Molecular docking and pharmacogenomics of Vinca alkaloids and their monomeric precursors, vindoline and catharanthine
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Serkan Sertel
- Yujie Fu
- Yuangang Zu
- Blanka Rebacz
- Badireenath Konkimalla
- Peter K Plinkert
- Alwin Kraemer
- Juerg Gertsch
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000287996900004&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.bcp.2010.12.026
- eISSN
- 1873-2968
- Externe Identifier
- Clarivate Analytics Document Solution ID: 730AX
- PubMed Identifier: 21219884
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- BIOCHEMICAL PHARMACOLOGY
- Schlüsselwörter
- Centrosomal clustering
- Molecular docking
- Multidrug resistance
- Pharmacogenomics
- Vinca alkaloids
- Paginierung
- 723 - 735
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Titel
- Molecular docking and pharmacogenomics of <i>Vinca</i> alkaloids and their monomeric precursors, vindoline and catharanthine
- Sub types
- Article
- Ausgabe der Zeitschrift
- 81
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Serkan Sertel
- Yujie Fu
- Yuangang Zu
- Blanka Rebacz
- Badireenath Konkimalla
- Peter K Plinkert
- Alwin Krämer
- Jürg Gertsch
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2010.12.026
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Biochemical Pharmacology
- Sprache
- en
- Paginierung
- 723 - 735
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.bcp.2010.12.026
- Datum der Datenerfassung
- 2018
- Titel
- Molecular docking and pharmacogenomics of Vinca alkaloids and their monomeric precursors, vindoline and catharanthine
- Ausgabe der Zeitschrift
- 81
Data source: Crossref
- Abstract
- Vinblastine and vincristine are dimeric indole alkaloids derived from Catharanthus roseus (formerly: Vinca rosea). Their monomeric precursor molecules are vindoline and catharanthine. While vinblastine and vincristine are well-known mitotic spindle poisons, not much is known about vindoline and catharanthine. Vindoline and catharanthine showed weak cytotoxicity, while vinblastine, vincristine, and the semisynthetic vindesine and vinorelbine revealed high cytotoxicity towards cancer cells. This may reflect a general biological principle of poisonous plants. Highly toxic compounds are not only active towards predators, but also towards plant tissues. Hence, plants need mechanisms to protect themselves from their own poisons. One evolutionary strategy to solve this problem is to generate less toxic precursors, which are dimerized to toxic end products when needed. As shown by in silico molecular docking and biochemical approaches, vinblastine, vincristine and vinorelbine bound with high affinity to α/β-tubulin and inhibited tubulin polymerization, whereas the effects of vindoline and catharanthine were weak. Similarly, vinblastine produced high fractions of mono- and multipolar mitotic spindles, while vindoline and catharanthine did only weakly affect bipolar mitotic spindle formation. Here, we show that vinblastine contributes to cell death by interference with spindle polarity. P-glycoprotein-overexpressing multidrug-resistant CEM/VCR1000 cells were highly resistant towards vincristine and cross-resistant to vinblastine, vindesine, and vinorelbine, but not or only weakly cross-resistant to vindoline and catharanthine. In addition to tubulin as primary target, microarray-based mRNA signatures of responsiveness of these compounds have been identified by COMPARE and signaling pathway profiling.
- Addresses
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.
- Autoren
- Serkan Sertel
- Yujie Fu
- Yuangang Zu
- Blanka Rebacz
- Badireenath Konkimalla
- Peter K Plinkert
- Alwin Krämer
- Jürg Gertsch
- Thomas Efferth
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2010.12.026
- eISSN
- 1873-2968
- Externe Identifier
- PubMed Identifier: 21219884
- Open access
- false
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Biochemical pharmacology
- Schlüsselwörter
- Cell Line, Tumor
- Animals
- Swine
- Humans
- Catharanthus
- Vinca Alkaloids
- Vinblastine
- Multidrug Resistance-Associated Proteins
- Drug Delivery Systems
- Pharmacogenetics
- Cell Death
- Protein Binding
- Dose-Response Relationship, Drug
- Tubulin Modulators
- Spindle Apparatus
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2011
- Paginierung
- 723 - 735
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Datum der Datenerfassung
- 2011
- Titel
- Molecular docking and pharmacogenomics of vinca alkaloids and their monomeric precursors, vindoline and catharanthine.
- Sub types
- Comparative Study
- Journal Article
- Ausgabe der Zeitschrift
- 81
Data source: Europe PubMed Central
- Abstract
- Vinblastine and vincristine are dimeric indole alkaloids derived from Catharanthus roseus (formerly: Vinca rosea). Their monomeric precursor molecules are vindoline and catharanthine. While vinblastine and vincristine are well-known mitotic spindle poisons, not much is known about vindoline and catharanthine. Vindoline and catharanthine showed weak cytotoxicity, while vinblastine, vincristine, and the semisynthetic vindesine and vinorelbine revealed high cytotoxicity towards cancer cells. This may reflect a general biological principle of poisonous plants. Highly toxic compounds are not only active towards predators, but also towards plant tissues. Hence, plants need mechanisms to protect themselves from their own poisons. One evolutionary strategy to solve this problem is to generate less toxic precursors, which are dimerized to toxic end products when needed. As shown by in silico molecular docking and biochemical approaches, vinblastine, vincristine and vinorelbine bound with high affinity to α/β-tubulin and inhibited tubulin polymerization, whereas the effects of vindoline and catharanthine were weak. Similarly, vinblastine produced high fractions of mono- and multipolar mitotic spindles, while vindoline and catharanthine did only weakly affect bipolar mitotic spindle formation. Here, we show that vinblastine contributes to cell death by interference with spindle polarity. P-glycoprotein-overexpressing multidrug-resistant CEM/VCR1000 cells were highly resistant towards vincristine and cross-resistant to vinblastine, vindesine, and vinorelbine, but not or only weakly cross-resistant to vindoline and catharanthine. In addition to tubulin as primary target, microarray-based mRNA signatures of responsiveness of these compounds have been identified by COMPARE and signaling pathway profiling.
- Date of acceptance
- 2010
- Autoren
- Serkan Sertel
- Yujie Fu
- Yuangang Zu
- Blanka Rebacz
- Badireenath Konkimalla
- Peter K Plinkert
- Alwin Krämer
- Jürg Gertsch
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/21219884
- DOI
- 10.1016/j.bcp.2010.12.026
- eISSN
- 1873-2968
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Biochem Pharmacol
- Schlüsselwörter
- Animals
- Catharanthus
- Cell Death
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Drug Delivery Systems
- Humans
- Multidrug Resistance-Associated Proteins
- Pharmacogenetics
- Protein Binding
- Spindle Apparatus
- Swine
- Tubulin Modulators
- Vinblastine
- Vinca Alkaloids
- Sprache
- eng
- Country
- England
- Paginierung
- 723 - 735
- PII
- S0006-2952(11)00013-X
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2011
- Titel
- Molecular docking and pharmacogenomics of vinca alkaloids and their monomeric precursors, vindoline and catharanthine.
- Sub types
- Comparative Study
- Journal Article
- Ausgabe der Zeitschrift
- 81
Data source: PubMed
- Beziehungen:
- Property of