The pseudoginsenoside F11 ameliorates cisplatin-induced nephrotoxicity without compromising its anti-tumor activity in vivo

Abstract

The clinical use of cisplatin was severely limited by its associated nephrotoxicity. In this study, we investigated whether the pseudoginsenoside F11 had protective effects against cisplatin-induced nephrotoxicity. To clarify it, one in vivo model of cisplatin-induced acute renal failure was performed. The results showed that pretreatment with F11 reduced cisplatin-elevated blood urea nitrogen and creatinine levels, as well as ameliorated the histophathological damage. Further studies showed that F11 could suppress P53 activation, inverse the ratio of Bax/Bcl2 and the anti-oxidative and free radical levels induced by cisplatin, which in turn inhibited tubular cell apoptosis. Importantly, F11 enhanced rather than inhibited the anti-tumor activity of cispaltin in murine melanoma and Lewis lung cancer xenograft tumor models. Our findings suggested that administering F11 with cisplatin might alleviate the associated nephrotoxicity without compromising its therapeutic efficiency. This finding provides a novel potential strategy in the clinical treatment of cancer.

Figure 1. Effects of the pseudoginsenoside F11 on level of BUN and Cre in cisplatin-injected rats.

The animals were treated as indicated and the levels of BUN and Cre were detected. All data were expressed as means ± SD (n = 8). *: p<0.05, compared with the control group; #: p<0.05, compared with CDDP group.

Figure 2. Effects of the pseudoginsenoside F11 on kidney morphology in cisplatin-injected rats.

The kidneys were conducted for H.E staining after treatment, and light microscope observations were carried out. The injury in renal tubules was blindly assessed based on a 4 - point scale, and the results were expressed as means ± SD (n = 8). The black arrows indicated the representative morphological changes: tubular degeneration, swelling, extensive epithelial vacuolization and luminal ectasia (400× magnifications). *: p<0.05, compared with control group; #: p<0.05, compared with CDDP group.

Figure 3. Effects of the pseudoginsenoside F11 on tubular cell apoptosis in cisplatin-injected rats.

The animals were treated as indicated, and the fixed kidney tissues were performed for TUNEL staining. The slides were scanned by a confocal fluorescence microscope (A) and around 1000 cells (DAPI staining cells) were chosen randomly to quantify the number of apoptotic cells in renal tubules (B). The red arrows indicated the TUNEL-positive cells. *: p<0.05, compared with control group; #: p<0.05, compared with CDDP group.

Figure 4. Effects of the pseudoginsenoside F11 on the expression of P53, Bax, Bcl2, Cl-capase 3 and Cl-caspase 9 in cisplatin-injected rats.

The animals were treated as indicated, and the kidney samples were lysed in RAPI buffer. The total protein expressions were shown.

Figure 5. Effects of the pseudoginsenoside F11 on GSH-px, SOD and LPO levels in cisplatin-injected rats.

The animals were treated as indication and the levels of GSH-px, SOD and LPO were detected. All data were expressed as means ± SD (n = 8). *: p<0.05, compared with control group; #: p<0.05, compared with CDDP group.

Figure 6. Effects of the pseudoginsenoside F11 on the anti-tumor activity of cisplatin against B16 melanoma and Lewis lung cancer xenograft tumors in C57BL/6 mice.

The C57BL/6 mice were transplanted with Lewis lung cancer (A) or B16 melanoma (B) tumors, and treated as shown. Following treatment, the mice were sacrificed and the tumors were peeled off and weighed. All data were expressed as means ± SD (n = 10). *: p<0.05, compared with control group.