stilbenes and Carcinoma--Renal-Cell

Pterostilbene (PTE) has inhibitory effect on a wide array of tumors. However, the therapeutic potential of PTE in renal cancer cells and the underlying mechanisms have not been evaluated. In this study, the aim is to demonstrate the growth inhibitory and the underlying mechanisms of PTE on human renal cell carcinoma (RCC) cells in vitro. By cell viability, cell morphology and colony formation assays, we found that PTE significantly suppressed the proliferation of RCC cells, while had little toxicity to the normal renal cell line HK-2. Flow cytometry assay revealed that PTE potently induced the apoptosis of RCC cells in a concentration-dependent manner, which was also testified by up-regulation of the pro-apoptosis-related protein (Cyto C, Bad, Bak, Bax, Cleaved-caspase 3, Cleaved-caspase 9, Cleaved-poly(ADP-ribose)polymerase (PARP)) and down-regulation of the anti-apoptosis-related protein Bcl-2. Moreover, cell cycle being arrested in S phase and down-regulation of p-Akt and p-extracellular signal-regulated kinase (ERK)1/2 were observed following treatment with PTE in RCC cells, indicating that PTE exerted remarkable anti-tumor activity in RCC cells possibly via cell cycle arrest and inactivation of Akt and ERK1/2 signaling pathways. Immunofluorescence analysis of γH2AX and detecting the expression levels of γH2AX, proliferating cell nuclear antigen (PCNA) and Rad51 by Western blot showed that PTE induced the DNA damages response in RCC cells. Taken together, the results of the present study demonstrated that PTE was a potential preventive and therapeutic agent for human renal cell carcinoma.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Renal Cell; Caspase 3; Caspase 9; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Damage; Humans; MAP Kinase Signaling System; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes

The aim of this study was to assess the effect of sitagliptin with or without resveratrol on carcinogen-induced clear cell renal cell carcinoma. Sixty male Wistar rats were divided into 6 equal groups as follows: control; clear cell renal cell carcinoma group; clear cell renal cell carcinoma+sitagliptin group; clear cell renal cell carcinoma+resveratrol group; clear cell renal cell carcinoma+carboxymethyl cellulose group and clear cell renal cell carcinoma+sitagliptin+resveratrol group. Blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta-d-glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT) and urinary albumin excretion rate (UAER) were determined. Renal tissue antioxidant enzymes, lactate dehydrogenase (LDH), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), transforming growth factor beta-1 (TGF-β1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and signal transducers and activators of transcription-3 (STAT3) were determined. Parts of the kidneys were subjected to histopathological and immunohistochemical examination for nuclear factor kappa B (p65). Sitagliptin and/or resveratrol induced significant improvement of the renal functions with significant increase in tissue antioxidant defenses and Nrf2/HO-1 content associated with significant decrease in tissue LDH, TGF-β1, TNF-α, IL-6 and STAT3 and alleviated the histopathological and immunohistochemical changes compared to the untreated clear cell renal cell carcinoma group. These effects were significant in sitagliptin/resveratrol combination group compared to the use of each of these drugs alone. In conclusion, sitagliptin/resveratrol combination might represent a beneficial therapeutic modality for amelioration of experimentally-induced clear cell renal cell carcinoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Carcinoma, Renal Cell; Immunohistochemistry; Kidney Function Tests; Kidney Neoplasms; Male; Neoplasms, Experimental; Rats; Rats, Wistar; Resveratrol; Sitagliptin Phosphate; Stilbenes

Resveratrol, known as phytoalexin, is a natural compound. Clinical studies have revealed that resveratrol has a variety of effects including anti‑inflammatory, antivirus and tumor suppressor activities. It has been reported that it may serve an important role in renal cell carcinoma (RCC) however, the molecular mechanism underlying resveratrol‑induced apoptosis in RCC is still unclear. The aim of the present study was to determine whether resveratrol could suppress RCC progression. Analysis of apoptosis demonstrated that resveratrol may act as a RCC suppressor in a dose‑ and time‑dependent manner. In addition, the results of the MTT and cell migration experiments revealed that resveratrol significantly decreased cell viability and migration. In addition, the expression of the anti‑apoptosis gene B‑cell lymphoma 2 (Bcl‑2) was downregulated by resveratrol, and the expression of pro‑apoptosis gene Bcl‑2‑associated X was upregulated at the mRNA and protein levels. Resveratrol also promoted the expression of p53 and activated phospho‑AMP‑activated protein kinase (AMPK). The phosphorylation of mammalian target of rapamycin (mTOR) was inhibited and the autophagy‑associated genes, light chain 3, autophagy related (ATG)5 and ATG7, were upregulated at the mRNA and protein levels. In conclusion, resveratrol suppressed RCC viability and migration, and promoted RCC apoptosis via the p53/AMPK/mTOR‑induced autophagy signaling pathway.

Topics: AMP-Activated Protein Kinases; Autophagy; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Gene Expression; Humans; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Topics: Cadherins; Carcinoma, Renal Cell; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Vimentin

Signal transducers and activators of transcription (STAT) proteins are critical transcription factor that are aberrantly activated in various types of malignancies, including renal cell carcinoma (RCC).. We investigated the effect of resveratrol (RES), an edible polyphenol phytoalexin on STAT3 and STAT5 activation cascade in both Caki-1 and 786-O RCC cell lines.. We found that RES suppressed both constitutive STAT3 (tyrosine residue 705 and serine residue 727) and STAT5 (tyrosine residue 694 and 699) activation, which correlated with the suppression of the upstream kinases (JAK1, JAK2, and c-Src) in RCC. Also, RES abrogated DNA binding capacity and nuclear translocation of these two transcription factors. RES-induced an increased expression of PTPε and SHP-2 and the deletion of these two genes by small interfering RNA abolished the ability of RES to inhibit STAT3 activation, suggesting the critical role of both PTPε and SHP-2 in its possible mechanism of action. Moreover, RES induced S phase cell cycle arrest, caused induction of apoptosis, loss of mitochondrial membrane potential, and suppressed colony formation in RCC. We also found that RES downregulated the expression of STAT3/5-regulated antiapoptotic, proliferative, and metastatic gene products; and this correlated with induction of caspase-3 activation and anti-invasive activity. Beside, RES potentiated sorafenib induced inhibitory effect on constitutive STAT3 and STAT5 phosphorylation, apoptotic effects in 786-O cells, and this correlated with down-regulation of various oncogenic gene products.. Overall, our results suggest that RES is a blocker of both STAT3 and STAT5 activation and thus may exert potential growth inhibitory effects against RCC cells.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Humans; Kidney Neoplasms; Membrane Potential, Mitochondrial; Niacinamide; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptor-Like Protein Tyrosine Phosphatases, Class 4; Resveratrol; S Phase Cell Cycle Checkpoints; Signal Transduction; Sorafenib; STAT3 Transcription Factor; STAT5 Transcription Factor; Stilbenes

4T1 mouse mammary adenocarcinomas and Caki-1 human renal cell carcinomas grown in mouse dorsal window chambers were serially treated with the vascular disrupting agent (VDA) OXi4503 and their responses compared. The real-time in vivo response was assessed using spectral imaging of microvascular hemoglobin saturation. To our knowledge this is the first use of spectral imaging technology for investigation of vascular disrupting agents. Previous research showing tumor size dependence in the treatment response to VDAs suggested that for the size of tumors used in this study only a moderate response would be observed; however, the tumors unexpectedly had very different responses to treatment. Caki-1 tumors showed little permanent vessel damage and experienced transient vessel collapse with time-dependent oxygenation changes followed by recovery starting at 6 h after treatment. Caki-1 tumors did not manifest necrotic avascular regions even after repeated treatments. These results are consistent with those obtained using other imaging modalities and histology. In contrast, similarly sized 4T1 tumors showed extensive vessel disintegration, minor vascular collapse, and a drop in tumor oxygenation up to 6 h post-treatment, after which reperfusion of collapsed vessels and extensive vascular remodeling and neovascularization of the tumor rim occurred from 8-48 h. The completely disintegrated vessels did not recover and left behind avascular and apparently necrotic regions in the tumor core. Spectral imaging appears to be a useful technique for in vivo investigation of vascular disrupting agents. The differential responses of these two tumor-types suggest that further investigation of the mechanisms of action of VDAs and individual characterization of tumor VDA-responses may be needed for optimal clinical use of these agents.

Topics: Animals; Carcinoma, Renal Cell; Diphosphates; Female; Humans; Kidney Neoplasms; Mammary Neoplasms, Experimental; Mice; Oxygen; Stilbenes; Xenograft Model Antitumor Assays

Bcl-2 protects cancer cells from the apoptotic effects of various chemotherapeutic agents. Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to bypass chemoresistance in cancer cells. Previously we designed and synthesized the resveratrol analogue HS-1793 displaying stronger antitumor efficacy than resveratrol and further demonstrated the HS-1793 resistance conferred by Bcl-2 in human leukemic U937 cells. We undertook this study to determine if HS-1793 treatment can bypass the anti-apoptotic effects of Bcl-2 in human renal cancer cells, with a specific focus on the involvement of promyelocytic leukemia nuclear bodies (PML-NBs). Experiments were conducted with Bcl-2-overexpressing human renal clear cell carcinoma Caki-1 cells. Various apoptosis assessment assays demonstrated that HS-1793 overcomes the resistance conferred by Bcl-2 in Caki-1 cells by inducing apoptosis. We elucidated that HS-1793-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with overcoming the anti-apoptotic effects of Bcl-2 in Caki-1 cells. Our findings show that the resveratrol analogue HS-1793 might provide a novel promising strategy for overcoming the resistance conferred by Bcl-2 via PML protein and the formation of mature PML-NBs.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Flow Cytometry; Fluorescent Antibody Technique; Humans; Intranuclear Inclusion Bodies; Kidney Neoplasms; Leukemia, Promyelocytic, Acute; Membrane Potential, Mitochondrial; Microscopy, Confocal; Naphthols; Nuclear Proteins; Promyelocytic Leukemia Protein; Proto-Oncogene Proteins c-bcl-2; Resorcinols; Resveratrol; Stilbenes; Transcription Factors; Tumor Suppressor Proteins

The present study evaluated the treatment efficacy of the vascular disrupting agents CA4P and OXi4503 in an orthotopically transplanted human renal cell carcinoma xenograft model (Caki-1). Experiments used vascular casting, vessel density assessments as well as tumour necrosis measurements to evaluate the efficacy of these agents. After treatment with either agent, assessment of the vascular casts showed an almost total eradication of tumour blood vessels. Histological evidence further supported this observation, showing extensive central tumour necrosis with only a small viable rim of tumour cells remaining at the periphery. These results suggest that vascular disrupting agents CA4P and OXi4503 may have utility in the treatment of renal cell carcinoma, an encouraging result given that current conventional therapies have been currently largely unsuccessful in managing this disease.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Diphosphates; Female; Humans; Kidney Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Silicon; Stilbenes; Transplantation, Heterologous

Studies have shown that Resveratrol (RE) can inhibit cancer initiation, promotion, and progression. However the gene expression profile in renal cell carcinoma (RCC) in response to RE treatment has never been reported. To understand the potential anticancer effect of RE on RCC at molecular level, we profiled and analyzed the expression of 2059 cancer-related genes in a RCC cell line RCC54 treated with RE. Biological functions of 633 genes were annotated based on biological process ontology and clustered into functional categories. Twenty-nine highly differentially expressed genes in RE treated RCC54 were identified and the potential implications of some gene expression alterations in RCC carcinogenesis were identified. RE was also shown to inhibit cell growth and induce cell death of RCC cells. The expression alterations of selected genes were validated using reverse transcription polymerase chain reaction. In addition, the gene expression profiles under different RE treatments were analyzed and visualized using singular value decomposition. The findings from this study support the hypothesis that RE induces differential expression of genes that are directly or indirectly related to the inhibition of RCC cell growth and induction of RCC cell death. In addition, it is apparent that the gene expression alterations due to RE treatment depend strongly on RE concentration. This study provides a general understanding of the overall genetic response of RCC54 to RE treatment and yields insights into the understanding of the cancer preventive mechanism of RE in RCC.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Renal Cell; Chemoprevention; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Phenols; Resveratrol; Ribonucleotide Reductases; Stilbenes; Vasodilator Agents

Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bevacizumab; Bibenzyls; Biological Availability; Biomarkers; Carcinoma, Renal Cell; Clinical Trials as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Endostatins; Endothelial Growth Factors; Endothelium, Vascular; Growth Inhibitors; Humans; Kidney Neoplasms; Microtubules; Neoplasms; Neovascularization, Pathologic; Ontario; Receptors, Vascular Endothelial Growth Factor; Stilbenes

Resveratrol, a natural phytoestrogen, has been reported to promote differentiation of murine MC3T3-E1 osteoblasts and to inhibit proliferation of prostate cancer cell lines. In the present study we tested the effects of resveratrol on the increased proliferation of human AHTO-7 osteoblastic cell line induced by conditioned media (CM) from a panel of carcinoma cell lines. This compound was found to modulate AHTO-7 proliferation in a tamoxifen-sensitive mechanism at lower concentrations, but failed to induce the osteoblast differentiation marker alkaline phosphatase (ALP) in contrast to vitamin D3. The proliferative response of AHTO-7 cells to conditioned media from carcinoma cell lines was diminished (30-71.4% inhibition) upon pretreatment with 0.5 microM resveratrol. Highest inhibition was demonstrated for pancreas (BxPC3, Panc-1), breast (ZR75-1) and renal (ACHN) carcinoma cell line supernatants whereas the effect on colon carcinoma (SW620, Colo320DM) cell CM and prostate cancer (PC3, DU145 and LNCaP) CM was less pronounced. Direct addition of resveratrol affected only supernatants of cell lines (<25% inhibition) exhibiting growth stimulatory activity for normal WI-38 lung fibroblasts. Resveratrol inhibited proliferation of DU145 and LNCaP cells in concentrations exceeding 5 microM, altered cell cycle distribution of all prostate cancer cell lines in concentrations as low as 0.5 microM, but did not inhibit the production of osteoblastic factors by these lines. In conclusion, resveratrol failed to induce ALP activity as marker of osteoblast differentiation in human osteoblastic AHTO-7 cells, however, inhibited their response to osteoblastic carcinoma-derived growth factors in concentrations significantly lower than those to reduce growth of cancer cells, thus effectively modulating tumor - osteoblast interaction.

Topics: Alkaline Phosphatase; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma, Renal Cell; Cell Differentiation; Cell Line; Culture Media, Conditioned; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Kidney Neoplasms; Lung; Male; Osteoblasts; Pancreatic Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Resveratrol; Stilbenes; Tamoxifen; Tumor Cells, Cultured