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

Abstract

Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted α-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 µmole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6/BeKa) with p-glycoprotein expression.

Discovery of the tryptanthrin‐derived indoloquinazoline as an anti‐breast cancer agent via ERK/JNK activation

“…Dihydroxyquingdainone, a tryptanthrin analog, inhibits growth of lymphoma cells through the modulation of intrinsic apoptosis and caspase-3 activation. 38 Our data demonstrated that CIQ dose-dependently induced apoptosis in breast cancer cells. Furthermore, for caspase-3-expressing MDA-MB-231 cells, CIQ induce caspase-3 activation and the decreased of caspase-8 were observed.…”

“…Pathania et al 22 reported that a synthetic tryptanthrin derivative causes apoptosis through inducing caspase activation and suppressing STAT3 signaling in leukemia cells. Dihydroxyquingdainone, a tryptanthrin analog, inhibits growth of lymphoma cells through the modulation of intrinsic apoptosis and caspase‐3 activation 38 . Our data demonstrated that CIQ dose‐dependently induced apoptosis in breast cancer cells.…”

Ruthenium Complex HB324 Induces Apoptosis via Mitochondrial Pathway with an Upregulation of Harakiri and Overcomes Cisplatin Resistance in Neuroblastoma Cells In Vitro

“…Additionally, we tested the complex on cytarabine-resistant MaKo cells (co-resistances: fludarabine, cladribine, clofarabine, cyclophosphamide, and vincristine) [ 9 ], methotrexate-resistant JeBa cells (co-resistances: mitoxantrone, idarubicin, daunorubicin, doxorubicin, and epirubicin) [ 42 ], and etoposide-resistant JeFri cells (co-resistances: cytarabine and methotrexate) [ 9 ], each in comparison to the baseline Nalm-6 cell line. In all experiments, HB324 was able to overcome the resistant cells, similarly to that shown for the NaKu cells (see Supplementary Materials, Figures S5–S7 ).…”

A Thia-Analogous Indirubin N-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells

“…Accordingly, indirubin and its derivatives are currently being discussed to overcome imatinib resistance in CML [75]. Other published data have shown that an indigoid derivative can overcome chemoresistance in leukaemia cells [76] and that I3M sensitises multiple myeloma cells to bortezomib-induced apoptosis and overcomes bortezomib resistance via proteasome inhibition [77].…”