Clinical utility of ingenol mebutate in the management of actinic keratosis: perspectives from clinical practice

Skroza, Nevena; Bernardini, Nicoletta; Proietti, Ilaria; Potenza, Concetta

doi:10.2147/tcrm.s145779

Cited by 11 publications

(7 citation statements)

References 47 publications

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“…IM presents two mechanisms of action: at high concentrations (~200-300 µM), it induces rapid induction of cell death in the treated area and at low concentrations (~0.1 µM) it activates inflammatory response, capable of eliminating the residual cells. Pharmacology, mode of action, pharmacokinetics, dosing, and rout of administration of ingenol mebutate have been reviewed in more details by Skroza et al (2018). Homoharringtonine (HHT) is a naturally-occurring ester of the alkaloid cephalotaxine isolated from various trees of the Cephalotaxus genus (Cephalotaxaceae) and is approved for the treatment of chronic myeloid leukemia.…”

Section: Other Plant-derived Anticancer Agentsmentioning

confidence: 99%

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

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Cancer is a severe health problem that continues to be a leading cause of death worldwide. Increasing knowledge of the molecular mechanisms underlying cancer progression has led to the development of a vast number of anticancer drugs. However, the use of chemically synthesized drugs has not significantly improved the overall survival rate over the past few decades. As a result, new strategies and novel chemoprevention agents are needed to complement current cancer therapies to improve efficiency. Naturally occurring compounds from plants known as phytochemicals, serve as vital resources for novel drugs and are also sources for cancer therapy. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, and podophyllotoxin analogs. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancer. The specific mechanisms include increasing antioxidant status, carcinogen inactivation, inhibiting proliferation, induction of cell cycle arrest and apoptosis; and regulation of the immune system. The primary objective of this review is to describe what we know to date of the active compounds in the natural products, along with their pharmacologic action and molecular or specific targets. Recent trends and gaps in phytochemical based anticancer drug discovery are also explored. The authors wish to expand the phytochemical research area not only for their scientific soundness but also for their potential druggability. Hence, the emphasis is given to information about anticancer phytochemicals which are evaluated at preclinical and clinical level.

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Section: Other Plant-derived Anticancer Agentsmentioning

confidence: 99%

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

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“…Firstly, in our previous studies, we observed that under the influence of cyclosporin A therapy in patients with psoriasis, there is a change in the transcriptional activity of TGFβ1-3 and TGFβRI-III [ 17 , 18 ]. Studies have indicated that CsA therapy significantly increases the risk of skin cancer [ 39 , 40 ]. Therefore, it seems reasonable to better understand how CsA also affects other transcripts of TGF β -dependent path genes.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the silencing of SKP2 and PRKR2B after the addition of cyclosporin A may confirm its anti-inflammatory properties and efficacy. In addition, it can be assumed that in the described relationship between CsA therapy and an increased risk of cancer [ 39 , 40 ], the SKP2 and PRKR2B genes are not involved or their role is marginal.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Adalimumab and Cyclosporine A on the Expression Profile of the Genes Related to TGFβ Signaling Pathways in Keratinocyte Cells Treated with Lipopolysaccharide A

Adwent

Grabarek

Kojs‐Mrożkiewicz³

et al. 2020

Mediators of Inflammation

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Background. In the treatment of moderate to severe psoriasis, cyclosporine A (CsA) conventional therapy is used and biological, anti-cytokine treatment using, for example, anti-TNF drug—adalimumab. Aim. This study aimed at investigating the effect of CsA and adalimumab on the profile of mRNAs and protein expression associated with transforming growth factor β (TGFβ) pathways in human keratinocyte (HaCaT) culture previously exposed to lipopolysaccharide (LPS). Materials and Methods. HaCaT culture was exposed to 1 ng/ml LPS for 8 hours+8 μg/ml adalimumab for 2, 8, and 24 hours or 1 ng/ml LPS for 8 hours+100 ng/ml CsA for 2, 8, and 24 hours and compared to the control culture. Sulphorodamine B cytotoxicity assay was performed. The expression profile of mRNA related to TGFβ paths was indicated by microarray and RTqPCR analyses. The ELISA test was used to analyze changes on the proteome level. Statistical analysis consisted of ANOVA analysis and the post hoc Tukey test (p<0.05). Results. The cytotoxicity test showed that LPS, adalimumab, and cyclosporine in the concentration used in this experiment did not have any cytotoxicity effect on HaCaT cells. The largest fold changes (FC) in expression in (∣FC∣>4.00) was determined for TGFβ1-3, TGFβRI-III, SKIL, SMURF2, SMAD3, BMP2, BMP6, JAK2, UBE2D1, SKP2, EDN1, and PRKAR2B (p<0.05). In addition, on the protein level, the direct changes observed at mRNA were the same. Conclusion. Analysis of the microarray expression profile of genes associated with TGFβ signaling pathways has demonstrated the potential of cyclosporin A and adalimumab to induce changes in their transcriptional activity. The anti-TNF drug seems to affect TGFβ cascades to a greater extent than cyclosporin A. The obtained results suggest that the regularity of taking the drug is important for the efficacy of psoriasis therapy.

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“…The highest malignant transformation rates are found in males, elderly patients, individuals with phototypes I and II, human papillomavirus infection, a family history of skin cancer, and in immune-suppressed individuals [8][9][10]. However, despite the advances in the recognition of clinic, dermoscopic and histologic patterns, it is not yet possible to predict which lesions will advance to SCC [11]. For this reason, an early diagnosis and effective treatment are recommended.…”

Section: Introductionmentioning

confidence: 99%

“…There are many variables that may influence the therapy choice in an individual, such as the number and location of lesions, age and immunological status of the patient, personal history of previous skin lesions and previous treatments [11]. Nevertheless, since AKs are usually multiple and often subclinical, a field-directed approach is suggested to remove clinically visible as well as non-visible lesions within the treatment area to prevent the development to invasive SCC [12].…”

Section: Introductionmentioning

confidence: 99%

Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel

Segura¹,

Gadea²,

Nonell³

et al. 2020

PLoS ONE

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Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood. In this study, we evaluated the gene expression profiles of actinic keratosis lesions before and after treatment with ingenol mebutate using microarray technology. Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evaluated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 consecutive days. Diagnostic and clearance of lesions was determined by clinical, dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Differentially expressed genes were identified, and enrichment analyses were performed using STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebutate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially expressed genes were identified following treatment, and downregulated genes (114 of 128) revealed changes in pathways important to epidermal development, keratinocyte differentiation and cornification. In responder patients, 388 downregulated genes (of 450 differentially expressed genes) were also involved in development/differentiation of the epidermis, and immune system-related pathways, such as cytokine and interleukin signaling. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, differentially expressed genes were mainly associated with cornification, keratinization and keratinocyte differentiation. Overall, the present study provides insight into the gene expression profile of actinic keratoses after treatment with ingenol mebutate, as well as identification of genetic signatures that could predict treatment response.

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Clinical utility of ingenol mebutate in the management of actinic keratosis: perspectives from clinical practice

Cited by 11 publications

References 47 publications

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

The Influence of Adalimumab and Cyclosporine A on the Expression Profile of the Genes Related to TGFβ Signaling Pathways in Keratinocyte Cells Treated with Lipopolysaccharide A

Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel

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