Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition.

摘要: Rhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. Aberrant expression of Anaplastic Lymphoma Kinase (ALK) MET gene has been implicated progression RMS, especially alveolar subtype. This observation suggests that crizotinib (PF-02341066), a kinase inhibitor against ALK MET, may have therapeutic role although its antitumour activity this malignancy not yet studied. RH4 RH30 RMS (ARMS) cell lines were treated with then assessed by using proliferation, viability, migration colony formation assays. Multiple approaches, including flow cytometry, immunofluorescence, western blotting siRNA-based knock-down, used order to investigate possible molecular mechanisms linked activity. In vitro treatment inhibited proteins, as well Insulin-like Growth Factor 1 Receptor (IGF1R), concomitant robust dephosphorylation AKT ERK, two downstream kinases involved proliferation survival. Exposure impaired growth, accumulation at G2/M phase was attributed an altered activation checkpoint regulators, such Cyclin B1 Cdc2. Crizotinib able induce apoptosis autophagy dose-dependent manner, shown caspase-3 activation/PARP proteolytic cleavage down-regulation LC3 activation/p62 down-regulation, respectively. The reactive oxygen species (ROS) seemed contribute effects cells. Moreover, crizotinib-treated cells exhibited decreased migratory/invasive capacity clonogenic potential. These results provide further insight into affected ARMS inferring it could be useful tool cancer treatment.