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9-benzylidene-naphtho[2,3-b]thiophen-4-ones and benzylidene-9(10H)-anthracenones as novel tubulin interacting agents with high apoptosis-inducing activity
Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany; Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, Canada.
Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
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2007 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 575, no 1-3, 34-45 p.Article in journal (Refereed) Published
Abstract [en]

Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time-dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis-inducing activity and therefore show promise for the development of novel chemotherapeutics.

Place, publisher, year, edition, pages
Elsevier, 2007. Vol. 575, no 1-3, 34-45 p.
Keyword [en]
Microtubule; Inhibition of tubulin polymerization; 9-Benzylidene-naphtho[2, 3-b]thiophen-4-ones; Benzylidene-9(10H)-anthracenones; Apoptosis; G2/M arrest
National Category
Cancer and Oncology Cell Biology Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-86932DOI: 10.1016/j.ejphar.2007.07.050ISI: 000250801100005PubMedID: 17707367OAI: oai:DiVA.org:liu-86932DiVA: diva2:583335
Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06

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Los, Marek Jan

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