rottlerin and Psoriasis

Rottlerin is a natural polyphenolic compound, which was initially indicated and marketed as a PKC delta inhibitor and recently proposed and patented as an anti-hypertensive drug. In vitro results from our Laboratory and data from the literature suggest a potential use of Rottlerin in the treatment/control of psoriasis, a skin disease characterized by abnormal cellular proliferation, abnormal angiogenesis and inflammation. Rottlerin, indeed, is an antioxidant and a potent inhibitor of the transcription factor NFkappaB, a key mediator of immune responses and a crucial regulator of cell cycle and apoptosis in immune cells, endothelial cells and keratinocytes. Herein, we will review the multiple activities of Rottlerin (antioxidant, antiproliferative, antiangiogenic and anti-inflammatory) that give to the drug the potential to be used as a new therapeutic approach against psoriasis.

Topics: Acetophenones; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Benzopyrans; Cell Proliferation; Drug Discovery; Humans; Keratinocytes; Neovascularization, Pathologic; NF-kappa B; Oxidative Stress; Phytotherapy; Protein Kinase Inhibitors; Psoriasis; Reactive Oxygen Species

Rottlerin is a natural polyphenolic compound that was initially indicated as a PKCδ inhibitor. However, it was recently revealed that it may target a number of molecules and have biological effects on various cell types and is considered as a possible agent for tumor and cell proliferative diseases. Psoriasis is a chronic inflammatory cutaneous disorder with undefined etiology and is characterized by abnormal cellular proliferation, angiogenesis, and inflammation. Therefore, this paper investigates the regulatory effects of rottlerin on normal human epidermal keratinocytes (NHEKs) and imiquimod (IMQ)-induced psoriasiform (IPI) lesions. In vitro results showed that rottlerin inhibited cell proliferation in NHEKs through growth arrest and NFκB inhibition. It may also induce apoptosis in an autophagy-dependent pathway. We found that rottlerin inhibited human microvascular endothelial cells tube formation on matrigel. Rottlerin also decreased the cell senescence of keratinocytes and intracellular ROS generation, which indicated its antioxidant effect. We also showed that rottlerin affects the expression of keratinocyte proliferation biomarkers. In 12-O-tetradecanoylphorbol13-acetate (TPA)-induced keratinocytes, rottlerin significantly inhibited the expression of the induced pro-inflammatory cytokines in keratinocytes. An animal experiment provided the corresponding evidence based on this evidence in vitro, by using IPI model, we found that rottlerin could relieve the psoriasiform of BALB/c mice by inhibiting keratinocyte proliferation, inflammatory cell infiltration, and vascular proliferation. In conclusion, our results suggest that rottlerin may prove useful in the development of therapeutic agents against psoriasis. However, the deep mechanism still requires further study.

Topics: Acetophenones; Adjuvants, Immunologic; Adolescent; Adult; Aminoquinolines; Animals; Apoptosis; Autophagy; Benzopyrans; Cell Proliferation; Cells, Cultured; Female; Humans; Imiquimod; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Middle Aged; NF-kappa B; Psoriasis; Reactive Oxygen Species; Young Adult