B-nor-methylene Colchicinoid PT-100 Selectively Induces Apoptosis in Multidrug-Resistant Human Cancer Cells via an Intrinsic Pathway in a Caspase-Independent Manner - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue ACS Omega Année : 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

Andreas Stein
  • Fonction : Auteur
Corazon Frias
  • Fonction : Auteur
Sina M Hopff
  • Fonction : Auteur
Nicola Wilke
  • Fonction : Auteur
Arul Mariappan
  • Fonction : Auteur
Jörg-Martin Neudörfl
  • Fonction : Auteur
Alexey Yu Fedorov
Aram Prokop
  • Fonction : Auteur
Hans-Günther Schmalz
  • Fonction : Auteur

Résumé

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 Bring contracted 6-exomethylene 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 Nalm6derived 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 β-tubulin at the interface to the α-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.
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hal-03829931 , version 1 (26-10-2022)

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Andreas Stein, Persefoni Hilken Née Thomopoulou, Corazon Frias, Sina M Hopff, Paloma Varela, et al.. 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, 2022, 7 (3), pp.2591 - 2603. ⟨10.1021/acsomega.1c04659⟩. ⟨hal-03829931⟩
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