Sensitization of cisplatin therapy by a naphthalimide based organoselenium compound through modulation of antioxidant enzymes and p53 mediated apoptosis

Abstract

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.

Keywords::

• anti-cancer drug
• oxidative stress
• selenium
• antioxidant
• apoptosis

Acknowledgments

The authors wish to thank the Prof. (Dr.) Jaydip Biswas, Director, Chittaranjan National Cancer Institute, India for support in this study. Somnath Singha Roy gratefully acknowledges Council of Scientific and Industrial Research, New Delhi, India for Junior Research Fellowship (01(2160)/07/EMRII). Abhishek Basu and Arin Bhattacharjee gratefully acknowledge Indian Council of Medical Research, New Delhi, India for Senior Research Fellowship (no. 3/2/2/58/2011/NCD-III and no. 45/36/2008/PHA-BMS, respectively).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.