phenanthrenes and Kidney-Neoplasms

It has been established that signal transducer and activator of transcription 3 serves as an oncoprotein in various human cancers; targeting it is therefore a reasonable approach for emerging cancer therapies. Cryptotanshinone, a natural compound extracted from the root of Salvia miltiorrhiza Bunge, has been identified as a potential STAT3 inhibitor. However, its functional role in renal cell carcinomas remains largely unknown. Therefore, we investigated the mode of action for cryptotanshinone. We found that cryptotanshinone substantially suppressed cancer cell growth while it promoted cell apoptosis by inhibiting the phosphorylation of STAT3 at Tyr705 and its blocking nuclear translocation. Coordinately, P-AKT, CyclinD1, C-MYC, MEKK2, and HGF were down-regulated and cell cycle progression was arrested at the G0/G1 phase, thereby attenuating cell proliferation. Moreover, the level of Cleaved-Caspase-3 was elevated while Bcl-2 and Survivin were down-regulated, accounting for the increased apoptosis. Furthermore, in vivo results revealed that cryptotanshinone effectively inhibits tumorigenesis in an A498-xenografted mouse model. Taken together, our data gives a more comprehensive understanding of how cryptotanshinone functions in renal cell carcinomas and demonstrates its potential as a powerful therapeutic approach to treat renal cell carcinomas.

Topics: Animals; Apoptosis; Carcinoma, Renal Cell; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drugs, Chinese Herbal; Genes, myc; Humans; Kidney Neoplasms; Male; Mice; Models, Biological; Phenanthrenes; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Renal cell carcinoma (RCC) is resistant to traditional cancer therapies, and metastatic RCC (mRCC) is incurable. The shortcomings in current therapeutic options for patients with mRCC provide the rationale for the development of novel treatment protocols. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be a potent inducer of tumor cell death in vitro and in vivo, and a number of TRAIL death receptor agonists (recombinant TRAIL or TRAIL death receptor-specific mAb) have been developed and tested clinically. Unfortunately the clinical efficacy of TRAIL has been underwhelming and is likely due to a number of possible mechanisms that render tumors resistant to TRAIL, prompting the search for drugs that increase tumor cell susceptibility to TRAIL. The objective of this study was to determine the effectiveness of combining the diterpene triepoxide triptolide, or its water-soluble prodrug, Minnelide, with TRAIL receptor agonists against RCC in vitro or in vivo, respectively. TRAIL-induced apoptotic death of human RCC cells was increased in the presence of triptolide. The triptolide-induced sensitization was accompanied by increased TRAIL-R2 (DR5) and decreased heat shock protein 70 expression. In vivo treatment of mice bearing orthotopic RCC (Renca) tumors showed the combination of Minnelide and agonistic anti-DR5 mAb significantly decreased tumor burden and increased animal survival compared to either therapy alone. Our data suggest triptolide/Minnelide sensitizes RCC cells to TRAIL-induced apoptosis through altered TRAIL death receptor and heat shock protein expression.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Diterpenes; Drug Synergism; Epoxy Compounds; Female; Humans; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Organophosphates; Phenanthrenes; Prodrugs; Receptors, TNF-Related Apoptosis-Inducing Ligand; Recombinant Proteins; Specific Pathogen-Free Organisms; Survival Analysis; TNF-Related Apoptosis-Inducing Ligand; Tumor Burden

Renal cell carcinoma (RCC) is the most frequent type of renal-originated malignancy. Although nephrectomy is successfully used to save the lives of patients with localized RCC, treatment of advanced and other refractory RCCs is poor and still inadequate. Here, we show that triptolide, a small molecule and a well-known anti-inflammatory and anti-immunity agent used in the clinic, is capable of inducing cell apoptosis via the mitochondrial pathway in the 786-0 RCC cell line. This induction occurred in concert with reduced expression of genes related to the stabilization of mitochondria such as Bcl-2 and Bcl-XL. Cell cycle analysis showed that exposure to triptolide decreased the proportion of cells in the G0/G1 and G2/M phases, and increased the proportion of cells in the S phase. Cell accumulation in the S phase can be attributed to reduced expression of cell cycle checkpoint regulators such as cyclin A, cyclin B, CDK1, CDK2 and retinoblastoma proteins (Rb). These results raise the possibility that triptolide-induced apoptosis is mediated by cell cycle arrest. Similarly, in another human RCC cell line, OS-RC-2, triptolide-induced apoptosis and cell accumulation in S phase were also observed. Therefore, triptolide emerges as a stimulator of apoptosis by influencing coordinate regulation of proliferation and apoptosis, and may be applicable to the treatment of human renal cell carcinoma.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Carcinoma, Renal Cell; Caspases; Cell Cycle; Cytochromes c; Diterpenes; Epoxy Compounds; Humans; Kidney Neoplasms; Mitochondria; Phenanthrenes; Tumor Cells, Cultured

Topics: Aristolochic Acids; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Obesity; Phenanthrenes; Phytotherapy; Risk

Topics: Anti-Obesity Agents; Aristolochia; Aristolochic Acids; Atrophy; Biomarkers; Carcinogens; Carcinoma, Papillary; Carcinoma, Transitional Cell; DNA Adducts; DNA Damage; Drugs, Chinese Herbal; Female; Fibrosis; Humans; Kidney Neoplasms; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Male; Neprilysin; Phenanthrenes; Phytotherapy; Plant Preparations; Postoperative Complications; Urinary Bladder Neoplasms

Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.

Topics: Adult; Aristolochic Acids; Carcinogens; Carcinoma in Situ; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Female; Humans; Kidney; Kidney Diseases; Kidney Neoplasms; Middle Aged; Phenanthrenes; Tumor Suppressor Protein p53; Ureter; Ureteral Neoplasms

Topics: Analgesics; Animals; Aristolochic Acids; Balkan Nephropathy; Carcinogens; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Humans; Kidney Neoplasms; Phenacetin; Phenanthrenes; Weight Loss

Topics: Aniline Compounds; Animals; Anthracenes; Azo Compounds; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cystadenoma; Epithelial Cells; Epithelium; Female; Hyperplasia; Kidney; Kidney Neoplasms; Kidney Tubules; Maternal-Fetal Exchange; Mice; Mice, Inbred Strains; Organ Culture Techniques; Phenanthrenes; Polycyclic Compounds; Pregnancy; Stimulation, Chemical

Topics: Adenocarcinoma; Animals; Carcinogens; Carcinoma, Transitional Cell; Diet; Female; Fluorenes; Injections, Subcutaneous; Intestinal Neoplasms; Kidney Neoplasms; Male; Neoplasms, Experimental; Phenanthrenes; Rats; Spectrum Analysis