Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target

Giatti, Silvia; Domizio, Alessandro Di; Diviccaro, Silvia; Falvo, Eva; Caruso, Donatella; Contini, Alessandro; Melcangi, Roberto Cosimo

doi:10.1021/acs.jmedchem.0c02039

Cited by 18 publications

(14 citation statements)

References 91 publications

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“…It may be expected that the presence of MV1035 makes it difficult for the methylated nucleobase within DNA to reach the right site for the enzymatic reaction ( Figure 2 C,D). Noteworthy, the PBS for MV1035 within ALKBH2 was identified despite being partially closed and apparently inaccessible to the ligand (see Supplementary Figure S1 and Supplementary Table S2 ) thanks to SPILLO-PBSS’s ability to take into account protein flexibility [ 16 , 28 , 29 ].…”

Section: Resultsmentioning

confidence: 99%

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

Malacrida

Domizio²,

Bentivegna

et al. 2022

Biology

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Glioblastoma (GBM, grade IV glioma) represents the most aggressive brain tumor and patients with GBM have a poor prognosis. Until now surgical resection followed by radiotherapy and temozolomide (TMZ) treatment represents the standard strategy for GBM. We showed that the imidazobenzoxazin-5-thione MV1035 is able to significantly reduce GBM U87-MG cells migration and invasiveness through inhibition of the RNA demethylase ALKBH5. In this work, we focus on the DNA repair protein ALKBH2, a further MV1035 target resulting from SPILLO-PBSS proteome-wide scale in silico analysis. Our data demonstrate that MV1035 inhibits the activity of ALKBH2, known to be involved in GBM TMZ resistance. MV1035 was used on both U87-MG and two patient-derived (PD) glioma stem cells (GSCs): in combination with TMZ, it has a significant synergistic effect in reducing cell viability and sphere formation. Moreover, MV1035 induces a reduction in MGMT expression in PD-GSCs cell lines most likely through a mechanism that acts on MGMT promoter methylation. Taken together our data show that MV1035 could act as an inhibitor potentially helpful to overcome TMZ resistance and able to reduce GBM migration and invasiveness.

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Section: Resultsmentioning

confidence: 99%

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

Malacrida

Domizio²,

Bentivegna

et al. 2022

Biology

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“…Giatti et al identified an off-target effect of finasteride on phenylethanolamine N-methyltransferase (PNMT), a limiting enzyme for the production of epinephrine (EPI) from norepinephrine. 105 Catecholamines including EPI have been found…”

Section: Androgen Mediation Of Angiogenesismentioning

confidence: 99%

From organ injury to disability: a proposed model for 5-alpha reductase inhibitor syndrome

Montaigne¹

2022

Preprint

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Persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors (PD-5ARI) may be explained as the aftermath of a pathological recovery from microvasculopathy or ischemia in multiple systems. Focusing on persistent sexual dysfunction, the most common class of symptoms: 5ARIs’ inhibition of angiogenesis leads to stress on penile microvasculature, depriving the tissue of blood supply and oxygen. These hypoxic conditions lead to tissue injury and atrophy, triggering a pathological recovery that further alters penile tissue, including smooth muscle loss, fibrosis, damage to vascular architecture and impairment of neural pathways supporting arousal and erectile function. This damaging cascade may result in severe and lasting sexual dysfunction. Persistent neuropsychiatric, cognitive, sensory and sleep dysfunctions emerging from 5ARI treatment may similarly be explained as pathological responses to microvasculopathy or ischemia in supporting structures, particularly those in the limbic system. Systemic spread is proposed to arise from a vicious cycle of tissue injury, oxidative stress and proinflammatory activity which spreads via the vascular network, leading to systemic endothelial dysfunction. The latter may in turn set off a damaging cascade in other organs and tissues. Risks of developing PD-5ARI may arise from 5ARI-mediated disruptions of vascular tone, angiogenesis and neoangiogenesis. Pharmacovigilance data, animal studies and human studies provide converging evidence for the proposed etiopathology. It is, moreover, consistent with variable presentation and severity of PD-5ARI symptoms; irreversibility of symptoms; typically normal results of clinical lab tests; and resistance to treatment.

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“…Importantly, some of these effects of finasteride persisted even one month after withdrawal [ 51 ]. Furthermore, recent studies show finasteride exerts inhibitory effects on the rate-limiting enzyme responsible for adrenaline production, complicating its use in stress-related studies [ 52 ]. Given the role of sex steroids in the organisation of the HPA axis during the perinatal period and puberty [ 53 ], the use of finasteride during pregnancy or sensitive postnatal developmental windows may lead to sex-specific side-effects; hence, outcomes should be considered with this caveat in mind.…”

Section: Role Of Neurosteroids In Programming During the Critical Dev...mentioning

confidence: 99%

Neurosteroids and early-life programming: An updated perspective

Sze

Brunton²

2022

Current Opinion in Endocrine and Metabolic Research

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Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target

Cited by 18 publications

References 91 publications

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

From organ injury to disability: a proposed model for 5-alpha reductase inhibitor syndrome

Neurosteroids and early-life programming: An updated perspective

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