Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma

Tampucci, Silvia; Carpi, Sara; Digiacomo, Maria; Polini, Beatrice; Fogli, Stefano; Burgalassi, Susi; Macchia, Marco; Nieri, Paola; Manera, Clementina; Monti, Daniela

doi:10.3390/molecules24091793

Cited by 12 publications

(11 citation statements)

References 44 publications

(53 reference statements)

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“…Molecular hybridization is a new concept in drug design and development, based on the combination of pharmacophoric moieties of different bioactive molecules to produce new compounds with improved affinity and efficacy in comparison to the parent drugs [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis

et al. 2020

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Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. The pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. The activity of compound 3, one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. The hybrid compounds showed a higher potency in inhibiting PGE2 production, but not in modifying the platelet aggregation and the TXB2 production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound 3 was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. In conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis

et al. 2020

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“…The topical application of drugs represents one of the most preferable routes for drug administration because of advantages as first pass metabolism bypass and increased patient compliance [ 13 ]. For the last few decades, the nanotechnologies have been studied to enhance drug bioavailability following topical application [ 10 , 14 , 15 , 16 , 17 ] and received increasing attention for the treatment of melanoma [ 2 , 7 , 18 ]. Still, the field is open for the development of more potent and biocompatible topical formulations.…”

Section: Introductionmentioning

confidence: 99%

pH-Responsive Nanostructures Based on Surface Active Fatty Acid-Protic Ionic Liquids for Imiquimod Delivery in Skin Cancer Topical Therapy

et al. 2020

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For topical treatment of skin cancer, the design of pH-responsive nanocarriers able to selectively release the drug in the tumor acidic microenvironment represents a reliable option for targeted delivery. In this context, a series of newly synthesized surface-active fatty acid-protic ionic liquids (FA-PILs), based on tetramethylguanidinium cation and different natural hydrophobic fatty acid carboxylates, have been investigated with the aim of developing a pH-sensitive nanostructured drug delivery system for cutaneous administration in the skin cancer therapy. The capability of FA-PILs to arrange in micelles when combined with each other and with the non-ionic surfactant d-α-Tocopherol polyethylene glycol succinate (vitamin E TPGS) as well as their ability to solubilize imiquimod, an immuno-stimulant drug used for the treatment of skin cancerous lesions, have been demonstrated. The FA-PILs-TPGS mixed micelles showed pH-sensitivity, suggesting that the acidic environment of cancer cells can trigger nanostructures’ swelling and collapse with consequent rapid release of imiquimod and drug cytotoxic potential enhancement. The in vitro permeation/penetration study showed that the micellar formulation produced effective imiquimod concentrations into the skin exposed to acid environment, representing a potential efficacious and selective drug delivery system able to trigger the drug release in the tumor tissues, at lower and less irritating drug concentrations.

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“…The HacaT non-tumorigenic keratinocyte cell line was used as a control and was acquired from the Experimental Zooprophylactic Institute of Lombardia and Emilia Romagna (Brescia, Italy). The HacaT cell line can be used as non-tumor control of the A431 cells (56)(57)(58)(59)(60) and it is considered a reliable model for skin diseases and for in vitro carcinogenesis of human skin keratinocytes (61,62). The HacaT and A431 cell lines were cultured under the same culture conditions to prevent differences in phototoxicity related to different growth mediums.…”

Section: Methodsmentioning

confidence: 99%

Apoptotic mechanism activated by blue light and cisplatinum in cutaneous squamous cell carcinoma cells

et al. 2021

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New approaches are being studied for the treatment of skin cancer. It has been reported that light combined with cisplatinum may be effective against skin cancer. In the present study, the effects of specific light radiations and cisplatinum on A431 cutaneous squamous cell carcinoma (cScc) and HacaT non-tumorigenic cell lines were investigated. Both cell lines were exposed to blue and red light sources for 3 days prior to cisplatinum treatment. Viability, apoptosis, cell cycle progression and apoptotic-related protein expression levels were investigated. The present results highlighted that combined treatment with blue light and cisplatinum was more effective in reducing cell viability compared with single treatments. Specifically, an increase in the apoptotic rate was observed when the cells were treated with blue light and cisplatinum, as compared to treatment with blue light or cisplatinum alone. combined treatment with blue light and cisplatinum also caused cell cycle arrest at the S phase. Treatment with cisplatinum following light exposure induced the expression of apoptotic proteins in the A431 and HacaT cell lines, which tended to follow different apoptotic mechanisms. On the whole, these data indicate that blue light combined with cisplatinum may be a promising treatment for cScc.

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Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma

Cited by 12 publications

References 44 publications

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis

pH-Responsive Nanostructures Based on Surface Active Fatty Acid-Protic Ionic Liquids for Imiquimod Delivery in Skin Cancer Topical Therapy

Apoptotic mechanism activated by blue light and cisplatinum in cutaneous squamous cell carcinoma cells

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