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Cited by 82Drug Transport and Resistance MechanismsUltrasound and Hyperthermia ApplicationsHeat shock proteins research

Regulation of the multidrug resistance transporter P-glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

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Wartenberg, Maria, Gronczynska, Sabina, Bekhite, Mohamed M., Saric, Tomo, Niedermeier, Wilhelm, Hescheler, Jürgen, Sauer, Heinrich·2005·International Journal of Cancer
DOI 10.1002/ijc.20596
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Abstract

Hyperthermia is an important component of many cancer treatment protocols. In our study the regulation of the multidrug resistance (MDR) transporter P‐glycoprotein by hyperthermia was studied in multicellular prostate tumor spheroids. Hyperthermia treatment of small (50–100 μm) tumor spheroids significantly increased P‐glycoprotein and mdr‐1 mRNA expression with a maximum effect at 42°C, whereas only moderate elevation of P‐glycoprotein was found in large (350–450 μm) tumor spheroids. Hyperthermia caused an elevation of intracellular reactive oxygen species (ROS). Inhibition of ROS generation with NADPH‐oxidase inhibitors diphenylen iodonium (DPI) and 4‐(2‐aminoethyl)benzenesulfonyl fluoride (AEBSF) abolished P‐glycoprotein expression but did not affect its transcript levels following heat treatment. This indicates that P‐glycoprotein levels are controlled by regulating its translation rate or stability. Hyperthermia incubation resulted in a differential activation of p38 mitogen‐activated protein kinase (MAPK), extracellular regulated kinase 1,2 (ERK1,2), and c‐jun N‐terminal kinase (JNK) immediately, 4 hr and 24 hr after treatment. Furthermore, upregulation of hypoxia‐inducible factor 1α (HIF‐1α) was observed. Elevation of HIF‐1α and P‐glycoprotein expression following hyperthermia treatment were abolished upon coadministration of the p38 inhibitor SB203580. In contrast the JNK inhibitor SP600125 and the ERK1,2 inhibitor UO126 resulted in increase of HIF‐1α and P‐glycoprotein in the control as well as the hyperthermia‐treated samples, indicating negative regulation of intrinsic HIF‐1α and P‐glycoprotein expression by ERK1,2 and JNK signaling cascades. In summary our data demonstrate that hyperthermia‐induced upregulation of P‐glycoprotein and HIF‐1α is mediated by activation of p38, whereas ERK1,2 and JNK are involved in repression of P‐glycoprotein and HIF‐1α under control conditions.

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  • The efficacy of chemotherapeutic agents that function through oxygen-dependent ROS generation-such as doxorubicin, cisplatin, and imexon-is markedly diminished in hypoxic regions due to insufficient oxygen availability.

    “For instance, the efficacy of chemotherapeutic agents that function through oxygen-dependent ROS generation—such as doxorubicin, cisplatin, and imexon—is markedly diminished in hypoxic regions due to insufficient oxygen availability [109,110,111,112].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [110]

    The 'Induction of P-glycoprotein expression and MDR phenotype by hyperthermia' section reports reduced doxorubicin efficacy after heat treatment, attributed to increased P-glycoprotein expression. Our copy does not say that insufficient oxygen in hypoxic regions diminishes the efficacy of doxorubicin, cisplatin, or imexon through reduced ROS generation (searched for those drugs, hypoxia, and oxygen availability). No page number was available in the indexed passages. (LLM, conf=0.76)

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Authors
Wartenberg, M., Gronczynska, S., Bekhite, M. M., Saric, T., Niedermeier, W., Hescheler, J., & Sauer, H.
Affiliations
  • University of Cologne (DE)
  • Justus-Liebig-Universität Gießen (DE)
Corresponding author
Sauer, Heinrich
ORCID
Venue
International Journal of Cancer
Publisher
Wiley
Published
2004-09-23
Volume
113
Issue
2
Pages
229-240
ISSN
  • 0020-7136 (ISSN-L)
  • 1097-0215
DOI
10.1002/ijc.20596
OpenAlex
W2078844125
Cited by
82
References
70
Citations by year
2026: 3 · 2025: 4 · 2024: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 4 · 2017: 2 · 2016: 2 · 2015: 5 · 2014: 6 · 2013: 4 · 2012: 6
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • International Journal of Cancer (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
P-glycoprotein, multidrug resistance, hyperthermia, reactive oxygen species, NADPH oxidase, p38 MAPK, ERK1/2, JNK, HIF-1α, heat shock
MeSH terms
DNA-Binding Proteins, Humans, Hyperthermia, Induced, Male, Nuclear Proteins, Prostatic Neoplasms, RNA, Messenger, Transcription Factors, Up-Regulation, Reactive Oxygen Species, Helix-Loop-Helix Motifs, Spheroids, Cellular, ATP Binding Cassette Transporter, Subfamily B, Member 1, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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