Severe psoriasis treated with a new macrolide: everolimus

Frigerio, E.; Colombo, M.; Franchi, C.; Altomare, A.; Garutti, C.; Altomare, G. F.

doi:10.1111/j.1365-2133.2006.07602.x

Cited by 36 publications

(26 citation statements)

References 12 publications

(13 reference statements)

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“…Clinical trials indicated that rapamycin, the prototypical mTOR inhibitor could significantly reduce the clinical score of psoriasis when treating psoriasis patients (Ormerod et al, 2005;Reitamo et al, 2001). Everolimus, a semisynthetic macrolide and a member of the mTOR inhibitors family, could lead to the resolution of recalcitrant psoriatic manifestations (Frigerio et al, 2007;Wei & Lai, 2015). Our results show that metformin significantly inhibited the phosphorylation of mTOR and its downstream gene p70S6K, indicating that metformin may also contribute to the inhibition of keratinocyte proliferation and inflammation.…”

Section: Discussionmentioning

confidence: 50%

Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

Liu

Yang

et al. 2015

Pharmaceutical Biology

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Context: The antidiabetic drug metformin exhibits antiproliferative and pro-apoptotic effects in various cells, suggesting its potential to treat a variety of malignant and non-malignant hyperplastic diseases. Clinical studies indicate that psoriasis patients with metformin treatment have a better response than those without metformin. Objective: The present study evaluates the antiproliferative activity and anti-inflammatory responses of metformin in human keratinocytes in vitro and explores the underlying mechanisms. Materials and methods: HaCaT cells were incubated with metformin at 0, 25, 50, and 100 mM for 48 h. Antiproliferative activity was evaluated by MTT and apoptotic response was examined by flow cytometry. ELISA was used to detect IL-6, TNF-a, and VEGF protein expression. Western blot was used to investigate the expression of the mammalian target of rapamycin (mTOR) and its downstream effectors p70 ribosomal S6 kinase (p70S6K). Results: The survival rates of HaCaT cells treated with metformin at 50 mM were reduced to 75.6, 59.4, and 30.3% at 24, 48, and 72 h, respectively. The number of apoptotic HaCaT cells was significantly increased at 50 mM metformin after 48 h treatment. Metformin can exert an antiinflammatory effect by direct inhibition of IL-6, TNF-a, and VEGF. Metformin at 50 mM significantly reduced the phosphorylation of mTOR and p70S6K, by 49.0 and 62.1%, respectively. Discussion and conclusion: Metformin treatment significantly inhibited proliferation and proinflammatory responses in HaCaT cells by a mechanism associated with inhibition of the mTOR signaling pathway. The results indicate that metformin may be used as a potential therapeutic agent for psoriasis.

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Section: Discussionmentioning

confidence: 50%

Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

Liu

Yang

et al. 2015

Pharmaceutical Biology

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“…Remarkably, systemic rapamycin or its derivatives have been used for its immunosuppresive properties in anti-psoriatic trials alone or in combination with sub-therapeutic doses of cyclosporine and showed promising success [39–41]. However, our data support the notion that psoriasis patients could rather benefit from the topical use of mTOR inhibitors on the affected skin, which showed encouraging results in a small trial [42].…”

Section: Discussionmentioning

confidence: 64%

Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation

et al. 2017

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Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.

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“…Serious adverse reactions are noninfectious pneumonitis, infections with opportunistic pathogens, and oral ulcerations. Frigerio et al 154 reported a case of a woman with treatment resistant, chronic, relapsing psoriasis that was treated with a combination of everolimus 1.5 mg twice daily and cyclosporine (50 mg daily). The patient had significant improvement, but treatment was discontinued because the patient developed leukopenia by the fifth week.…”

Section: Everolimusmentioning

confidence: 98%