Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

Abstract

Cancer drug resistance remains a major obstacle in clinical oncology. As most anticancer drugs are of natural origin, we investigated the anticancer potential of a standardized cold-water leaf extract from Nerium oleander L., termed Breastin. The phytochemical characterization by nuclear magnetic resonance spectroscopy (NMR) and low- and high-resolution mass spectrometry revealed several monoglycosidic cardenolides as major constituents (adynerin, neritaloside, odoroside A, odoroside H, oleandrin, and vanderoside). Breastin inhibited the growth of 14 cell lines from hematopoietic tumors and 5 of 6 carcinomas. Remarkably, the cellular responsiveness of odoroside H and neritaloside was not correlated with all other classical drug resistance mechanisms, i.e., ATP-binding cassette transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS), tumor suppressors (TP53, WT1), and others (GSTP1, HSP90, proliferation rate), in 59 tumor cell lines of the National Cancer Institute (NCI, USA), indicating that Breastin may indeed bypass drug resistance. COMPARE analyses with 153 anticancer agents in 74 tumor cell lines of the Oncotest panel revealed frequent correlations of Breastin with mitosis-inhibiting drugs. Using tubulin-GFP-transfected U2OS cells and confocal microscopy, it was found that the microtubule-disturbing effect of Breastin was comparable to that of the tubulin-depolymerizing drug paclitaxel. This result was verified by a tubulin polymerization assay in vitro and molecular docking in silico. Proteome profiling of 3171 proteins in the NCI panel revealed protein subsets whose expression significantly correlated with cellular responsiveness to odoroside H and neritaloside, indicating that protein expression profiles can be identified to predict the sensitivity or resistance of tumor cells to Breastin constituents. Breastin moderately inhibited breast cancer xenograft tumors in vivo. Remarkably, in contrast to what was observed with paclitaxel monotherapy, the combination of paclitaxel and Breastin prevented tumor relapse, indicating Breastin’s potential for drug combination regimens.

Autoren

Luay J Rashan
Nadire Özenver
Joelle C Boulos
Mona Dawood
Wynand P Roos
Katrin Franke
Ioannis Papasotiriou
Ludger A Wessjohann
Heinz-Herbert Fiebig
Thomas Efferth

DOI

10.3390/molecules28041871

eISSN

1420-3049

Ausgabe der Veröffentlichung

4

Zeitschrift

Molecules

Sprache

en

Online publication date

2023

Paginierung

1871 - 1871

Status

Published online

Herausgeber

MDPI AG

Herausgeber URL

http://dx.doi.org/10.3390/molecules28041871

Datum der Datenerfassung

2023

Titel

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

Ausgabe der Zeitschrift

28

Data source: Crossref

Abstract

Cancer drug resistance remains a major obstacle in clinical oncology. As most anticancer drugs are of natural origin, we investigated the anticancer potential of a standardized cold-water leaf extract from <i>Nerium oleander</i> L., termed Breastin. The phytochemical characterization by nuclear magnetic resonance spectroscopy (NMR) and low- and high-resolution mass spectrometry revealed several monoglycosidic cardenolides as major constituents (adynerin, neritaloside, odoroside A, odoroside H, oleandrin, and vanderoside). Breastin inhibited the growth of 14 cell lines from hematopoietic tumors and 5 of 6 carcinomas. Remarkably, the cellular responsiveness of odoroside H and neritaloside was not correlated with all other classical drug resistance mechanisms, i.e., ATP-binding cassette transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS), tumor suppressors (TP53, WT1), and others (GSTP1, HSP90, proliferation rate), in 59 tumor cell lines of the National Cancer Institute (NCI, USA), indicating that Breastin may indeed bypass drug resistance. COMPARE analyses with 153 anticancer agents in 74 tumor cell lines of the Oncotest panel revealed frequent correlations of Breastin with mitosis-inhibiting drugs. Using tubulin-GFP-transfected U2OS cells and confocal microscopy, it was found that the microtubule-disturbing effect of Breastin was comparable to that of the tubulin-depolymerizing drug paclitaxel. This result was verified by a tubulin polymerization assay in vitro and molecular docking in silico. Proteome profiling of 3171 proteins in the NCI panel revealed protein subsets whose expression significantly correlated with cellular responsiveness to odoroside H and neritaloside, indicating that protein expression profiles can be identified to predict the sensitivity or resistance of tumor cells to Breastin constituents. Breastin moderately inhibited breast cancer xenograft tumors in vivo. Remarkably, in contrast to what was observed with paclitaxel monotherapy, the combination of paclitaxel and Breastin prevented tumor relapse, indicating Breastin's potential for drug combination regimens.

Addresses

Frankincense Biodiversity Unit, Research Center, Dhofar University, Salalah 211, Oman.

Autoren

Luay J Rashan
Nadire Özenver
Joelle C Boulos
Mona Dawood
Wynand P Roos
Katrin Franke
Ioannis Papasotiriou
Ludger A Wessjohann
Heinz-Herbert Fiebig
Thomas Efferth

DOI

10.3390/molecules28041871

eISSN

1420-3049

Externe Identifier

PubMed Identifier: 36838857
PubMed Central ID: PMC9960564

Open access

true

ISSN

1420-3049

Ausgabe der Veröffentlichung

4

Zeitschrift

Molecules (Basel, Switzerland)

Schlüsselwörter

Cell Line, Tumor
Animals
Humans
Nerium
Neoplasms
Paclitaxel
Tubulin
Plant Extracts
Antineoplastic Agents
Molecular Docking Simulation

Sprache

eng

Medium

Electronic

Online publication date

2023

Open access status

Open Access

Paginierung

1871

Datum der Veröffentlichung

2023

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2023

Titel

Molecular Modes of Action of an Aqueous <i>Nerium oleander</i> Extract in Cancer Cells In Vitro and In Vivo.

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

28

Files

https://www.mdpi.com/1420-3049/28/4/1871/pdf?version=1676627653 https://europepmc.org/articles/PMC9960564?pdf=render

Data source: Europe PubMed Central

Abstract

Cancer drug resistance remains a major obstacle in clinical oncology. As most anticancer drugs are of natural origin, we investigated the anticancer potential of a standardized cold-water leaf extract from Nerium oleander L., termed Breastin. The phytochemical characterization by nuclear magnetic resonance spectroscopy (NMR) and low- and high-resolution mass spectrometry revealed several monoglycosidic cardenolides as major constituents (adynerin, neritaloside, odoroside A, odoroside H, oleandrin, and vanderoside). Breastin inhibited the growth of 14 cell lines from hematopoietic tumors and 5 of 6 carcinomas. Remarkably, the cellular responsiveness of odoroside H and neritaloside was not correlated with all other classical drug resistance mechanisms, i.e., ATP-binding cassette transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS), tumor suppressors (TP53, WT1), and others (GSTP1, HSP90, proliferation rate), in 59 tumor cell lines of the National Cancer Institute (NCI, USA), indicating that Breastin may indeed bypass drug resistance. COMPARE analyses with 153 anticancer agents in 74 tumor cell lines of the Oncotest panel revealed frequent correlations of Breastin with mitosis-inhibiting drugs. Using tubulin-GFP-transfected U2OS cells and confocal microscopy, it was found that the microtubule-disturbing effect of Breastin was comparable to that of the tubulin-depolymerizing drug paclitaxel. This result was verified by a tubulin polymerization assay in vitro and molecular docking in silico. Proteome profiling of 3171 proteins in the NCI panel revealed protein subsets whose expression significantly correlated with cellular responsiveness to odoroside H and neritaloside, indicating that protein expression profiles can be identified to predict the sensitivity or resistance of tumor cells to Breastin constituents. Breastin moderately inhibited breast cancer xenograft tumors in vivo. Remarkably, in contrast to what was observed with paclitaxel monotherapy, the combination of paclitaxel and Breastin prevented tumor relapse, indicating Breastin's potential for drug combination regimens.

Date of acceptance

2023

Autoren

Luay J Rashan
Nadire Özenver
Joelle C Boulos
Mona Dawood
Wynand P Roos
Katrin Franke
Ioannis Papasotiriou
Ludger A Wessjohann
Heinz-Herbert Fiebig
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/36838857

DOI

10.3390/molecules28041871

eISSN

1420-3049

Externe Identifier

PubMed Central ID: PMC9960564

Ausgabe der Veröffentlichung

4

Zeitschrift

Molecules

Schlüsselwörter

Apocynaceae
cardenolides
cardiac glycoside
mitotic spindle poison
phytotherapy
Humans
Antineoplastic Agents
Cell Line, Tumor
Molecular Docking Simulation
Neoplasms
Nerium
Paclitaxel
Plant Extracts
Tubulin
Animals

Sprache

eng

Country

Switzerland

PII

molecules28041871

Datum der Veröffentlichung

2023

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2023

Titel

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo.

Sub types

Journal Article

Ausgabe der Zeitschrift

28

Data source: PubMed

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

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