B-nor-methylene Colchicinoid PT-100 Selectively Induces Apoptosis in Multidrug-Resistant Human Cancer Cells via an Intrinsic Pathway in a Caspase-Independent Manner

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 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.

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

“…Based on the analysis of the protein-protein interaction network, the top 25 targets from 22-(4 py)-JA were related to NSCLC aggressiveness and found to participate in cancerassociated pathways. Apoptosis is a major mode of action of cancer therapies, and resistance to this programmed cell death facilitates long-lived cancer cells with an accumulation of gene mutations, contributing to uncontrolled cell growth, vascularization and tumor invasion [24,33]. We then focused on the apoptosis targets of 22-(4 py)-JA in NSCLC.…”

An organometallic analogue of combretastatin A-4 and its apoptosis-inducing effects on lymphoma, leukemia and other tumor cells in vitro

“…For this purpose, we incubated the vincristine- and daunorubicin-resistant cell lines Nalm-6/BeKa and Nalm-6/LiKa, respectively, with different concentrations of 3. Indeed, DNA fragmentation analysis showed that NAHO27 is also highly effective in inducing apoptosis in these resistant cell lines, which both show a co-resistance to anthracyclines (idarubicin, daunorubicin, doxorubicin, epirubicin), mitoxanthrone, fludarabine, vinca alkaloids (vincristine, vindesine, vinorelbine, vinblastine) and etoposide in vitro 25 ( Fig. 13A and B ).…”

Dihydroxyquingdainone Induces Apoptosis in Leukaemia and Lymphoma Cells via the Mitochondrial Pathway in a Bcl-2- and Caspase-3-Dependent Manner and Overcomes Resistance to Cytostatic Drugs In Vitro

“…This mechanism often results in multidrug resistance (MDR) [ 29 ], which has also been demonstrated for BeKa cells. BeKa cells show a co-resistance to anthracyclines (idarubicin, daunorubicin, doxorubicin, epirubicin), mitoxantrone, fludarabine, vinca alkaloids (vincristine, vindesine, vinorelbine, vinblastine) and etoposide in vitro [ 30 ].…”