Nimbolide inhibits 2D and 3D prostate cancer cells migration, affects microtubules and angiogenesis and suppresses B-RAF/p.ERK-mediated in vivo tumor growth

Publication type:
Journal article
Metadata:
Autoren
  • Nuha Mahmoud
  • Mona Dawood
  • Qi Huang
  • Jerome PL Ng
  • Fang Ren
  • Vincent KW Wong
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000726377200001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.phymed.2021.153826
eISSN
1618-095X
Externe Identifier
  • Clarivate Analytics Document Solution ID: XI8TS
  • PubMed Identifier: 34775358
ISSN
0944-7113
Zeitschrift
PHYTOMEDICINE
Schlüsselwörter
  • Animal study
  • E-cadherin
  • Meliaceae
  • Three-dimensional spheroid
  • Tube-formation assay
  • Tubulin acetylation
Artikelnummer
ARTN 153826
Datum der Veröffentlichung
2022
Status
Published
Titel
Nimbolide inhibits 2D and 3D prostate cancer cells migration, affects microtubules and angiogenesis and suppresses B-RAF/p.ERK-mediated <i>in vivo</i> tumor growth
Sub types
  • Article
Ausgabe der Zeitschrift
94

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Nuha Mahmoud
  • Mona Dawood
  • Qi Huang
  • Jerome PL Ng
  • Fang Ren
  • Vincent KW Wong
  • Thomas Efferth
DOI
10.1016/j.phymed.2021.153826
ISSN
0944-7113
Zeitschrift
Phytomedicine
Sprache
en
Artikelnummer
153826
Paginierung
153826 - 153826
Datum der Veröffentlichung
2022
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.phymed.2021.153826
Datum der Datenerfassung
2023
Titel
Nimbolide inhibits 2D and 3D prostate cancer cells migration, affects microtubules and angiogenesis and suppresses B-RAF/p.ERK-mediated in vivo tumor growth
Ausgabe der Zeitschrift
94

Data source: Crossref

Abstract
<h4>Background</h4>Prostate cancer (PCa) is the most prominent malignancy among men worldwide. PCa cells have a high tendency to metastasize to various distant organs, and this activity is the main cause of PCa mortality. Nimbolide is a promising phytochemical constituent of neem Azadirachta indica (Meliaceae). Previous studies showed that nimbolide exhibited potent anticancer activity however, its role against PCa tumorigenesis has not been fully elucidated.<h4>Purpose</h4>Our work aims to explore the role of nimbolide in regulating the essential tumor-associated processes involved in the metastatic cascade in PCa cells.<h4>Study design</h4>Cytotoxicity assay, wound healing and spheroid invasion assays, western blotting, immunofluorescence, tube-formation assay, in vivo and immunohistochemistry.<h4>Methods</h4>The cytotoxicity of nimbolide towards PCa cell lines was assessed by resazurin assays. The cell mobility and migration of nimbolide-treated DU145 cells were determined by wound healing and spheroid invasion assays. Tubulin network was visualized using U2OS cells and DU145 cells. The effect of nimbolide on E-cadherin, β-catenin, acetylated α-tubulin and HDAC6 protein expressions levels were measured by Western blot. The potentiality of nimbolide to inhibit angiogenesis was revealed by HUVEC tube-formation assay. Nimbolide antitumor effect was studied in a syngeneic model of murine prostate cancer.<h4>Results</h4>The current study indicated that nimbolide negatively affected the migratory and invasive capacity of DU145 prostate cancer cells in 2D and three-dimensional (3D) spheroid cultures. Interestingly, nimbolide induced downregulation of E-cadherin without any influence on the expression level of β-catenin. Additionally, we demonstrated that nimbolide influenced the microtubule network which was supported by the upregulation of acetylated α-tubulin and the reduction in HDAC6 protein. Moreover, the inhibitory effect of nimbolide on angiogenesis was clearly observed in HUVEC tube formation assay. In vivo experiments revealed the significant suppression of PCa growth and targeting of the B-RAF/p.ERK signaling pathway by nimbolide.<h4>Conclusion</h4>Our results showed that nimbolide inhibited 2D and 3D prostate cancer cells migration and downregulated E-cadherin protein expression, a marker for metastatic chemoresistance and tumor recurrence. Nimbolide stabilized the microtubules, combated angiogenesis and suppressed B.RAF/ERK-mediated in vivo tumor growth. Nimbolide may be considered as potential therapeutic agent for metastatic and advanced PCa patients and merits further investigations.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany.
Autoren
  • Nuha Mahmoud
  • Mona Dawood
  • Qi Huang
  • Jerome PL Ng
  • Fang Ren
  • Vincent KW Wong
  • Thomas Efferth
DOI
10.1016/j.phymed.2021.153826
eISSN
1618-095X
Externe Identifier
  • PubMed Identifier: 34775358
Open access
false
ISSN
0944-7113
Zeitschrift
Phytomedicine : international journal of phytotherapy and phytopharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Microtubules
  • Animals
  • Humans
  • Mice
  • Prostatic Neoplasms
  • Limonins
  • Cell Proliferation
  • Male
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Paginierung
153826
Datum der Veröffentlichung
2022
Status
Published
Datum der Datenerfassung
2021
Titel
Nimbolide inhibits 2D and 3D prostate cancer cells migration, affects microtubules and angiogenesis and suppresses B-RAF/p.ERK-mediated in vivo tumor growth.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
94

Data source: Europe PubMed Central

Abstract
BACKGROUND: Prostate cancer (PCa) is the most prominent malignancy among men worldwide. PCa cells have a high tendency to metastasize to various distant organs, and this activity is the main cause of PCa mortality. Nimbolide is a promising phytochemical constituent of neem Azadirachta indica (Meliaceae). Previous studies showed that nimbolide exhibited potent anticancer activity however, its role against PCa tumorigenesis has not been fully elucidated. PURPOSE: Our work aims to explore the role of nimbolide in regulating the essential tumor-associated processes involved in the metastatic cascade in PCa cells. STUDY DESIGN: Cytotoxicity assay, wound healing and spheroid invasion assays, western blotting, immunofluorescence, tube-formation assay, in vivo and immunohistochemistry. METHODS: The cytotoxicity of nimbolide towards PCa cell lines was assessed by resazurin assays. The cell mobility and migration of nimbolide-treated DU145 cells were determined by wound healing and spheroid invasion assays. Tubulin network was visualized using U2OS cells and DU145 cells. The effect of nimbolide on E-cadherin, β-catenin, acetylated α-tubulin and HDAC6 protein expressions levels were measured by Western blot. The potentiality of nimbolide to inhibit angiogenesis was revealed by HUVEC tube-formation assay. Nimbolide antitumor effect was studied in a syngeneic model of murine prostate cancer. RESULTS: The current study indicated that nimbolide negatively affected the migratory and invasive capacity of DU145 prostate cancer cells in 2D and three-dimensional (3D) spheroid cultures. Interestingly, nimbolide induced downregulation of E-cadherin without any influence on the expression level of β-catenin. Additionally, we demonstrated that nimbolide influenced the microtubule network which was supported by the upregulation of acetylated α-tubulin and the reduction in HDAC6 protein. Moreover, the inhibitory effect of nimbolide on angiogenesis was clearly observed in HUVEC tube formation assay. In vivo experiments revealed the significant suppression of PCa growth and targeting of the B-RAF/p.ERK signaling pathway by nimbolide. CONCLUSION: Our results showed that nimbolide inhibited 2D and 3D prostate cancer cells migration and downregulated E-cadherin protein expression, a marker for metastatic chemoresistance and tumor recurrence. Nimbolide stabilized the microtubules, combated angiogenesis and suppressed B.RAF/ERK-mediated in vivo tumor growth. Nimbolide may be considered as potential therapeutic agent for metastatic and advanced PCa patients and merits further investigations.
Date of acceptance
2021
Autoren
  • Nuha Mahmoud
  • Mona Dawood
  • Qi Huang
  • Jerome PL Ng
  • Fang Ren
  • Vincent KW Wong
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/34775358
DOI
10.1016/j.phymed.2021.153826
eISSN
1618-095X
Zeitschrift
Phytomedicine
Schlüsselwörter
  • Animal study
  • E-cadherin
  • Meliaceae
  • Three-dimensional spheroid
  • Tube-formation assay
  • Tubulin acetylation
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Limonins
  • Male
  • Mice
  • Microtubules
  • Prostatic Neoplasms
Sprache
eng
Country
Germany
Paginierung
153826
PII
S0944-7113(21)00367-6
Datum der Veröffentlichung
2022
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Nimbolide inhibits 2D and 3D prostate cancer cells migration, affects microtubules and angiogenesis and suppresses B-RAF/p.ERK-mediated in vivo tumor growth.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
94

Data source: PubMed

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