BKM120 induces apoptosis and inhibits tumor growth in medulloblastoma

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20 percent of all childhood brain tumors. New treatment strategies are needed to improve patient survival outcomes and to reduce adverse effects of current therapy. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway plays a key role in cellular metabolism, proliferation, survival and angiogenesis, and is often constitutively activated in human cancers, providing unique opportunities for anticancer therapeutic intervention. The aim of this study was to evaluate the pre-clinical activity of BKM120, a selective pan-class I PI3K inhibitor, on MB cell lines and primary samples. IC50 values of BKM120 in the twelve MB cell lines tested ranged from 0.279 to 4.38 μM as determined by cell viability assay. IncuCyte ZOOM Live-Cell Imaging system was used for kinetic monitoring of cytotoxicity of BKM120 and apoptosis in MB cells. BKM120 exhibited cytotoxicity in MB cells in a dose and time-dependent manner by inhibiting activation of downstream signaling molecules AKT and mTOR, and activating caspase-mediated apoptotic pathways. Furthermore, BKM120 decreased cellular glycolytic metabolic activity in MB cell lines in a dose-dependent manner demonstrated by ATP level per cell. In MB xenograft mouse study, DAOY cells were implanted in the flank of nude mice and treated with vehicle, BKM120 at 30 mg/kg and 60 mg/kg via oral gavage daily. BKM120 significantly suppressed tumor growth and prolonged mouse survival. These findings help to establish a basis for clinical trials of BKM120, which could be a novel therapy for the treatment of medulloblastoma patients.

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

“…Here, to develop new inhibitors with different chemo-types from those so far examined, we first performed in-silico drug screening of nearly 2 million commercially available compounds and approved neuropathic drugs that are expected to overcome blood–brain–barrier (BBB) limits, yielding 52 compounds that potentially bind to the mSin3 PAH1 domain. The binding ability of the 52 compounds was examined by NMR screening methods 30 , including two ligand-based screening methods, saturation transfer difference (STD) 31 , 32 and WaterLOGSY 33 , 34 , and one protein-based screening method, heteronuclear single quantum coherence (HSQC), while their inhibitor activity was examined by using a medulloblastoma cell line, DAOY 35 – 37 .…”

BKM-120 reduz a viabilidade celular e secreção de hormônio adrenocorticotrófico em linhagem celular de tumores corticotróficos de camundongo AtT-20/D16v-F2

“…BKM120 (Novartis Pharma AG, Basel, Switzerland) é um pan-inibidor oral da via PI3K, derivado de pirimidina. Conhecido como buparlisib, é um potente inibidor de todas as isoformas da PI3K classe I, capaz de penetrar a barreira hematoencefálica Zhao, Hall et al 2017). Estudos mostram que BKM120 possui um grande efeito antiproliferativo e pró-apoptótico em linhagens celulares e modelos animais de tumor sólido através da inibição específica da função biológica da AKT…”

“…Em linhagens celulares de gliomas e glioblastomas humanos com diferentes características genotípicas o BKM120 foi capaz de reduzir a viabilidade celular após 72h de tratamento . Em outro estudo, utilizando doze linhagens celulares de meduloblastoma foi observado que todas eram sensíveis ao BKM120, com om valores IC50 que variaram de 0,279 a 4,38 μM após 48h de incubação (Zhao, Hall et al 2017). De fato, estudos préclínicos demonstram que o BKM120 tem efeito anti-proliferativo e pró-apoptótico em uma variedade de linhas de células tumorais, xenoenxertos e em pacientes com câncer associado a mutações ativadoras de PI3K.…”

“…Os efeitos colaterais frequentes relacionados ao tratamento incluíram erupção cutânea, hiperglicemia, diarreia, anorexia e alteração do humor (37% cada), náusea (31%), fadiga (26%), prurido (23%) e mucosite (23%) . Dessa forma, o composto BKM120 é uma droga com interessantes propriedades farmacológicas, altamente seletivo para PI3K de classe I e capaz de atravessar a barreira hematoencefálica Zhao, Hall et al 2017),fornecendo assim uma possível abordagem terapêutica adicional para pacientes com Doença de Cushing.…”

“…BKM120 is currently being clinically evaluated for the treatment of different adult cancers including advanced solid tumors, breast cancer, meduloblastoma, colon cancer, colorectal cancer Geuna, Milani et al 2015;Solberg, Waaler et al 2017;Yang, Li et al 2017;Zhao, Hall et al 2017). The effects of the treatment with PI3K inhibitors were evaluated in rat pituitary somatolactotroph tumors and in primary cell cultures of human pituitary lactotroph tumors with promising results ).…”