasis and recurrence in patients with locally advanced cervical cancer

  2015cites this paper
• Gene expression alterations in chronic hypoxic MCF7 breast cancer cell line.

  2014cites this paper
• Role of stromal fibroblasts in prostate carcinoma progression and metabolic reprogramming of cancer cells

  2014cites this paper
• Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination

  2014cites this paper
• Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2.

  2013cites this paper
• Targeting cellular metabolism to improve cancer therapeutics

  2013cites this paper
• Molecular imaging with a fluorescent antibody targeting carbonic anhydrase IX can successfully detect hypoxic ductal carcinoma in situ of the breast

  2013cites this paper
• Expression of the RNA Helicase DDX3 and the Hypoxia Response in Breast Cancer

  2013cites this paper
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  2012cites this paper
• Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

  2012cites this paper
• Topics on Drug Metabolism

  2012cites this paper
• Killing Hypoxic Cell Populations in a 3D Tumor Model with EtNBS-PDT

  2011cites this paper
• Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase

  2011cites this paper
• Subcellular FIH-1 expression patterns in invasive breast cancer in relation to HIF-1α expression

  2011cites this paper
• Pronounced tumour regression after radiotherapy is associated with negative/weak glucose transporter-1 expression in rectal cancer.

  2011cites this paper
• Insulin Receptor Substrate-2 (IRS-2): A Novel Hypoxia-Responsive Gene in Breast Cancer: A Dissertation

  2011cites this paper
• Redox environment and its meaning for breast cancer cells fate.

  2011cites this paper
• EtNBS and EtNBS-COOH PDT efficacy in ovarian cancer cells

  2011cites this paper
• The role of hypoxia inducible factor-1alpha in gynecological cancer.

  2011cites this paper
• Necrosis related HIF-1α expression predicts prognosis in patients with endometrioid endometrial carcinoma

  2010cites this paper
• A theoretical quantitative model for evolution of cancer chemotherapy resistance

  2010cites this paper
• Researchquantitative model for evolution of cancer chemotherapy resistance

  2010cites this paper
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  2010cites this paper
• Mathematical Oncology Adaptive Therapy

  2009cites this paper
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  2009cites this paper
• Adaptive therapy.

  2009cites this paper
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  2008cites this paper
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  2008cites this paper
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  2007cites this paper
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  2007cites this paper
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• Success Predictors of Adjuvant Chemotherapy in Node-Negative Breast Cancer Patients Under 55 years1

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• Identification by phage display of single-domain antibody fragments specific for the ODD domain in hypoxia-inducible factor 1alpha

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• Measuring response to chemotherapy in locally advanced breast cancer: methodological considerations

  2004cites this paper