Targeting Immunometabolism in Glioblastoma

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

Section: The Role Of Antipsychotics In Hindering the Growth Of Gbm Cells At The Ten Cancer Hallmarksmentioning

confidence: 99%

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Persico¹,

Abbruzzese²,

Matteoni³

et al. 2022

“…The TAMs in glioblastoma have great plasticity and diversity and express genes related to both M2 and M1 states that may break down L-arginine either via Arg-1 enzyme or iNOS, respectively, depending on the result on the pathway promoted [88][89][90]. M1 states show high expression of IL-12, IL-23, and a low expression of IL-10 and also produce high levels of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, and increase in the expression of iNOS and ROS [91].…”

Section: Reprogramming Between M1 and M2 States 41 The Proof Is In The Tam Pudding: Glioblastoma And Inosmentioning

confidence: 99%

“…However, the balance within the human glioblastomas TME is mainly shifted to an overall tumor supporting state for these TAMs in light of the poor prognosis observed in glioblastoma associated with their accumulation [93]. Therefore, strategic mechanisms to induce iNOS-derived NO and ROS in TAMs may directly destroy tumor cells in glioblastoma, which could also include cytotoxicity through stimulating Th1 responses by the production of CXCL9 and CXCL10 and by generating cytotoxic CD8 cells via IL1β and TNFα [90,94]. As glioblastoma tumor cells are also very adaptive, arginine metabolism in the tumor cells has been examined and found to be very active in the tumor cells [95].…”

Section: Reprogramming Between M1 and M2 States 41 The Proof Is In The Tam Pudding: Glioblastoma And Inosmentioning

confidence: 99%

Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO

Kashfi

Kannikal

Nath

2021

Nitric oxide and its production by iNOS is an established mechanism critical to tumor promotion or suppression. Macrophages have important roles in immunity, development, and progression of cancer and have a controversial role in pro- and antitumoral effects. The tumor microenvironment consists of tumor-associated macrophages (TAM), among other cell types that influence the fate of the growing tumor. Depending on the microenvironment and various cues, macrophages polarize into a continuum represented by the M1-like pro-inflammatory phenotype or the anti-inflammatory M2-like phenotype; these two are predominant, while there are subsets and intermediates. Manipulating their plasticity through programming or reprogramming of M2-like to M1-like phenotypes presents the opportunity to maximize tumoricidal defenses. The dual role of iNOS-derived NO also influences TAM activity by repolarization to tumoricidal M1-type phenotype. Regulatory pathways and immunomodulation achieve this through miRNA that may inhibit the immunosuppressive tumor microenvironment. This review summarizes the classical physiology of macrophages and polarization, iNOS activities, and evidence towards TAM reprogramming with current information in glioblastoma and melanoma models, and the immunomodulatory and therapeutic options using iNOS or NO-dependent strategies.

“…In normal physiology, adenosine and ATP are found in the cytosol, while at the extracellular level they are rarely observable [ 97 ]. In gliomagenesis, intracellular adenosine can be secreted bidirectionally and ATP liberated extracellularly induced by inflammation or hypoxia [ 98 ].…”

Section: Metabolism In Glioblastomamentioning

confidence: 99%

Glioblastoma: Relationship between Metabolism and Immunosuppressive Microenvironment

Hernández

Doménech

Muñoz-Mármol

et al. 2021

Glioblastoma (GBM) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping this tumor microenvironment (TME) regulate tumor initiation, progression, and treatment response. Genetic alterations and metabolism pathways are two main elements that influence tumor immune cells and TME. In this manuscript, we review how both factors can contribute to an immunosuppressive state and overview the strategies being tested.