Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis.

OBJECTIVE: The heterogeneity of soft tissue sarcoma (STS) represents a major challenge for the development of effective therapeutics. Comprised of over 50 different histology subtypes of various etiologies, STS subsets are further characterized as either karyotypically simple or complex. Due to the number of genetic anomalies associated with genetically complex STS, development of therapies demonstrating potency against this STS cluster is especially challenging and yet greatly needed. Verticillin A is a small molecule natural product with demonstrated anticancer activity; however, the efficacy of this agent has never been evaluated in STS. Therefore, the goal of this study was to explore verticillin A as a potential STS therapeutic. METHODS: We performed survival (MTS) and clonogenic analyses to measure the impact of this agent on the viability and colony formation capability of karyotypically complex STS cell lines: malignant peripheral nerve sheath tumor (MPNST) and leiomyosarcoma (LMS). The in vitro effects of verticillin A on apoptosis were investigated through annexin V/PI flow cytometry analysis and by measuring fluorescently-labeled cleaved caspase 3/7 activity. The impact on cell cycle progression was assessed via cytometric measurement of propidium iodide intercalation. In vivo studies were performed using MPNST xenograft models. Tumors were processed and analyzed using immunohistochemistry (IHC) for verticillin A effects on growth (Ki67) and apoptosis (cleaved caspase 3). RESULTS: Treatment with verticillin A resulted in decreased STS growth and an increase in apoptotic levels after 24 h. 100 nM verticillin A induced significant cellular growth abrogation after 24 h (96.7, 88.7, 72.7, 57, and 39.7% reduction in LMS1, S462, ST88, SKLMS1, and MPNST724, respectively). We observed no arrest in cell cycle, elevated annexin, and a nearly two-fold increase in cleaved caspase 3/7 activity in all MPNST and LMS cell lines. Control normal human Schwann (HSC) and aortic smooth muscle (HASMC) cells displayed higher tolerance to verticillin A treatment compared to sarcoma cell lines, although toxicity was seen in HSC at the highest treatment dose. In vivo studies mirrored the in vitro results: by day 11, tumor size was significantly reduced in MPNST724 xenograft models with treatment of 0.25 and 0.5 mg/kg verticillin A. Additionally, IHC assessment of tumors demonstrated increased cleaved caspase 3 and decreased proliferation (Ki67) following treatment with verticillin A. CONCLUSION: Advancement in the treatment of karyotypically complex STS is confounded by the high level of genetic abnormalities found in these diseases. Consequently, the identification and investigation of novel therapies is greatly needed. Our data suggest that verticillin A selectively inhibits MPNST and LMS growth via induction of apoptosis while exhibiting minimal to moderate effects on normal cells, pointing to verticillin A as a potential treatment for MPNST and LMS, after additional preclinical validation.

Endocrinological cancers and the internet.

Endocrine cancers are some of the commonest forms of cancer getting mention as early as in old papyruses of Egypt. Our current knowledge about this cluster of cancer has grown immensely with improved survival rates. In the era of specialization and super specialization, we started peeking into these conditions more elaborately and beyond microscopically. The growing awareness demanded categorization of information into disease basics like molecular pathology of initiation and progression; advanced diagnostics; new therapeutic options; patient awareness and involvement in clinical trials. Recent advances in genomics and hereditary counseling have delineated pre-disease forecasting possibilities. With advanced diagnostics and therapeutic modalities, we saw an increase in cancer survivors demanding extra care and moral support. Throughout these developments, we went through a boost in global information communications, the main thrust being the Internet. Networking of computers globally generated a platform that created a ripple of knowledge far and wide. The purpose of this review is to investigate how the Internet is supporting the growth and development of the field of endocrine cancer, and present and future scope of the Internet as a tool for professionals involved in this area. The information furnished here were collected from cited references as well as all websites mentioned in the tables.

Interleukin-1 receptor antagonist gene polymorphism and obesity: A pilot study from north India.

The main adverse consequences of excess bodyweight are cardiovascular disease, type II diabetes, and several cancers, IL-1Ra serum concentration has been reported earlier to increase in human obesity and it is therefore assumed that the polymorphism of IL-1Ra may influence cytokine production. We designed this study to investigate whether the IL-1Ra polymorphism was associated with obesity. A total number of 103 individuals; 19 lean (BMI<25 Kg/m(2)), 51 overweight (BMI 25-29.9 Kg/m(2)) and 33 obese (BMI≥30.0 Kg/m(2)) were enrolled in this study. Genotyping was performed using a polymerase chain reaction PCR amplification of the intron-2 fragment harboring a variable number of tandem repeat (VNTR) nucleotide sequences 86 pb of tandem repeat. The PCR products were separated on 2% agarose gel. Statistical analysis was performed using SPSS software (version 11.5). We found no significant difference in genotype and allele frequencies between the three groups; lean vs. overweight and lean vs. obese (p=0.323; 0.202; 0.123 and 0.068 resp). However, an increased risk for obesity had a propensity to be higher in those having genotype II/II. This genotype has been reported to be a 'high producer' of IL-1Ra. Although no statistically significant relationship between IL-1Ra polymorphism and BMI was observed, however, a trend towards an increase of allele(*)II in overweight and obese group was observed. This may suggest that IL-1Ra appears to be induced by inflammatory stimuli as well as obesity-associated factors. This is relatively a pilot study: but nevertheless, may assist in identifying the pathophysiological cause for obesity.