Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

Autoren

Yasuhiro Tajima
Hiroshi Nakagawa
Ai Tamura
Onat Kadioglu
Kazuhiro Satake
Yuji Mitani
Hayato Murase
Luis Octavio Regasini
Vanderlan da Silva Bolzani
Toshihisa Ishikawa
Gert Fricker
Thomas Efferth

DOI

10.1016/j.phymed.2013.08.024

ISSN

0944-7113

Ausgabe der Veröffentlichung

3

Zeitschrift

Phytomedicine

Sprache

en

Paginierung

323 - 332

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.phymed.2013.08.024

Datum der Datenerfassung

2022

Titel

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

Ausgabe der Zeitschrift

21

Data source: Crossref

Abstract

The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibited some level of cytotoxicity against both CCRF-CEM and CEM/ADR5000 cells. In ATPase assays, three of the four guanidine alkaloids were found to stimulate the ATPase activity of ABCB1. Notably, nitensidine A was clearly found to stimulate the ATPase activity of ABCB1 as strongly as the control drug, verapamil. Furthermore, the cytotoxic effect of nitensidine A on CEM/ADR5000 cells was synergistically enhanced by verapamil. Nitensidine A inhibited the extrusion of calcein by ABCB1. In the present study, the possibility of interaction between ABCB1 and two synthetic nitensidine A analogs (nitensidine AT and AU) were examined to gain insight into the mechanism by which nitensidine A stimulates the ATPase activity of ABCB1. The ABCB1-dependent ATPase activity stimulated by nitensidine A was greatly reduced by substituting sulfur (S) or oxygen (O) for the imino nitrogen atom (N) in nitensidine A. Molecular docking studies on human ABCB1 showed that, guanidine alkaloids from P. nitens dock to the same binding pocket as verapamil. Nitensidine A and its analogs exhibit similar binding energies to verapamil. Taken together, this research clearly indicates that nitensidine A is a novel substrate for ABCB1. The present results also suggest that the number, binding site, and polymerization degree of the isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their stimulation of ABCB1's ATPase activity.

Addresses

Department of Applied Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan.

Autoren

Yasuhiro Tajima
Hiroshi Nakagawa
Ai Tamura
Onat Kadioglu
Kazuhiro Satake
Yuji Mitani
Hayato Murase
Luis Octavio Regasini
Vanderlan da Silva Bolzani
Toshihisa Ishikawa
Gert Fricker
Thomas Efferth
Thomas Efferth

DOI

10.1016/j.phymed.2013.08.024

eISSN

1618-095X

Externe Identifier

PubMed Identifier: 24135452

Funding acknowledgements

Deutsches Krebsforschungszentrum:
Ministry of Education, Culture, Sports, Science and Technology:
Chubu University: 24M01B
Fundação de Amparo à Pesquisa do Estado de São Paulo: 03/02176-7
Japan Society for the Promotion of Science: 24592822
Chubu University: 23IM04A

Open access

false

ISSN

0944-7113

Ausgabe der Veröffentlichung

3

Zeitschrift

Phytomedicine : international journal of phytotherapy and phytopharmacology

Schlüsselwörter

Cell Line, Tumor
Humans
Fabaceae
Leukemia, T-Cell
Guanidines
Verapamil
Monoterpenes
Fluoresceins
ATP-Binding Cassette Transporters
Plant Extracts
Antineoplastic Agents, Phytogenic
Phytotherapy
Drug Resistance, Multiple
Structure-Activity Relationship
Drug Resistance, Neoplasm
Adenosine Triphosphatases
Molecular Docking Simulation
ATP Binding Cassette Transporter, Subfamily B

Sprache

eng

Medium

Print-Electronic

Online publication date

2013

Paginierung

323 - 332

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2013

Titel

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

21

Data source: Europe PubMed Central

Abstract

The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibited some level of cytotoxicity against both CCRF-CEM and CEM/ADR5000 cells. In ATPase assays, three of the four guanidine alkaloids were found to stimulate the ATPase activity of ABCB1. Notably, nitensidine A was clearly found to stimulate the ATPase activity of ABCB1 as strongly as the control drug, verapamil. Furthermore, the cytotoxic effect of nitensidine A on CEM/ADR5000 cells was synergistically enhanced by verapamil. Nitensidine A inhibited the extrusion of calcein by ABCB1. In the present study, the possibility of interaction between ABCB1 and two synthetic nitensidine A analogs (nitensidine AT and AU) were examined to gain insight into the mechanism by which nitensidine A stimulates the ATPase activity of ABCB1. The ABCB1-dependent ATPase activity stimulated by nitensidine A was greatly reduced by substituting sulfur (S) or oxygen (O) for the imino nitrogen atom (N) in nitensidine A. Molecular docking studies on human ABCB1 showed that, guanidine alkaloids from P. nitens dock to the same binding pocket as verapamil. Nitensidine A and its analogs exhibit similar binding energies to verapamil. Taken together, this research clearly indicates that nitensidine A is a novel substrate for ABCB1. The present results also suggest that the number, binding site, and polymerization degree of the isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their stimulation of ABCB1's ATPase activity.

Date of acceptance

2013

Autoren

Yasuhiro Tajima
Hiroshi Nakagawa
Ai Tamura
Onat Kadioglu
Kazuhiro Satake
Yuji Mitani
Hayato Murase
Luis Octavio Regasini
Vanderlan da Silva Bolzani
Toshihisa Ishikawa
Gert Fricker
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/24135452

DOI

10.1016/j.phymed.2013.08.024

eISSN

1618-095X

Ausgabe der Veröffentlichung

3

Zeitschrift

Phytomedicine

Schlüsselwörter

ABCB1
ATP-binding cassette (ABC) transporter
Guanidine alkaloid
P-glycoprotein
Pterogyne nitens
ATP Binding Cassette Transporter, Subfamily B
ATP-Binding Cassette Transporters
Adenosine Triphosphatases
Antineoplastic Agents, Phytogenic
Cell Line, Tumor
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Fabaceae
Fluoresceins
Guanidines
Humans
Leukemia, T-Cell
Molecular Docking Simulation
Monoterpenes
Phytotherapy
Plant Extracts
Structure-Activity Relationship
Verapamil

Sprache

eng

Country

Germany

Paginierung

323 - 332

PII

S0944-7113(13)00327-9

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2014

Titel

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

21

Data source: PubMed

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

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