Mitochondrial Mode of Action of a Thymidine-based Cisplatin Analog Breaks Resistance in Cancer Cells
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Onambele, Liliane A.; Koth, Daniel; Czaplewska, Justyna; Schubert, Ulrich S.; Görls, Helmar; Yano, Shigenobu; Obata, Makoto; Gottschaldt, Michael; Prokop, Aram
- 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 dthreo
configurations. Complexes of the
general formula [MCl2L] 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-dthreo-
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.
- Year:
- 2010
- Type of Publication:
- Article
- Keywords:
- antitumor agents; apoptosis; drug resistance; nucleosides; platinum
- Journal:
- Chemistry - A European Journal
- Volume:
- 16
- Pages:
- 14498 - 14505