Sorafenib versus sunitinib as first-line treatment agents in Chinese patients with metastatic renal cell carcinoma: the largest multicenter retrospective analysis of survival and prognostic factors.

BACKGROUND: To compare the efficacy of sorafenib and sunitinib with regard to overall survival (OS) and progression free survival (PFS) in Chinese patients with metastatic renal cell carcinoma (mRCC). METHODS: A multicenter, retrospective study was performed to elucidate the relationship between clinical variables and prognosis comparing sorafenib and sunitinib as first-line treatment agents in Chinese patients with mRCC. Between September 2006 and December 2014, 845 patients received either sorafenib (400 mg bid; n = 483) or sunitinib (50 mg q.d; n = 362). The primary end point was OS and PFS. RESULTS: The percentage of patients with low and moderate risk according to Memorial Sloan-Kettering Cancer Centre (MSKCC) score was significantly higher in sunitinib group, and that with high risk was significantly higher in sorafenib group (15.1 vs. 5.2%; p < 0.001). Median OS was similar in sorafenib and sunitinib group (24 vs. 24 months; p = 0.298). Sorafenib group exhibited higher mPFS compared to sunitinib group (11.1 vs. 10.0 months; p = 0.028). Treatment (sorafenib vs sunitinib), pathology, Eastern Cooperative Oncology Group (ECOG) performance status, MSKCC scores, Heng's criteria of risk, and number of metastases were identified as significant predictors for OS and along with liver metastasis for PFS. Clinical outcomes in terms of mOS was significantly better with sorafenib in patients ≥65 years of age (p = .041), ECOG 0 (p = 0.0001), and median MSKCC risk score (p = 0.008). CONCLUSIONS: Sorafenib and sunitinib are both effective in treating mRCC. However, sorafenib might be more effective in elderly patients (≥65 years) and in patients with an ECOG status of 0, classified under MSKCC moderate risk.

Protective Effects of Berberine on Renal Injury in Streptozotocin (STZ)-Induced Diabetic Mice.

Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-ß/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-ß/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-ß/Smad/EMT signaling activity.

Berberine activates Nrf2 nuclear translocation and inhibits apoptosis induced by high glucose in renal tubular epithelial cells through a phosphatidylinositol 3-kinase/Akt-dependent mechanism.

Apoptosis of tubular epithelial cells is a major feature of diabetic kidney disease, and hyperglycemia triggers the generation of free radicals and oxidant stress in tubular cells. Berberine (BBR) is identified as a potential anti-diabetic herbal medicine due to its beneficial effects on insulin sensitivity, glucose metabolism and glycolysis. In this study, the underlying mechanisms involved in the protective effects of BBR on high glucose-induced apoptosis were explored using cultured renal tubular epithelial cells (NRK-52E cells) and human kidney proximal tubular cell line (HK-2 cells). We identified the pivotal role of phosphatidylinositol 3-kinase (PI3K)/Akt in BBR cellular defense mechanisms and revealed the novel effect of BBR on nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and heme oxygenase (HO)-1 in NRK-52E and HK-2 cells. BBR attenuated reactive oxygen species production, antioxidant defense (GSH and SOD) and oxidant-sensitive proteins (Nrf2 and HO-1), which also were blocked by LY294002 (an inhibitor of PI3K) in HG-treated NRK-52E and HK-2 cells. Furthermore, BBR improved mitochondrial function by increasing mitochondrial membrane potential. BBR-induced anti-apoptotic function was demonstrated by decreasing apoptotic proteins (cytochrome c, Bax, caspase3 and caspase9). All these findings suggest that BBR exerts the anti-apoptosis effects through activation of PI3K/Akt signal pathways and leads to activation of Nrf2 and induction of Nrf2 target genes, and consequently protecting the renal tubular epithelial cells from HG-induced apoptosis.

Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling.

Evidence has demonstrated that hypoxia may have a central pathogenic mechanism in the development of diabetic nephropathy (DN). Epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in kidney is a contributor to the renal accumulation of matrix protein in DN and is highly associated with the progression of tubulointerstitial fibrosis. Zinc (Zn) has anti-fibrosis effects in liver and lungs. In the present study, we aimed to investigate the effect of Zn on renal tubulointerstitial fibrosis especially under hypoxic conditions and its association with DN. We found that Zn treatment blockaded tubular EMT and attenuated renal tubulointerstitial fibrosis by downregulation of hypoxia-inducible factor alpha (HIF-1α) in the kidneys of diabetic streptozotocin-treated mice. High glucose (HG)/hypoxic conditions stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker E-cadherin and ZO-1 while the increase in mesenchymal markers α-smooth muscle actin (α-SMA). Zn supplement mainly prevented HG/hypoxic-induced HIF-1α accumulation and EMT marker changes. In co-treatment Zn with PI3K/Akt/GSK-3ß signaling pathway, inhibitor LY294002 prevented HG/hypoxic-induced HIF-1α increase and EMT changes, suggesting that Zn may mediate HG/hypoxic-induced EMT through PI3K/Akt/GSK-3ß pathway. Therefore, we concluded that Zn had an important anti-fibrosis role under HG/hypoxic conditions, and a novel mechanism contributing to Zn protection on renal tubular epithelial cells from HG/hypoxia-induced EMT through activation of PI3K/Akt/GSK-3ß signaling pathway, which subsequently leads to the downregulation of the expression of HIF-1α.

Effect of zinc on high glucose-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells.

Zinc (Zn) as an essential dietary element has been indicated in a number of protein functions in the prevention of numerous types of epithelial-to-mesenchymal transition (EMT)-driven fibrosis in vivo. However, relatively little is known regarding its effect in the EMT of the renal tubular epithelial cells, which play an important role in renal tubulointerstitial fibrosis and is an important component of the renal injury that is associated with diabetic nephropathy. The present study investigated the effect of Zn on the high glucose (HG)-induced EMT in a normal rat kidney tubular epithelial cell line (NRK-52E cells) and the underlying molecular mechanisms by immunofluorescence staining and western blot analysis. The present study identified that 10 µM of Zn supplementation prevented EMT changes, such as the loss of E-cadherin and the increase in α-smooth muscle actin and vimentin expression. Conversely, depletion of Zn with N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine in these cells aggravated changes in HG-induced EMT markers. Additionally, 10 µM Zn supplementation inhibited HG-induced transforming growth factor-ß1 overexpression and reactive oxygen species production. Of note, HG increased phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) pathways activation and Zn reversed HG-induced expression of PI3K/Akt, extracellular-signal-regulated kinase (ERK) and p38 MAPK, as well as EMT proteins. Finally, inhibitors of PI3K/Akt, ERK and p38 MAPK, and Zn supplementation blocked the HG-induced EMT in NRK-52E cells. These results indicate that physiologically optimal levels of Zn can inhibit HG-induced EMT of the NRK-52E cells possibly through several mechanisms, including abrogation of HG-induced oxidative stress, and PI3K/Akt, p38 MAPK and ERK activation in NRK-52E cells.

Zinc modulates high glucose-induced apoptosis by suppressing oxidative stress in renal tubular epithelial cells.

Hyperglycemia is a characteristic of diabetic nephropathy, inducing renal tubular cell apoptosis by eliciting oxidative stress and inflammation. Zinc (Zn) is known as an essential trace element in many enzymes and proteins involved in antioxidant defenses, electron transport, and exerting antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of Zn on high glucose-induced cytotoxicity were explored using cultured renal tubular epithelial cells (NRK-52E). The authors discovered that Zn supplementation inhibited high glucose (HG)-induced NRK-52E cell apoptosis by attenuating reactive oxygen species production, inhibiting HG-induced caspase-3 and caspase-9 activation, and inhibiting the release of cytochrome c from mitochondria to the cytosol. Further analysis revealed that Zn supplementation facilitated cell survival through increasing nuclear translocation of NF-E2-related factor 2 (Nrf2), leading to increased regulation of levels of two antioxidant enzymes, hemeoxygenase-1 and glutamate cysteine ligase, which provided an adaptive survival response against the HG-induced oxidative cytotoxicity. Moreover, the Zn-mediated increases in Nrf2 activity were suppressed by the pharmacological inhibition of Akt or extracellular signal-regulated kinase 1/2. Taken together, these findings suggest that Zn antiapoptosis capacity through the activation of Akt and ERK signal pathways leads to Nrf2 activation and, subsequently, Nrf2 target gene induction, thereby protecting the NRK-52E cells from HG-induced apoptosis.

[Phase II clinical trial of sorafenib plus local chemotherapy in the treatment of metastatic renal cell carcinoma with pleural effusion].

OBJECTIVE: To evaluate the safety and efficacy of sorafenib plus cisplatin in the treatment of metastatic renal cell carcinoma (mRCC) with pleural effusion. METHODS: A total of 30 patients with mRCC (clear cell carcinoma) with pleural effusion from April 2009 to January 2011 were recruited. All received sorafenib 400 mg twice daily. And 11 patients in chemotherapy group received sorafenib plus local chemotherapeutic perfusion of cisplatin 40 mg weekly for 2 weeks while another 19 patients in control group received sorafenib alone. RESULTS: The response rate of pleural effusion was 10/11 for chemotherapy group versus 3/19 for control group (χ(2) = 13.097, P < 0.01). Followed up to April 30(th), 2011, 5 of 11 patients in chemotherapy group and 10 of 19 patients in control group died. Among those on sorafenib, the median overall survival time was 22 months (95%CI: 2.12 - 41.88) for local chemotherapy versus 9 months (95%CI: 8.20 - 9.80) without local therapy (P = 0.04). The most common events in local chemotherapy group were I-II thoracic pain, nausea and vomiting. And the incidence rates were 8/11 and 9/11 versus 4/19 and 3/19 respectively (P < 0.01). The main laboratory abnormalities were similar in two groups. CONCLUSION: The regimen of sorafenib plus pleural cavity perfusion of cisplatin is both effective and safe in the treatment of mRCC with pleural effusion. It may control local symptoms and achieve a better overall survival.