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

Rebecca Hamm, Yoshikazu Sugimoto, Heinrich Steinmetz, Thomas Efferth

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)893-903
Number of pages11
JournalInvestigational New Drugs
Volume32
Issue number5
DOIs
Publication statusPublished - 2014 Oct 1

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Vacuolar Proton-Translocating ATPases
Neoplasms
P-Glycoprotein
Drug Resistance
archazolid B
Cell Line
ATP-Binding Cassette Transporters
MCF-7 Cells
Liver Neoplasms
Verapamil
Tumor Cell Line
Epidermal Growth Factor Receptor
Doxorubicin
Colonic Neoplasms
Blood Cells
Leukemia
Breast Neoplasms
Drug Therapy
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B. / Hamm, Rebecca; Sugimoto, Yoshikazu; Steinmetz, Heinrich; Efferth, Thomas.

In: Investigational New Drugs, Vol. 32, No. 5, 01.10.2014, p. 893-903.

Research output: Contribution to journalArticle

Hamm, Rebecca ; Sugimoto, Yoshikazu ; Steinmetz, Heinrich ; Efferth, Thomas. / Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B. In: Investigational New Drugs. 2014 ; Vol. 32, No. 5. pp. 893-903.
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