Inhibition of cell growth, induction of apoptosis and mechanism of action of the novel platinum compound cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate.
Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4'-6-diamidine-2'-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique. When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue. Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.
Mariggiò
Maria A
MA
Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Patologia Generale e Oncologia Sperimentale, Università di Bari, Italy. maurizio.viale@istge.it
Cafaggi
Sergio
S
Ottone
Massimo
M
Parodi
Brunella
B
Vannozzi
Maria O
MO
Mandys
Vaclav
V
Viale
Maurizio
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D053938:DNA Fragmentation; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D005456:Fluorescent Dyes; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008856:Microscopy, Fluorescence; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011343:Procaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D007211:Indoles; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; C080075:cisplatin-procaine complex; C007293:DAPI; D011343:Procaine; D002945:Cisplatin