Sensitization of cisplatin therapy by a naphthalimide based organoselenium compound through modulation of antioxidant enzymes and p53 mediated apoptosis.
The widely used anti-cancer drug cisplatin imparts various toxic manifestations in the host, with nephrotoxicity being the most severe one. The trace element selenium shows antioxidant activity in both human and animals. The present study was designed to assess the chemoprotecting and chemoenhancing efficacy of a naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione during cisplatin chemotherapy in mice bearing Ehrlich ascites carcinoma cells. Cisplatin (5 mg/kg b.w.) was administered intraperitoneally and the organoselenium compound (3 mg/kg b.w.) was given by oral gavage in concomitant and pretreatment schedule. The effects of the test compound was evaluated by assaying biochemical, hematological, histological, genotoxicity parameters and by investigating induction of apoptosis in tumor cells, and calculating tumor growth response in the host. The organoselenium compound significantly prevented cisplatin induced generation of reactive oxygen species (ROS), reactive nitrogen species, and onset of lipid peroxidation in the kidney tissue of the experimental mice. In addition, the test compound was also substantially restored cisplatin induced depleted activities of the renal antioxidant enzymes and reduced glutathione level; prevented the serum blood urea nitrogen level, creatinine level, chromosomal aberration, DNA damage, histological alterations of kidney, and normalized the hematological profile of the tumor bearing mice. Furthermore, the organoselenium compound alone or during combination therapy induced apoptosis in tumor cells through mitochondria mediated and DNA damage mediated pathway and ultimately increased the life span of the tumor bearing host. Hence, the results showed that the test compound not only reduced the toxicity of cisplatin but also enhanced its anti-tumor efficacy.
Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute , Kolkata, West Bengal , India.
P
P
Ghosh
S
S
Singha Roy
A
A
Basu
A
A
Bhattacharjee
S
S
Bhattacharya
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002869:Chromosome Aberrations / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use* / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D053644:Naphthalimides / Q000627:therapeutic use*; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C582176:2-(5-selenocyanatopentyl)benzo(de)isoquinoline-1,3-dione; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D053644:Naphthalimides; D016566:Organoselenium Compounds; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
anti-cancer drug; antioxidant; apoptosis; oxidative stress; selenium