Resistance mechanisms of cancer cells to the novel vacuolar H+-ATPase inhibitor archazolid B

Publication type:
Journal article
Metadata:
Autoren
  • Rebecca Hamm
  • Yoshikazu Sugimoto
  • Heinrich Steinmetz
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000342411500011&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s10637-014-0134-1
eISSN
1573-0646
Externe Identifier
  • Clarivate Analytics Document Solution ID: AP9PK
  • PubMed Identifier: 25065443
ISSN
0167-6997
Ausgabe der Veröffentlichung
5
Zeitschrift
INVESTIGATIONAL NEW DRUGS
Schlüsselwörter
  • ABC transporters
  • Drug resistance
  • EGFR
  • Myxobacterial compounds
  • p53
Paginierung
893 - 903
Datum der Veröffentlichung
2014
Status
Published
Titel
Resistance mechanisms of cancer cells to the novel vacuolar H<SUP>+</SUP>-ATPase inhibitor archazolid B
Sub types
  • Article
Ausgabe der Zeitschrift
32

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Rebecca Hamm
  • Yoshikazu Sugimoto
  • Heinrich Steinmetz
  • Thomas Efferth
DOI
10.1007/s10637-014-0134-1
eISSN
1573-0646
ISSN
0167-6997
Ausgabe der Veröffentlichung
5
Zeitschrift
Investigational New Drugs
Sprache
en
Online publication date
2014
Paginierung
893 - 903
Datum der Veröffentlichung
2014
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s10637-014-0134-1
Datum der Datenerfassung
2023
Titel
Resistance mechanisms of cancer cells to the novel vacuolar H+-ATPase inhibitor archazolid B
Ausgabe der Zeitschrift
32

Data source: Crossref

Abstract
Resistance of cancer cells towards chemotherapy is the major cause of therapy failure. Hence, the evaluation of cellular defense mechanisms is essential in the establishment of new chemotherapeutics. Archazolid B, a novel vacuolar H(+)-ATPase inhibitor, displayed cytotoxicity in the low nanomolar range on a panel of different tumor cell lines. First, we investigated tumor-specific cytotoxicity of archazolid B by comparing cancer to non-cancer cells. Breast, liver and colon cancer cells displayed higher drug sensitivity than corresponding non-tumorous cells, whereas leukemia cell lines were as sensitive as peripheral mononuclear blood cells. Investigating classical drug resistance mechanisms, archazolid B was identified as a possible substrate of the ABC transporters ABCB1 (P-glycoprotein) and ABCG2 (BCRP), whereas collateral sensitivity was observed in ABCB5-expressing cells. Our results pointed to a possible binding competition of archazolid B with verapamil on P-glycoprotein. However, archazolid B did not reverse resistance towards doxorubicin indicating that it might be a substrate but not an inhibitor of P-glycoprotein mediated transport. Furthermore, the cytotoxicity of archazolid B was independent of the p53 status of the cell. Mechanisms of aquired resistance were investigated establishing an archazolid B-resistant MCF-7 cell line. Interestingly, drug resistance was not conferred by aberrant expression or DNA mutations of the gene encoding vacuolar H(+)-ATPase subunit c, the direct target of archazolids. Instead, long-term treatment with archazolid B led to a slight overexpression of ABCB1 and a significant overexpression of the epidermal growth factor receptor and reduced cell growth, all of which can be assumed to contribute to archazolid B resistance.
Addresses
  • Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
Autoren
  • Rebecca Hamm
  • Yoshikazu Sugimoto
  • Heinrich Steinmetz
  • Thomas Efferth
  • Thomas Efferth
DOI
10.1007/s10637-014-0134-1
eISSN
1573-0646
Externe Identifier
  • PubMed Identifier: 25065443
Open access
false
ISSN
0167-6997
Ausgabe der Veröffentlichung
5
Zeitschrift
Investigational new drugs
Schlüsselwörter
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • Macrolides
  • Thiazoles
  • Vacuolar Proton-Translocating ATPases
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Sequence Analysis, DNA
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Drug Resistance, Neoplasm
  • Tumor Suppressor Protein p53
  • Molecular Docking Simulation
  • ErbB Receptors
Sprache
eng
Medium
Print-Electronic
Online publication date
2014
Paginierung
893 - 903
Datum der Veröffentlichung
2014
Status
Published
Datum der Datenerfassung
2014
Titel
Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
32

Data source: Europe PubMed Central

Abstract
Resistance of cancer cells towards chemotherapy is the major cause of therapy failure. Hence, the evaluation of cellular defense mechanisms is essential in the establishment of new chemotherapeutics. Archazolid B, a novel vacuolar H(+)-ATPase inhibitor, displayed cytotoxicity in the low nanomolar range on a panel of different tumor cell lines. First, we investigated tumor-specific cytotoxicity of archazolid B by comparing cancer to non-cancer cells. Breast, liver and colon cancer cells displayed higher drug sensitivity than corresponding non-tumorous cells, whereas leukemia cell lines were as sensitive as peripheral mononuclear blood cells. Investigating classical drug resistance mechanisms, archazolid B was identified as a possible substrate of the ABC transporters ABCB1 (P-glycoprotein) and ABCG2 (BCRP), whereas collateral sensitivity was observed in ABCB5-expressing cells. Our results pointed to a possible binding competition of archazolid B with verapamil on P-glycoprotein. However, archazolid B did not reverse resistance towards doxorubicin indicating that it might be a substrate but not an inhibitor of P-glycoprotein mediated transport. Furthermore, the cytotoxicity of archazolid B was independent of the p53 status of the cell. Mechanisms of aquired resistance were investigated establishing an archazolid B-resistant MCF-7 cell line. Interestingly, drug resistance was not conferred by aberrant expression or DNA mutations of the gene encoding vacuolar H(+)-ATPase subunit c, the direct target of archazolids. Instead, long-term treatment with archazolid B led to a slight overexpression of ABCB1 and a significant overexpression of the epidermal growth factor receptor and reduced cell growth, all of which can be assumed to contribute to archazolid B resistance.
Date of acceptance
2014
Autoren
  • Rebecca Hamm
  • Yoshikazu Sugimoto
  • Heinrich Steinmetz
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/25065443
DOI
10.1007/s10637-014-0134-1
eISSN
1573-0646
Ausgabe der Veröffentlichung
5
Zeitschrift
Invest New Drugs
Schlüsselwörter
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Drug Resistance, Neoplasm
  • ErbB Receptors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrolides
  • Molecular Docking Simulation
  • Sequence Analysis, DNA
  • Thiazoles
  • Tumor Suppressor Protein p53
  • Vacuolar Proton-Translocating ATPases
Sprache
eng
Country
United States
Paginierung
893 - 903
Datum der Veröffentlichung
2014
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2015
Titel
Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
32

Data source: PubMed

Beziehungen:
Property of

Tools