title: The microtubule binding drug EM011 inhibits the growth of paediatric low grade gliomas.
abstract: Low grade gliomas are a heterogeneous group of tumours representing the most common form of neoplasms in the central nervous system among children. Although gross total resection remains the principal treatment, it is often impractical especially for the resection of tumours within eloquent regions of the brain. Instead Radiotherapy is utilised in such cases, but because of its associated toxicities, it is refrained from use among younger children. These limitations coupled with hypersensitivity and toxicities associated with some commonly used chemotherapeutic agents, have ignited the need to search for safer and more effective treatments for paediatric low grade gliomas. In this study, we investigated the EM011 drug on the growth of two pilocytic and one diffuse paediatric astrocytoma cell lines, using an assortment of cancer assays. We discovered that treatments of low grade gliomas with EM011 abrogated cell viability by inducing a decrease in cell proliferation and an arrest in the S and G2M cell cycle phases, followed by a converse increase in apoptosis in a dose and time dependent manner. The cell migratory and invasion indices, as well as anchorage independent growth in soft agarose, were significantly attenuated. These findings were mechanistically associated with a transient release of AIF, a disruption of microtubule architecture, and a decline in the expression of key genes which drive cancer progression including EGFR, mTORC1, JUN and multiple MMPs. In fact, the activity of MMP2 was also perturbed by EM011. These findings, in conjunction with the insignificant adverse side effects established from other studies, make EM011 an appealing chemotherapeutic agent for the treatment of paediatric low grade gliomas.
authors: Pediatric Research Unit, Centre de Recherche du CHUL, Québec, QC, Canada G1V 4G2.
authors: Norbert F
authors: NF
authors: Ajeawung
authors: Harish C
authors: HC
authors: Joshi
authors: Deepak
authors: D
authors: Kamnasaran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D004149:Dioxoles / Q000494:pharmacology*; D018093:Gelatinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D060787:Neoplasm Grading; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D059467:Transcriptome; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D004149:Dioxoles; C510553:EM011 compound; D007546:Isoquinolines; D050257:Tubulin Modulators; D018093:Gelatinases