Thiazolidinediones: potential as therapeutics for psoriasis and perhaps other hyperproliferative skin disease.
The thiazolidinediones constitute a family of synthetic compounds that act as high-affinity ligands for persoxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor family. Although originally developed to facilitate glucose control in patients with Type 2 diabetes, a number of studies showed that these agents effectively inhibited epithelial cell proliferation and tissue inflammation. Many of the initial cell growth inhibition studies were conducted with malignant epithelial cells from various sites; however, in addition to malignant epithelial cells, other studies showed that rapidly proliferating epidermal keratinoctyes in culture were also sensitive to the growth-inhibiting action of these moieties. Additional studies subsequently demonstrated that some patients with plaque psoriasis responded to treatment with one or another member of the thiazolidinedione family. Due to the potential therapeutic benefit of these compounds in diseases such as psoriasis, studies have been conducted to elucidate mechanisms by which growth inhibition is achieved. Interference with a number of growth-influencing signalling pathways has been demonstrated. Of interest, some of the growth-inhibiting effects are seen under conditions in which PPAR-gamma activation may not be responsible for the activity. Based on therapeutic potential, additional ongoing studies are aimed at developing novel thiazolidinediones that may have better efficacy than the currently available agents. Other studies are aimed at identifying optimal ways to use these agents in the treatment of hyperplastic skin diseases such as psoriasis.
Varani
James
J
University of Michigan Medical School, Department of Pathology, 1301 Catherine Road/Box 0602, Ann Arbor, MI 48109, USA. varani@umich.edu
Bhagavathula
Narasimharao
N
Ellis
Charles N
CN
Pershadsingh
Harrihar A
HA
D000818:Animals; D003879:Dermatologic Agents / Q000627:therapeutic use*; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use*; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D012871:Skin Diseases / Q000188:drug therapy* / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry
D003879:Dermatologic Agents; D015507:Drugs, Investigational; D047495:PPAR gamma; D045162:Thiazolidinediones