Topical Application of a Dual ABC Transporter Substrate and NF-κB Inhibitor Blocks Multiple Sources of Cutaneous Inflammation in Mouse Skin

Abstract

Among the molecular signals underlying cutaneous inflammation is the transcription complex NF-kB, its upstream modulators, and cytokines and chemokines that are the downstream proinflammatory effectors. Central to NF-kB activation is IkB kinase (IKK), which phosphorylates IkBa, releasing NF-kB to the nucleus. In a screening of a kinase inhibitor library, we identified two IKK inhibitors that were high-affinity substrates for p-glycoprotein (ABCB1), the multidrug resistance protein known to facilitate transdermal drug delivery. ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile) and IKK 16 prevented both nuclear translocation of NF-kB and activation of a NF-kB reporter and reduced the induction of cytokine and chemokine transcripts in human or mouse keratinocytes by IL-1a, tumor necrosis factor-a, and phorbol myristate acetate. ACHP, but not IKK 16, was nontoxic to mouse or human keratinocytes at any dose tested. In mice, topical ACHP prevented the cutaneous inflammation induced by topical phorbol myristate acetate or imiquimod, reduced the inflammation from erythema doses of artificial sunlight, and lowered the tumor incidence of mice treated with 7,12-dimethyl benzanthracene when applied before phorbol myristate acetate. Topical ACHP also reduced the NF-kB and IL-17 inflammatory signature after multiple doses of imiquimod. Thus, ACHP and IKK 16 hit their NF-kB target in mouse and human keratinocytes, and ACHP is an effective topical nonsteroidal anti-inflammatory in mice.

Monovalent antibody-conjugated lipid-polymer nanohybrids for active targeting to desmoglein 3 of keratinocytes to attenuate psoriasiform inflammation

“…IMQ is known to decrease cAMP and then induce NF-κB phosphorylation 24 . This activation enhances expression of IL-1β, IL-6, TNF-α, and chemokines in keratinocytes 57 . PDE4 inhibitors elevate cellular cAMP by suppressing NF-κB phosphorylation.…”

Targeting anti-inflammatory immunonanocarriers to human and murine neutrophils via the Ly6 antigen for psoriasiform dermatitis alleviation

“…To ablate the inflammatory response of psoriasis in the skin, the drug penetration into the deeper cutis is important to inhibit immune cell infiltration. 54 We showed that the upregulated cytokine suppression by unfunctionalized and functionalized nanocarriers was comparable. The IVIS and RFL distribution results demonstrated a higher skin uptake of unfunctionalized nanoparticles compared to the targeted nanocarriers.…”

Effect of Ultraviolet Radiation on the Expression of Drug Transporters in In Vitro Skin Models

“…Using reverse transcription polymerase chain reaction (RT-PCR) we have shown expression of ABCB1, ABCC1, ABCC2 and ABCG2 in ex vivo human skin and in 3D-reconstructed human epidermis models, with ABCB1 and ABCG2 being barely expressed and ABCC1 being with the highest expression level. Functional analysis has shown that MDR1 and MRP1 expressed in the skin facilitate drug transdermal delivery the ABC transporter-mediated mechanism of absorptive transport represents a critical component of the effectiveness of the topical products [38,40]. In a subsequent RT-PCR analysis for the SLC gene family, we have shown expression of SLCO3A1, SLCO2B1, SLC47A2, SLCO4A1 and SLC47A1 in ex vivo human skin model, with SLC47A1 being highly expressed [36].…”