Stein, Andreas, Thomopoulou, Persefoni Hilken Nee, Frias, Corazon, Hopff, Sina M., Varela, Paloma ORCID: 0000-0001-5078-7102, Wilke, Nicola ORCID: 0000-0003-2832-7374, Mariappan, Arul, Neudoerfl, Jorg-Martin, Fedorov, Alexey Yu, Gopalakrishnan, Jay ORCID: 0000-0001-5907-3982, Gigant, Benoit ORCID: 0000-0002-5946-6759, Prokop, Aram and Schmalz, Hans-Gunther (2022). B-nor-methylene Colchicinoid PT-100 Selectively Induces Apoptosis in Multidrug-Resistant Human Cancer Cells via an Intrinsic Pathway in a Caspase-Independent Manner. ACS Omega, 7 (3). S. 2591 - 2604. WASHINGTON: AMER CHEMICAL SOC. ISSN 2470-1343

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Abstract

Colchicine, the main active alkaloid from Colchicum autumnale L., is a potent tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising biological activities. In particular, the previously undescribed colchicinoid PT-100, a B-ring contracted 6-exo-methylene colchicinoid, exhibits extraordinarily high antiproliferative and apoptosis-inducing effects on various types of cancer cell lines like acute lymphoblastic leukemia (Nalm6), acute myeloid leukemia (HL-60), Burkitt-like lymphoma (BJAB), human melanoma (MelHO), and human breast adenocarcinoma (MCF7) cells at low nanomolar concentrations. Apoptosis induction proved to be especially high in multidrug-resistant Nalm6-derived cancer cell lines, while healthy human leukocytes and hepatocytes were not affected by the concentration range studied. Furthermore, caspase-independent initiation of apoptosis via an intrinsic pathway was observed. PT-100 also shows strong synergistic effects in combination with vincristine on BJAB and Nalm6 cells. Cocrystallization of PT-100 with tubulin dimers revealed its (noncovalent) binding to the colchicine-binding site of beta-tubulin at the interface to the a-subunit. A pronounced effect of PT-100 on the cytoskeleton morphology was shown by fluorescence microscopy. While the reactivity of PT-100 as a weak Michael acceptor toward thiols was chemically proven, it remains unclear whether this contributes to the remarkable biological properties of this unusual colchicinoid.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stein, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomopoulou, Persefoni Hilken NeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frias, CorazonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopff, Sina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varela, PalomaUNSPECIFIEDorcid.org/0000-0001-5078-7102UNSPECIFIED
Wilke, NicolaUNSPECIFIEDorcid.org/0000-0003-2832-7374UNSPECIFIED
Mariappan, ArulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neudoerfl, Jorg-MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fedorov, Alexey YuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gopalakrishnan, JayUNSPECIFIEDorcid.org/0000-0001-5907-3982UNSPECIFIED
Gigant, BenoitUNSPECIFIEDorcid.org/0000-0002-5946-6759UNSPECIFIED
Prokop, AramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmalz, Hans-GuntherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-687871
DOI: 10.1021/acsomega.1c04659
Journal or Publication Title: ACS Omega
Volume: 7
Number: 3
Page Range: S. 2591 - 2604
Date: 2022
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 2470-1343
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BIOLOGICAL EVALUATION; MECHANISM; DERIVATIVES; ANTICANCER; MANAGEMENT; LEUKEMIA; THERAPY; ONCOSIS; TUBULIN; DRUGSMultiple languages
Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68787

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