A study on the potential protective effect of dibenzazepine against cisplatin-induced nephrotoxicity in rats

Abstract

Cisplatin (cis-diaminedichloroplatinum, CDDP), is an anti-tumor drug which represents one of the standard anti-cancer agents used to treat many solid tumors such as genitourinary cancers. However, due to its accumulation in renal epithelial cells. The mechanism of cisplatin-induced renal injury is complex and not fully understood; however, multiple cellular mechanisms were found to be involved including oxidative stress, inflammation and apoptosis. Inspite of using protective measures, successive cisplatin dosing results in progressive and irreversible nephrotoxicity. Therefore, searching for new signaling pathways involved in the nephrotoxicity induced by cisplatin may represent a promising alternative. Notch signaling pathway plays a crucial role in cell-cell communication. The Notch pathway is activated through ligand-receptor interaction of four receptors (Notch-1 to Notch-4) and five Notch ligands (Delta-like 1, 3, 4 and Jagged 1, 2), resulting in the expression of multiple target genes. Besides, the Notch signaling was found to be dysregulated in many types of cancer and involved in the proliferation, differentiation, self-renewal of cancer stem cells which are responsible for chemo- and radio-resistance. Indeed, Notch inhibition was shown to modulate the resistance of cancer cells to cisplatin. Interestingly, the Notch signaling pathway was found to play an important role in glomerular epithelial cells in diabetic nephropathy. However, the role of Notch signaling in the pathogenesis of cisplatin-induced nephrotoxicity has not been investigated before.

The present study was divided into three parts: First, the possible modulatory effect of DBZ on cisplatin cytotoxic activity in Hela and PC3 human cancer cell lines was assessed using MTT cytotoxicity assay. The IC50 of cisplatin was not significantly changed upon pretreatment with subtoxic concentration of DBZ in both cell lines.