Metformin and simvastatin exert additive antitumour effects in glioblastoma via senescence-state: clinical and translational evidence.

BACKGROUND: Glioblastoma is one of the most devastating and incurable cancers due to its aggressive behaviour and lack of available therapies, being its overall-survival from diagnosis ∼14-months. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs (e.g., metformin/statins) are emerging as efficient antitumour agents for several cancers. Herein, we evaluated the in vitro/in vivo effects of metformin and/or statins on key clinical/functional/molecular/signalling parameters in glioblastoma patients/cells. METHODS: An exploratory-observational-randomized retrospective glioblastoma patient cohort (n = 85), human glioblastoma/non-tumour brain human cells (cell lines/patient-derived cell cultures), mouse astrocytes progenitor cell cultures, and a preclinical xenograft glioblastoma mouse model were used to measure key functional parameters, signalling-pathways and/or antitumour progression in response to metformin and/or simvastatin. FINDINGS: Metformin and simvastatin exerted strong antitumour actions in glioblastoma cell cultures (i.e., proliferation/migration/tumoursphere/colony-formation/VEGF-secretion inhibition and apoptosis/senescence induction). Notably, their combination additively altered these functional parameters vs. individual treatments. These actions were mediated by the modulation of key oncogenic signalling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFß-pathways). Interestingly, an enrichment analysis uncovered a TGFß-pathway activation, together with AKT inactivation, in response to metformin + simvastatin combination, which might be linked to an induction of the senescence-state, the associated secretory-phenotype, and to the dysregulation of spliceosome components. Remarkably, the antitumour actions of metformin + simvastatin combination were also observed in vivo [i.e., association with longer overall-survival in human, and reduction in tumour-progression in a mouse model (reduced tumour-size/weight/mitosis-number, and increased apoptosis)]. INTERPRETATION: Altogether, metformin and simvastatin reduce aggressiveness features in glioblastomas, being this effect significantly more effective (in vitro/in vivo) when both drugs are combined, offering a clinically relevant opportunity that should be tested for their use in humans. FUNDING: Spanish Ministry of Science, Innovation and Universities; Junta de Andalucía; CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Spanish Ministry of Health, Social Services and Equality).

Music Therapy in Parkinson's Disease.

OBJECTIVES: Parkinson's disease (PD) is a chronic progressive neurologic disorder involving degeneration of the dopaminergic system. Its clinical manifestations include motor and nonmotor symptoms. Several nonpharmacologic therapies, such as music therapy (MT), have recently been developed in order to improve the clinical manifestations of this disease. The aim of this narrative literature review is to analyze the scientific evidence for the therapeutic effects of music in PD. DESIGN: We undertook a search in the databases of PubMed, PsycINFO, Scopus, MEDLINE, and Science Direct. SETTINGAND PARTICIPANTS: Inclusion criteria were articles including persons with PD rehabilitated with an MT intervention. MEASURES: Keywords used were music therapy, Parkinson's disease, auditory cueing, non-motor symptoms, motor symptoms, and quality of life. RESULTS: We detected a total of 27 articles, all of which analyzed the therapeutic effects of MT in PD. Of these, 20 studies analyzed the effects in motor symptoms (16 showed beneficial effects and 4, nonbeneficial effects); 9 studies analyzed the effects in nonmotor symptoms, 7 of which demonstrated beneficial effects; and 8 studies analyzed the effects on quality of life, with 6 reporting benefits. None of the articles analyzing nonmotor symptoms and quality of life showed negative effects. CONCLUSIONS/IMPLICATIONS: Most of the studies analyzed demonstrated that MT has beneficial effects for the nonpharmacologic treatment of motor and nonmotor symptoms and quality of life of persons with PD. The use of music as a therapeutic tool combined with conventional therapies should be taken into account.