Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer.

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.

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.

Preparation, Characterization and In Vitro Biological Evaluation of Novel Curcumin Derivatives as Cytotoxic and Apoptosis-Inducing Agents.

BACKGROUND: Curcumin is a natural polyphenol and lead compound of the rhizomes of curcuma longa and it has been widely used for pharmacological activities. OBJECTIVE: In this study, a series of novel derivatives of curcumin, with this group linked to a 2-amino-4- phenylpyran-3-carbonitrile system, have been synthesized and tested for their antitumor activities in vitro against a panel of three human cancer cell lines (MCF-7, A2780, and U-87MG). METHODS: The in vitro cytotoxic activity of the synthesized compounds was tested on three cancer cell lines (MCF-7, A2780, and U-87MG) using MTT colorimetric assay. Meanwhile, the ability of the active compounds to induce apoptosis in cancer cells was investigated by examination of caspase-3 and caspase-9 and mitochondrial membrane potential assay. RESULTS: Under relatively mild conditions in ethanol, the reaction of a series of substrates afforded the corresponding derivatives of curcumin mostly in good yields (13 analogues, 48-94% yields). Bioassay results indicated that compounds L6 (para-Bromo), L9 (para-Nitro) and L12 (meta-Methoxy) were the most active members in this study demonstrating potent activities against A2780 cancer cells and experimental results of fluorescent staining and flow cytometry analysis revealed that L6 and L9 could induce apoptosis in A2780 cells with apoptosis ratios of about 40% and 46%, respectively at 24h of treatment at 15.35µM and 23µM in A2780 cells. On the other hand, they could increase the caspase-3 activity slightly (10%), while having no significant impact on the activities of caspase-9. CONCLUSION: Those two derivatives could be considered as useful templates for future development to obtain more potent antitumor agents.

Synthesis and investigation of inhibitory activities of imidazole derivatives against the metallo-ß-lactamase IMP-1.

Mutations in bacteria can result in antibiotic resistance due to the overuse or abuse of ß-lactam antibiotics. One strategy which bacteria can become resistance toward antibiotics is secreting of metallo ß-lactamase enzymes that can open the lactam ring of the ß-lactam antibiotic and inactivate them. This issue is a threat for human health and one strategy to overcome this situation is co-administration of ß-lactam antibiotics with an inhibitor. So far, no clinically available inhibitors of metallo ß-lactamases (MBLs) reported and the clinically inhibitors of serine ß-lactamase are useless for MBLs. Accordingly, finding a potent inhibitor of the MBLs being very important. In this study, imidazole derivatives primarily were synthesized and their inhibitory activity were measured. Later in silico binding model was used to predict the configuration and conformation of the ligands into the active site of enzyme. Two molecules demonstrated with IC50 of 39 µM and 46 µM against MBL (IMP-1).

Synthesis and enzyme-based evaluation of analogues L-tyrosine thiol carboxylic acid inhibitor of metallo-ß-lactamase IMP-1.

The emergence of drug-resistant pathogenic bacteria is occurring due to the global overuse and misuse of ß-lactam antibiotics. Infections caused by some bacteria which secrete metallo-ß-lactamases (enzymes that inactivate ß-lactam antibiotics) are increasingly prevalent and have become a major worldwide threat to human health. These bacteria are resistant to ß-lactam antibiotics and MBL-inhibitor/ß-lactam antibiotic combination therapy can be a strategy to overcome this problem. So far, no clinically available inhibitors of metallo-ß-lactamases (MBLs) have been reported. In this study, L-benzyl tyrosine thiol carboxylic acid analogues (2a-2k) were synthesized after the study of computational simulation by adding of methyl, chloro, bromo and nitro groups to the benzyl ring for investigation of SAR analysis. Although the synthesized molecules 2a-k shows the potent inhibitory effects against metallo-ß-lactamase (IMP-1) with the range of Kic values of 1.04-4.77 µM, they are not as potent as the candidate inhibitor.