Differential processing of antitumour-active and antitumour-inactive trans platinum compounds by SKOV-3 ovarian cancer cells.
In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl(2)(NH(3))(2)] (trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans-Z and trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC(50) determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.
Boccarelli
Angelina
A
Department Biomedical Sciences and Human Oncology, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.
Giordano
Domenico
D
Natile
Giovanni
G
Coluccia
Mauro
M
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000633:toxicity; D053938:DNA Fragmentation / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D042822:Genomic Instability / Q000235:genetics; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; C512867:dichlorobis(1-methoxyethanimine)platinum(II); C034697:transplatin; D002945:Cisplatin