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

Rebecca Hamm, Yoshikazu Sugimoto, Heinrich Steinmetz, Thomas Efferth

研究成果: Article

5 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)893-903
ページ数11
ジャーナルInvestigational New Drugs
32
発行部数5
DOI
出版物ステータスPublished - 2014 10 1

Fingerprint

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)

これを引用

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

:: Investigational New Drugs, 巻 32, 番号 5, 01.10.2014, p. 893-903.

研究成果: Article

Hamm, Rebecca ; Sugimoto, Yoshikazu ; Steinmetz, Heinrich ; Efferth, Thomas. / Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B. :: Investigational New Drugs. 2014 ; 巻 32, 番号 5. pp. 893-903.
@article{e97340afb21a41d3b1bcd12c8984f0f0,
title = "Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B",
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.",
author = "Rebecca Hamm and Yoshikazu Sugimoto and Heinrich Steinmetz and Thomas Efferth",
year = "2014",
month = "10",
day = "1",
doi = "10.1007/s10637-014-0134-1",
language = "English",
volume = "32",
pages = "893--903",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "5",

}

TY - JOUR

T1 - Resistance mechanisms of cancer cells to the novel vacuolar H(+)-ATPase inhibitor archazolid B

AU - Hamm, Rebecca

AU - Sugimoto, Yoshikazu

AU - Steinmetz, Heinrich

AU - Efferth, Thomas

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84930745207&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930745207&partnerID=8YFLogxK

U2 - 10.1007/s10637-014-0134-1

DO - 10.1007/s10637-014-0134-1

M3 - Article

C2 - 25065443

AN - SCOPUS:84930745207

VL - 32

SP - 893

EP - 903

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 5

ER -