Diazenes: modificators of tumor cell resistance to cisplatin.
Most studies indicate that modulation of glutathione metabolism may be one of the most promising means of reversing clinical drug resistance. Five new diazene compounds have been synthesized: JK-279, JK-835, JK-913, JK-925 and LV-57 that should, according to their structure and biochemical properties, lower the GSH concentration. In the present study, we examined the influence of diazenes on cisplatin resistance in human cervical (HeLa) and laryngeal carcinoma (HEp2) cells as well as in their cisplatin-resistant sublines (HeLaCA and CK2, respectively). Intracellular GSH content was examined spectrophotometrically by the procedure developed by Tietze. The cell sensitivity to drugs was determined using a modified colorimetric MTT assay. Results show that all examined diazenes lowered GSH concentration. This decrease was insignificant for JK-835 and JK-925 in HeLa and HeLaCA cells, and JK-925 in CK2 cells. In human cervical carcinoma HeLa and HeLaCA cells, JK-279 was mostly active in sensitizing the cells to cisplatin, especially in drug-resistant cells. JK-913, JK-835 and LV-57 reverted partially resistance to cisplatin in HEp2 cells, while none of the diazenes was active in CK2 cells. In conclusion, diazene JK-279 may be useful in the combined treatment (cisplatin + diazene) for the certain type of cancer.
Osmak
M
M
Department of Molecular Genetics, Ruğer Bosković Institute, Zagreb, Croatia.
Bordukalo
T
T
Kosmrlj
J
J
Kvajo
M
M
Marijanović
Z
Z
Eljuga
D
D
Polanc
S
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D007202:Indicators and Reagents; D007700:Kinetics; D007822:Laryngeal Neoplasms; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007094:Imides; D007202:Indicators and Reagents; D005978:Glutathione; C038867:diazene; D002945:Cisplatin