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Abstract
Objective The research aimed to confirm the role of the transforming growth factor-β (TGF-β) in cisplatin- (CPT-) evoked kidney toxicity and elucidate the mechanism that ginsenoside Rb3 (Rb3) could alleviate the kidney toxicity by CPT during its treatment to oral cancer via TGF-β-mediated mitochondrial apoptosis. Methods The model of xenograft nude mice bearing oral carcinoma cells ACC83 was established and treated with CPT and/or Rb3, respectively. Bodyweights of the treated mice were weighed, and the kidney tissues were collected; following, the histopathology and the expression of TGF-β were examined using H&E staining and immunohistochemistry. Afterward, the renal cells GP-293 were treated with CPT and/or Rb3. The expression and phosphoration of TGF-β, Smad2, Smad3, Bcl-2, and Bax in GP-293 cells were detected by Western blotting. The cellular apoptosis and mitochondrial membrane potential were analyzed using flow cytometry. Results The xenograft nude mice exposure to CPT presented the bodyweight loss, necrotic areas, and the increased expression of TGF in kidney tissue, and Rb3 pretreatment relieved these changes evoked by CPT. In GP-293 cells, CPT administration induced the phosphorylation of Smad2 and Smad3, and Rb3 pretreatment suppressed the induced phosphorylation by CPT. Besides, flow cytometry analysis showed that Rb3 inhibited the CPT-evoked cellular apoptosis ratio and mitochondrial membrane depolarization. The Western blotting test indicated that Rb3 alleviated the cleavage of PARP, caspase 3, caspase 8, and caspase 9, the induction of Bax expression, and inhibition of Bcl-2 expression. Additionally, after treating with the TGF inhibitor of disitertide, Rb3 exhibited no alleviation effects on CPT-evoked cellular apoptosis ratio, inhibition of Bax expression, and induction of Bcl-2 expression in GP-293 cells. Conclusion Rb3 could alleviate CPT-evoked toxic effects on kidney cells during its treatment to oral cancer via TGF-β-mediated mitochondrial apoptosis.
Highlights
Oral cancer, occurring in the oral cavity and lip, is the sixth most common carcinoma and accounts for approximately 300,000 new cases around the earth [1]. e lack of early diagnosis strategy to oral cancer delayed the treatment and led to the dismal survival rates and mortality in oral cancer [2,3,4,5]
It was in the vague understanding that how CPT induced kidney toxicity, some shreds of evidence have shown that the pathway of NF-κB, autophagy, oxidative stress, and apoptosis are associated with the kidney toxicity by CPT
We found that CPT could induce the expression of transforming growth factor-β (TGF-β) in the kidney tissue of the xenograft nude mice model bearing oral tumor and in the human renal epithelial cells GP-293; CPT could mediate the TGF-β signal pathway characterizing by the expression and phosphorylation of Smad2 and Smad3 in GP-293 cells. e results demonstrated that TGF-β might take part in CPT-evoked kidney toxicity
Summary
Oral cancer, occurring in the oral cavity and lip, is the sixth most common carcinoma and accounts for approximately 300,000 new cases around the earth [1]. e lack of early diagnosis strategy to oral cancer delayed the treatment and led to the dismal survival rates and mortality in oral cancer [2,3,4,5]. There are plentiful of therapy methods for oral cancer in clinic and theory, the effective strategy for cancer treatment remains a challenge [8, 9]. Recent research studies have shown that several traditional Chinese herb extractions and their components could suppress CPT-trigged liver impairment, kidney injury, and myocardial damage [15, 16]. Among these active herb extractions and components, it was reported that Rb3 could alleviate CPT-evoked kidney injury in the cancer model [17]. The potential effect and mechanism of Evidence-Based Complementary and Alternative Medicine
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