Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition.

Statins are some of the most widely used drugs worldwide, but one of their major side effects is myotoxicity. Using mouse myoblast (C2C12) and human alveolar rhabdomyosarcoma cell lines (RH30) in both 2-dimensional (2D) and 3-dimensional (3D) cell culture, we investigated the mechanisms of simvastatin\u27s myotoxicity. We found that simvastatin significantly reduced cell viability in C2C12 cells compared to RH30 cells. However, simvastatin induced greater apoptosis in RH30 compared to C2C12 cells. Simvastatin-induced cell death is dependent on geranylgeranyl pyrophosphate (GGPP) in C2C12 cells, while in RH30 cells it is dependent on both farnesyl pyrophosphate (FPP) and GGPP. Simvastatin inhibited autophagy flux in both C2C12 and RH30 cells and inhibited lysosomal acidification in C2C12 cells, while autophagy inhibition with Bafilomycin-A1 increased simvastatin myotoxicity in both cell lines. Simvastatin induced greater cell death in RH30 cells compared to C2C12 in a 3D culture model with similar effects on autophagy flux as in 2D culture. Overall, our results suggest that simvastatin-induced myotoxicity involves both apoptosis and autophagy, where autophagy serves a pro-survival role in both cell lines. The sensitivity to simvastatin-induced myotoxicity differs between 2D and 3D culture, demonstrating that the cellular microenvironment is a critical factor in regulating simvastatin-induced cell death in myoblasts

Biologic and Clinical Aspects of Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a muscle-derived tumor and is the most common pediatric soft tissue sarcoma representing 5% of all childhood cancers. Statistically, soft tissue sarcomas account for approximately 10% of all cancers in children, of which more than half of these tumors are RMS. Thus, RMS is a major clinical problem in pediatric oncology. RMS is caused by a disruption in the pathway of primitive mesenchymal stem cells directed towards myogenesis. In most cases of patients diagnosed with RMS there is a genetic or chromosomal alteration involved. In past few years there have been discoveries of more therapeutic approaches that has improved the quality of life in RMS patients and has resulted in a better survival rate in this population from 25% to 60%. However, Additional researches and clinical trials are needed in order to minimize the devastating consequences of the pediatric cancer including RMS. In the current mini review we will briefly discuss current knowledge in RMS focusing on most common biological and clinical aspects of the disease

In Vivo Antifungal Activity and Computational Studies of Some Azole Derivatives against Candida Albicans

Resistance of Candida species is a major problem in the management of Candida infection. This study investigated in vivo antifungal activities of several new imidazole and triazole derivatives in a C. albicans systemic infection. The efficacy of derivatives was determined against systemic infection by C. albicans in mice with cyclophosphamide-induced immunosuppression, and the antifungal activities of the synthesized compounds were evaluated in comparison with fluconazole. Compounds 3 and 8 had the highest efficacy with minimum inhibitory concentration (MIC) values of 0.5–1 μM against the C. albicans pathogen. In vivo activities in immunosuppressed mice were also greater than fluconazole. Furthermore, docking analysis was carried out to know the binding mode of imidazole and triazole derivatives to the CYP51 active site of C. albicans and dihydrofolate reductase as a valid antifungal target. The docking study found that the antifungal results are well correlated with docking results. ADMET and in silico physicochemical parameters were also performed. This study demonstrates that compounds 3 and 8 are potential antifungal candidates against the C. albicans pathogen

A bioengineering method for modeling alveolar Rhabdomyosarcoma and assessing chemotherapy responses

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignant tumor. Treatment of RMS usually includes primary tumor resection along with systemic chemotherapy. Two-dimensional (2D) cell culture systems and animal models have been extensively used for investigating the potential efficacy of new RMS treatments. However, RMS cells behave differently in 2D culture than in vivo, which has recently inspired the adoption of three-dimensional (3D) culture environments. In the current paper, we will describe the detailed methodology we have developed for fabricating a 3D engineered model to study alveolar RMS (ARMS) in vitro. This model consists of a thermally cross-linked collagen disk laden with RMS cells that mimics the structural and bio-chemical aspects of the tumor extracellular matrix (ECM). This process is highly reproducible and produces a 3D engineered model that can be used to analyze the cytotoxicity and autophagy induction of drugs on ARMS cells. The most improtant bullet points are as following: • We fabricated 3D model of ARMS. • The current ARMS 3D model can be used for screening of chemotherapy drugs. • We developed methods to detect apoptosis and autophagy in ARMS 3D model to detect the mechansims of chemotherapy agents