Mitochondrial Mode of Action of a Thymidine‐Based Cisplatin Analogue Breaks Resistance in Cancer Cells

Abstract

Cisplatin analogue complexes with platinum(II) and palladium(II) starting from 3',5'-diamino-3',5'-dideoxy-thymidines were synthesized, both with the D-erythro- and D-threo configurations. Complexes of the general formula [MCl(2)L] were obtained and characterized. NMR spectroscopic measurements and single crystal X-ray structure analysis showed that the metal centers are coordinated to the ligands by the amino groups in 3'- and 5'-positions and not through the thymine moiety. All ligands and complexes showed no significant in vitro activities except thymiplatin (cis-dichloro(3',5'-diamino-3',5'-dideoxy-D-threo-thymidine)platinum(II)). Detailed in vitro studies on the apoptosis pathway in lymphoma (BJAB), leukemia (NALM-6), and melanoma cells (Mel-HO) as well as on transfected or resistant cell lines were carried out. Thymiplatin significantly induced an apoptotic response, which was found to be associated with the loss of mitochondrial membrane potential and with caspase activation. The activity was shown to be independent of Fas-associated protein with death domain (FADD), but dependent on Bcl-2 expression. As a consequence, for thymiplatin a mitochondrial mode of action could be assigned. Moreover, the compound showed activity in cells resistant to common drugs, such as daunorubicin and vincristin, and showed synergistic effects with doxorubicin, vincristin, cytarabin, and daunorubicin.

A spontaneous gold(i)-azide alkyne cycloaddition reaction yields gold-peptide bioconjugates which overcome cisplatin resistance in a p53-mutant cancer cell line

“…The effect on TrxR and a second thiol-containing enzyme, namely glutathione reductase (GR), was studied on the isolated enzymes following a published procedure. 32 All compounds show strong inhibitory effects on TrxR (EC 50 (Table 1). 53 The elevated generation of reactive oxygen species (ROS), produced by cellular respiration in mitochondria, indicates an imbalance of normal cell metabolism.…”

“…S6, ESI †). 50 Consequently, it can be concluded that apoptotic cell death pathways play an important role in the mode of action of these gold peptide conjugates. A highly important regulatory cellular function such as apoptosis can be triggered by a multitude of events and connected signalling pathways.…”

A metal-free salalen ligand with anti-tumor and synergistic activity in resistant leukemia and solid tumor cells via mitochondrial pathway

“…However, WQF 044 did not break the over-expression of Bcl-2 by 30-fold, existing in the MelHO/Bcl-2 cells, in a dose-dependent manner (Fig. 4 b) (Onambele 2010 ). Another interesting observation was the fivefold over-expression of BAX in the PCR array analysis (Table 2 ).…”

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

“…The intrinsic pathway is associated with the loss of the mitochondrial membrane potential and associated changes in its permeability. , Furthermore, caspase-9 participates as an initiator and caspase-3 as another key component in the mitochondrial pathway. , Western blot analysis after incubating BJAB cells with 5 and 8 nM 7 for 36 h revealed activation of caspase-9 (C9) but no significant activation of caspase-3 (C3) (Figure A). This indicates the involvement of the intrinsic pathway in the induction of apoptosis by 7 as reflected by the appearance of cleaved C9 and small consumption of procaspase-3.…”