Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain.
Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain.
EBioMedicine. 2023 Apr;90:104484. doi: 10.1016/j.ebiom.2023.104484. Epub 2023 Mar 10.
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.
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.
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/TGFβ-pathways). Interestingly, an enrichment analysis uncovered a TGFβ-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)].
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.
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).
由于其侵袭性行为和缺乏可用疗法，胶质母细胞瘤是最具破坏性和最难治愈的癌症之一，其诊断后的总生存期约为 14 个月。因此，迫切需要寻找新的治疗工具。有趣的是，代谢相关药物（如二甲双胍/他汀类药物）正在成为多种癌症的有效抗肿瘤药物。在此，我们评估了二甲双胍和/或他汀类药物对胶质母细胞瘤患者/细胞的关键临床/功能/分子/信号参数的体外/体内影响。
使用探索性观察性随机回顾性胶质母细胞瘤患者队列（n=85）、人胶质母细胞瘤/非肿瘤脑人细胞（细胞系/患者来源的细胞培养物）、小鼠星形胶质细胞祖细胞培养物和临床前异种移植胶质母细胞瘤小鼠模型来测量关键功能参数、信号通路和/或抗肿瘤进展对二甲双胍和/或辛伐他汀的反应。
二甲双胍和辛伐他汀在胶质母细胞瘤细胞培养物中发挥了强大的抗肿瘤作用（即增殖/迁移/肿瘤球/集落形成/VEGF 分泌抑制和凋亡/衰老诱导）。值得注意的是，与单独治疗相比，它们的联合使用可使这些功能参数相加改变。这些作用是通过调节关键致癌信号通路（即 AKT/JAK-STAT/NF-κB/TGFβ 通路）来介导的。有趣的是，富集分析揭示了二甲双胍+辛伐他汀联合治疗后 TGFβ 通路的激活和 AKT 的失活，这可能与衰老状态的诱导、相关的分泌表型以及剪接体成分的失调有关。值得注意的是，二甲双胍+辛伐他汀联合治疗的抗肿瘤作用也在体内观察到[即与人类的总生存期延长相关，以及在小鼠模型中肿瘤进展减少（肿瘤体积/重量/有丝分裂数减少，凋亡增加）]。
总的来说，二甲双胍和辛伐他汀降低了胶质母细胞瘤的侵袭性特征，当两种药物联合使用时，这种效果在体外/体内更有效（更有效），为其在人类中的应用提供了一个具有临床意义的机会，值得进一步研究。
西班牙科学、创新和大学部；安达卢西亚大区政府；CIBERobn（CIBER 是西班牙卫生、社会服务和平等部下属的卡洛斯三世健康研究所的一项倡议）。
