Sensitisation for cisplatin-induced apoptosis by isothiocyanate E-4IB leads to signalling pathways alterations.
A new synthetic isothiocyanate (ITC) derivative, ethyl 4-isothiocyanatobutanoate (E-4IB), appeared to be an effective modulator of cellular proliferation and potent inducer of apoptosis. In cooperation with cisplatin, this compound exerted synergistic effects in human ovarian carcinoma A2780 cells. In the present study we investigated in more detail E4IB-sensitisation for cisplatin-induced apoptosis. Sequential administration of both cytostatic agents led to increased intracellular platinum accumulation, glutathione level depletion and mitochondrial membrane potential dissipation. These events were accompanied with poly (ADP-ribosyl) polymerase cleavage, stimulation of caspase-3 activity, upregulation of p53, FasL and Gadd45alpha, cyclin B1 downregulation and an increase in mitogen-activated protein kinases JNK, ERK and p38 phosphorylation as well as PI3K level alterations. The presented results might have implications for developing new strategies aimed at therapeutic benefit of natural or synthetic ITCs in cooperation with various anticancer drugs.
Bodo
J
J
1Laboratory of Tumour Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, Bratislava, Slovakia.
Hunakova
L
L
Kvasnicka
P
P
Jakubikova
J
J
Duraj
J
J
Kasparkova
J
J
Sedlak
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005978:Glutathione; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D018797:Cell Cycle Proteins; D017879:Isothiocyanates; C082832:ethyl 4-isothiocyanatobutanoate; D011494:Protein Kinases; D053148:Caspase 3; D005978:Glutathione; D002945:Cisplatin