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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Adolescent, Anaplastic Lymphoma Kinase, Antineoplastic Agents, Apoptosis, Autophagy, CDC2 Protein Kinase, Caspase 3, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Child, Crizotinib, Cyclin B1, Cyclin-Dependent Kinases, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, G2 Phase Cell Cycle Checkpoints, Humans, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-met, Pyrazoles, Pyridines, RNA Interference, RNA, Small Interfering, RNA-Binding Proteins, Reactive Oxygen Species, Receptor Protein-Tyrosine Kinases, Receptors, Somatomedin, Rhabdomyosarcoma, Alveolar, Tumor Stem Cell Assay.
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Is crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells solely dependent on ALK and MET inhibition? Context: Rhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. Aberrant expression of Anaplastic Lymphoma Kinase (ALK) and MET gene has been implicated in the malignant progression of RMS, especially in the alveolar subtype. This observation suggests that crizotinib (PF-02341066), a kinase inhibitor against ALK and MET, may have a therapeutic role in RMS, although its antitumour activity in this malignancy has not yet been studied. RH4 and RH30 alveolar RMS (ARMS) cell lines were treated with crizotinib and then assessed by using proliferation, viability, migration and colony formation assays. Multiple approaches, including flow cytometry, immunofluorescence, western blotting and siRNA-based knock-down, were used in order to investigate possible molecular mechanisms linked to crizotinib activity. In vitro treatment with crizotinib inhibited ALK and MET proteins, as well as Insulin-like Growth Factor 1 Receptor (IGF1R), with a concomitant robust dephosphorylation of AKT and ERK, two downstream kinases involved in RMS cell proliferation and survival. Exposure to crizotinib impaired cell growth, and accumulation at G2/M phase was attributed to an altered expression and activation of checkpoint regulators, such as Cyclin B1 and Cdc2. Crizotinib was able to induce apoptosis and autophagy in a dose-dependent manner, as shown by caspase-3 activation/PARP proteolytic cleavage down-regulation and by LC3 activation/p62 down-regulation, respectively. The accumulation of reactive oxygen species (ROS) seemed to contribute to crizotinib effects in RH4 and RH30 cells. Moreover, crizotinib-treated RH4 and RH30 cells exhibited a decreased migratory/invasive capacity and clonogenic potential.
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These results provide a further insight into the molecular mechanisms affected by crizotinib in ARMS cells inferring that it could be a useful therapeutic tool in ARMS cancer treatment. Final Decision: no