Sulochana S. Bhandarkar

Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice

Hemangiomas are the most common type of tumor in infants. As they are endothelial cell-derived neoplasias, their growth can be regulated by the autocrine-acting Tie2 ligand angiopoietin 2 (Ang2). Using an experimental model of human hemangiomas, in which polyoma middle T-transformed brain endothelial (bEnd) cells are grafted subcutaneously into nude mice, we compared hemangioma growth originating from bEnd cells derived from wild-type, Ang2+/-, and Ang2-/- mice. Surprisingly, Ang2-deficient bEnd cells formed endothelial tumors that grew rapidly and were devoid of the typical cavernous architecture of slow-growing Ang2-expressing hemangiomas, while Ang2+/- cells were greatly impaired in their in vivo growth. Gene array analysis identified a strong downregulation of NADPH oxidase 4 (Nox4) in Ang2+/- cells. Correspondingly, lentiviral silencing of Nox4 in an Ang2-sufficient bEnd cell line decreased Ang2 mRNA levels and greatly impaired hemangioma growth in vivo. Using a structure-based approach, we identified fulvenes as what we believe to be a novel class of Nox inhibitors. We therefore produced and began the initial characterization of fulvenes as potential Nox inhibitors, finding that fulvene-5 efficiently inhibited Nox activity in vitro and potently inhibited hemangioma growth in vivo. In conclusion, the present study establishes Nox4 as a critical regulator of hemangioma growth and identifies fulvenes as a potential class of candidate inhibitor to therapeutically interfere with Nox function.

The antidepressant sertraline downregulates Akt and has activity against melanoma cells.

Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho‐p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon‐induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma.

Tris (Dibenzylideneacetone) Dipalladium, a N-Myristoyltransferase-1 Inhibitor, Is Effective against Melanoma Growth In vitro and In vivo

Purpose: Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA. Experimental Design: Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed. Results: Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma. Conclusion: Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.

Targeted therapy of oral hairy leukoplakia with gentian violet

Oral hairy leukoplakia (OHL) is a common oral manifestation of HIV infection. Clinically, these lesions appear as white plaques on the edges of the tongue. Pathophysiologically, these lesions occur because of infection of oral epithelium with Epstein-Barr virus (EBV). No universally effective therapy exists for OHL. We have previously shown that EBV infection and EBV viral products induce the generation of reactive oxygen. We have also demonstrated that the Food and Drug Administration-approved over-the-counter medication gentian violet is a potent inhibitor of reactive oxygen species. We thus chose to treat a patient with biopsy-proven OHL with topical gentian violet. Gentian violet solution was applied topically to the tongue of a patient with OHL. Complete clinical resolution was noted after three treatments. Treatment with topical gentian violet resulted in resolution of the lesions. Further studies with larger numbers of patients are required. The application of gentian violet can be used as a method to OHL treatment. Gentian violet is an inexpensive and safe therapy and, given that it inhibits reactive oxygen, this old therapy is now a targeted novel therapy.

Efficacy of rapamycin in scleroderma: A case study

Scleroderma is a common autoimmune disorder with no effective therapy. Current concepts of scleroderma include the hypothesis that scleroderma results from excess conversion of endothelial cells to fibroblast like cells, called endothelial mesenchymal transformation. This process is thought to be mediated by cytokines including transforming growth factor beta (TGFb), which causes increased collagen synthesis, resulting in fibrosis, the hallmark of the disease. In vitro studies have hypothesized that rapamycin may be of benefit in scleroderma due to antagonism of collagen synthesis. Given that rapamycin has antiangiogenic activities, inhibits wound healing, and prevents the synthesis of collagen in vivo, we tried rapamycin in a patient with scleroderma. We observed rapid improvement in skin stiffness and mobility. Our results provide the rationale for larger clinical trials of rapamycin in scleroderma and other fibrotic disorders.

Quality-of-Life Issues in Vitiligo

Vitiligo, an acquired disease of depigmentation, affects millions worldwide. The psychosocial and health-related quality of life (HRQL) impact of the disease varies based on several parameters, including country of origin, skin type, gender, age, marital status, and involved body site. Many instruments, both dermatology specific and dermatology nonspecific, have been used to measure HRQL. Assessing HRQL in vitiligo is an important part of disease management.

Tuberculosis verrucosa cutis lesions exhibit a greater microvessel count than lupus vulgaris lesions

Tuberculosis verrucosa cutis lesions exhibit a greater microvessel count than lupus vulgaris lesions Sulochana S. Bhandarkar, Padmavathy Lanka, Lakshmana Rao Lanka, Emir Veledar, Michael Y. Bonner, Jamie MacKelfresh and Jack L. Arbiser Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA; Department of Dermatology, Veterans Administration Medical Center, Atlanta, GA, USA; Department of Pathology, Vinayaka Mission’s Medical College, Karaikal, Pondicherry UT, India; Baptist Health South Flordia, Jacksonville, FL, USA; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA Correspondence: Jack L. Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 101 Woodruff Circle, Atlanta, GA 30322, USA, Tel.: (404) 727-5063, Fax: (404) 727-0923, e-mail: jarbise@emory.edu

Skin Diseases (Noncancerous)

This article is reproduced from the previous edition, volume 6, pp. 15–21,

Skin Diseases (Non-Cancerous)

Since skin is the largest organ in the body, skin-based diseases are among the most common diseases in the human population, ranging from cancerous to noncancerous diseases caused by infection, inflammation, and autoimmune disorders. The occurrence of skin diseases varies between continents with people being exposed to different elements. These different skin diseases have individualized diagnoses, treatments, and a unique social traumatic aspect. Given the abundance of dermatological diseases, this article only focuses on the most common skin diseases found around the world.