Mitochondrial mode of action of a thymidine-based cisplatin analogue breaks resistance in cancer cells.
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.
Onambele
Liliane A
LA
Children's Hospital of the City of Cologne, Amsterdamerstr. 59, 507335 Cologne, Germany.
Koth
Daniel
D
Czaplewska
Justyna A
JA
Schubert
Ulrich S
US
Görls
Helmar
H
Yano
Shigenobu
S
Obata
Makoto
M
Gottschaldt
Michael
M
Prokop
Aram
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D019254:Genes, bcl-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000378:metabolism*; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D053200:Fas-Associated Death Domain Protein; D009944:Organoplatinum Compounds; C557007:thymiplatin; D003561:Cytarabine; D014750:Vincristine; D010165:Palladium; D004317:Doxorubicin; D002945:Cisplatin; D013936:Thymidine; D003630:Daunorubicin