Therapeutic strategies for actinic keratoses – a systematic review

Nashan, Dorothée; Meiß, Frank; Müller, Marcel Lucas

doi:10.1684/ejd.2013.1923

Cited by 45 publications

(61 citation statements)

References 159 publications

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“…Except surgical removal of the lesion, 5-FU and Imiquimod are the most widely used topical therapeutics for skin cancer [48, 49]. However, 5-FU is occasionally accompanied by many side effects including local pain, itchiness, burning, stinging, and dermatitis.…”

Section: Discussionmentioning

confidence: 99%

Anticancer activity of a novel small molecule tubulin inhibitor STK899704

Sakchaisri¹,

Kim²,

Hwang³

et al. 2017

PLoS ONE

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We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.

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Section: Discussionmentioning

confidence: 99%

Anticancer activity of a novel small molecule tubulin inhibitor STK899704

Sakchaisri¹,

Kim²,

Hwang³

et al. 2017

PLoS ONE

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“…Z niektórych badań wręcz wynika, że jest ona metodą pierwszego wyboru. Kriodestrukcję można stosować zarówno metodą kontaktową, jak i natryskową, z tym że w terapii AK metoda natryskowa wydaje się przydatniejsza [83][84][85][86].…”

Section: Obszar Zagrożenia Nowotworowegounclassified

Actinic keratosis – state of art. Statement of experts of Polish Dermatological Society

Włodarkiewicz¹,

Adamski²,

Chodorowska³

et al. 2014

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“…AK lesions are regarded as premalignant lesions that unpredictably can progress into squamous cell carcinoma (SCC), if left untreated. Although liquid nitrogen cryotherapy and surgical interventions are efficacious treatment options against individual AK lesions, well-tolerated and effective therapies treating the entire UV-induced field change with good cosmetic outcome are essential to ensure high sustained clearance and a good long-term outcome for the patient [4, 5]. Traditionally, 5-fluorouracil, imiquimod, and diclofenac are used in field therapy with treatment lengths over weeks or months with photodynamic therapy (PDT) offering an alternative approach [4, 6].…”

Section: Introductionmentioning

confidence: 99%

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

Bertelsen

Stahlhut

Grue-Sørensen

et al. 2016

Dermatol Ther (Heidelb)

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IntroductionIngenol mebutate gel (Picato®, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and is characterized by high sustained clearance of actinic lesions. The inherent propensity of ingenol mebutate towards chemical rearrangement necessitates refrigeration of the final product. We sought to identify novel ingenol derivatives with enhanced chemical stability and similar or improved in vitro potency and in vivo efficacy.MethodsA number of ingenol esters were synthesized with full regiocontrol from ingenol. Chemical stability was determined in aqueous buffer at physiological pH and hydroalcoholic gel at lower pH. Acute cytotoxicity was determined in HeLa or HSC-5 cells. Keratinocyte proliferation, viability and caspase 3/7 activation was measured in primary epidermal keratinocytes. Relative gene expression levels were determined by real-time quantitative PCR. Evaluation of in vivo tumor ablating potential was performed in the murine B16 melanoma mouse model and in the UV-induced skin carcinogenesis model in hairless SKH-1 mice following topical treatment for two consecutive days with test compounds formulated at 0.1% in a hydroalcoholic gel.ResultsThis work resulted in the identification of ingenol disoxate (LEO 43204) displaying increased stability in a clinically relevant formulation and in aqueous buffer with minimal pH-dependent acyl migration degradation. Ingenol disoxate exhibited a significantly higher cytotoxic potency relative to ingenol mebutate. Likewise, cell growth arrest in normal human keratinocyte was more potently induced by ingenol disoxate, which was accompanied by protein kinase C dependent transcription of markers of keratinocyte differentiation. Most notably, ingenol disoxate possessed a superior antitumor effect in a B16 mouse melanoma model and significantly increased median survival time relative to ingenol mebutate. A significant effect on tumor ablation was also observed in a murine model of ultraviolet irradiation-induced skin carcinogenesis.ConclusionThese data illustrate that the favorable in vitro and in vivo pharmacological properties driving ingenol mebutate efficacy are either preserved or improved in ingenol disoxate. In combination with improved chemical stability to potentially facilitate storage of the final product at ambient temperatures, these features support further development of ingenol disoxate as a convenient and efficacious treatment modality of non-melanoma skin cancers.FundingLEO Pharma A/S.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-016-0137-2) contains supplementary material, which is available to authorized users.

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Therapeutic strategies for actinic keratoses – a systematic review

Cited by 45 publications

References 159 publications

Anticancer activity of a novel small molecule tubulin inhibitor STK899704

Anticancer activity of a novel small molecule tubulin inhibitor STK899704

Actinic keratosis – state of art. Statement of experts of Polish Dermatological Society

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

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