Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.

Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosomes. Our results are supported by both genetic ablation and pharmacological inhibition of TPC2. Mechanistically, our data show that loss/block of TPC2 results in reduced protein levels of MITF, a major regulator of melanoma progression, but an increased activity of the melanin-generating enzyme tyrosinase. TPC2 inhibition thus provides a twofold benefit in melanoma prevention and treatment by increasing, through interference with tyrosinase activity, the synthesis of UV blocking melanin in melanosomes and by decreasing MITF-driven melanoma progression by increased GSK3ß-mediated MITF degradation.

Topical RT1640 treatment effectively reverses gray hair and stem cell loss in a mouse model of radiation-induced canities.

Gray hair is a visible sign of tissue degeneration during aging. Graying is attributed to dysfunction of melanocyte stem cells (McSCs) that results in depletion of their melanin-producing progeny. This non-lethal phenotype makes the hair follicle and its pigment system an attractive model for investigating mechanisms that contribute to tissue aging and therapeutic strategies to combat this process. One potential combination therapeutic is RT1640, which is comprised of two drugs that are known to stimulate hair growth (cyclosporine A [CsA] and minoxidil), along with RT175, a non-immunosuppressive immunophilin ligand that is implicated in tissue regeneration. Using the ionizing radiation-induced acute mouse model of hair graying, we demonstrate that RT1640, over CsA alone, promotes regeneration of the hair pigment system during and following treatment. In non-irradiated mice, RT1640 is also physiologically active and successfully speeds hair growth and expands the McSC pool. It appears that this effect relies on the combined activities of the three drugs within RT1640 to simultaneously activate hair growth and McSCs as RT175 alone was insufficient to induce hair cycling in vivo, yet sufficient to drive the upregulation of the melanogenic program in vitro. This study sets the stage for further investigation into RT1640 and its components in McSC biology and, ultimately, melanocyte hypopigmentary disorders associated with disease and aging.

Eriodictyon angustifolium extract, but not Eriodictyon californicum extract, reduces human hair greying.

OBJECTIVE: Yerba Santa (Eriodictyon angustifolium and Eriodictyon californicum) has been used for many years in traditional medicine. However, the effect of Yerba Santa on melanogenesis has not yet been investigated. We aimed to assess the biological effects of Yerba Santa on hair pigmentation. METHODS: Yerba Santa extracts were assessed for their cytological effects following X-ray irradiation treatment and then tested directly for the prevention of human hair greying. Ultra-performance liquid chromatography (UPLC) was utilized to identify the individual extract components. RESULTS: Eriodictyon angustifolium extract significantly increased melanin synthesis in the melanoma cell line through activation of the WNT/MITF/tyrosinase-signalling pathway. In contrast, E. californicum had no effect on melanin synthesis. E. angustifolium extract also demonstrated a protective effect against the damage induced by X-ray irradiation in human keratinocytes. Application of the extracts to subjects who had grey beards demonstrated a reduced number of grey beard hair per year specifically with the E. angustifolium extract. A significant decrease in grey head hair was also observed after application of E. angustifolium extract. Upregulation of gene expression related to melanin production and WNT signalling was observed after the application of E. angustifolium extract. Sterubin was the most abundant flavonoid detected by UPLC in E. angustifolium extract. In addition, sterubin showed the highest difference in terms of quantity, between E. angustifolium and E. californicum extract. CONCLUSION: Eriodictyon angustifolium extract, which is abundant in sterubin, may be suitable as a potential cosmetic and medical agent for the prevention and improvement of hair greying.

OBJECTIF: Yerba Santa (Eriodictyon angustifolium et Eriodictyon californicum) est utilisé depuis de nombreuses années en médecine traditionnelle. Cependant, l'effet de Yerba Santa sur la mélanogenèse n'a pas encore été étudié. Notre objectif était d'évaluer les effets biologiques de Yerba Santa sur la pigmentation des cheveux. MÉTHODES: Les extraits de Yerba Santa ont été évalués pour leurs effets cytologiques après un traitement d'irradiation aux rayons X, puis testés directement pour la prévention du grisonnement des cheveux humains. La chromatographie liquide ultra-performante (UPLC) a été utilisée pour identifier les composants d'extrait individuels. RÉSULTATS: L'extrait d'E. angustifolium a augmenté de manière significative la synthèse de mélanine dans la lignée cellulaire du mélanome par l'activation de la voie de signalisation WNT/MITF/tyrosinase. En revanche, E. californicum n'a eu aucun effet sur la synthèse de mélanine. L'extrait d'E. angustifolium a également démontré un effet protecteur contre les dommages induits par l'irradiation aux rayons X dans les kératinocytes humains. L'application des extraits à des sujets qui avaient une barbe grise a démontré un nombre réduit de poils gris par an spécifiquement avec l'extrait d'E. angustifolium. Une diminution significative des cheveux gris a également été observée après l'application d'extrait d'E. angustifolium. Une régulation à la hausse de l'expression des gènes liée à la production de mélanine et à la signalisation WNT a été observée après l'application d'extrait d'E. angustifolium. La stérubine était le flavonoïde le plus abondant détecté par UPLC dans l'extrait d'E. angustifolium. De plus, la stérubine a montré la plus grande différence en termes de quantité entre E. angustifolium et E. californicum. CONCLUSION: L'extrait d'E. angustifolium, qui est abondant en stérubine, peut convenir comme agent cosmétique et médical potentiel pour la prévention et l'amélioration du grisonnement des cheveux.

A review of the etiologies, clinical characteristics, and treatment of canities.

Hair pigmentation is regulated by follicular melanogenesis, in which the process consists of melanin formation and transfer to keratinocytes in the hair shaft. Human hair follicles contain two types of melanin: the brown-black eumelanin and yellow-red pheomelanin. Eumelanin is commonly present in black and brown hair while pheomelanin is found in auburn and blonde hair. Hair follicle melanogenesis is under cyclical control and is concurrently coupled to hair growth. Many factors including intrinsic and extrinsic factors affect the follicular melanogenesis. Though many studies have been conducted to identify the pathogenesis and regulation of hair pigmentation, the etiology of canities and hair pigmentation is still unclear. The pathogenesis of canities or gray hair is believed to occur either from insufficient melanin formation due to melanocyte degeneration or a defect in melanosomal transfer. Canities is an aging sign which often interferes with one's socio-cultural adjustment. On the other hand, premature canities correlate with diseases such as osteopenia and cardiovascular disease. Risk factors associated with canities are not only genetic but also external causes. For example, smoking, alcohol consumption, and stress are among the most common factors. Camouflage techniques are still used as the primary treatment of canities. Further treatments for canities are being developed to achieve the true reversal of hair pigmentation.

Rapid hair depigmentation in patient treated with pazopanib.

Pazopanib is multitargeted tyrosine kinase inhibitor used for the treatment of metastatic renal cell carcinoma. Hair colour change is a common side effect of pazopanib therapy which usually develops gradually during few months of therapy. We report a case of the patient who developed multiple pazopanib side effects followed by rapid overnight hair and eyebrow depigmentation after only few weeks of therapy. In our research, we found no literature data of rapid loss of hair pigment due to therapy with any of listed multitargeted tyrosine kinase inhibitors. To the best of our knowledge, this is the first such case being reported. We presume that summation of different mechanisms probably led to rapid hair depigmentation. Considering the fact that pazopanib treatment was very effective in our patient, this side effect could be a good predictor of therapy success, although it presents very stressful event for patient and his family.

Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer.

Importance: New targeted therapies for cancer have been released in recent years, opening new horizons in the treatment of patients with cancer. However, their related adverse events (AE) are not fully characterized. Hair repigmentation (HR) is a nondescribed effect secondary to anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1 ) therapy for treatment of lung cancer (LC), in opposition to the vitiligo reactions that develop during melanoma treatment. Objective: To describe a new adverse event occurring during anti-PD-1/anti-PD-L1 therapy for LC. Design, Setting, and Participants: A case series from a descriptive observation of 14 patients with HR after anti-PD-1/anti-PD-L1 treatment, recruited between September and December, 2016, who were followed up to detect whether they developed cutaneous AE at the time HR was detected. The patients had all been treated in the dermatology department at Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Main Outcomes and Measures: Clinical observation of HR during anti-PD-1/anti-PD-L1 therapy for LC, proved by comparing old pictures provided by the patients and recent pictures taken during the follow-up. Results: Fourteen patients (13 men and 1 woman; mean age, 64.9 years) receiving anti-PD-1 or anti-PD-L1 therapy for non-small-cell lung cancer (NSCLC) presented hair repigmentation during follow-up. This hair repigmentation consisted in a diffuse darkening of the hair in 13 of 14 patients, or in black patches between white hairs in 1. Thirteen of 14 patients presented a good clinical response to the treatment, with at least stable disease, and only 1 had to stop the therapy after only 4 cycles of treatment owing to a life-threatening progression of the disease. Conclusions and Relevance: We present to our knowledge the first report of hair repigmentation owing to anti-PD-1/anti-PD-L1 therapy for lung cancer in a series of 14 patients. Hair repigmentation may be a good response marker in patients receiving anti-PD1/anti-PD-L1 therapy for LC.

Risk of Distinctive Hair Changes Associated With Pazopanib in Patients With Renal Cell Carcinoma (RCC) Versus Patients Without RCC: A Comparative Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review and meta-analysis was accomplished with the purpose of evaluating the risk of encountering selected hair changes in patients with cancer receiving pazopanib. METHODS: We favored relevant prospective randomized phase II and III trials that assessed pazopanib in patients with cancer, depicting various hair-related changes, as eligible for inclusion. RESULTS: After elimination of ineligible studies, a total of 11 clinical trials were regarded as eligible for the meta-analysis. The relative risk of all-grade alopecia and hair color changes was 1.75 (95% confidence interval, 1.33-2.31; P < .0001) and 4.54 (95% confidence interval, 3.67-5.62; P < .00001), respectively. Subgroup analyses of hair color changes according to the type of cancer treated revealed significant differences between renal cell carcinoma and non-renal cell carcinoma studies (P = .01). CONCLUSIONS: Our meta-analysis has established that pazopanib-based treatment can be significantly correlated to an elevated risk of all grade alopecia and hair color changes compared with controls.

Hair repigmentation associated with thalidomide use for the treatment of multiple myeloma.

A 75-year-old woman diagnosed with multiple myeloma in 2007 began treatment with monthly melphalan and prednisone for a total of 9 cycles in combination with thalidomide in 2009. The patient subsequently continued on thalidomide for long-term maintenance therapy. 3 years following initiation of thalidomide, the patient mentioned to her oncologist that her hair had become darker over the years. She attributed the change to thalidomide given the temporal relationship and progressive darkening over the course of therapy. The patient denies ever using any hair colouring treatments and had longstanding grey/white hair before beginning thalidomide in 2009. A case of hair repigmentation associated with the use of lenalidomide, a 4-amino-glutamyl analogue of thalidomide, in a patient with multiple myeloma was previously reported in the literature. We report herein the first case of hair repigmentation associated with the use of thalidomide, a related immunomodulatory drug.

Effect of ascorbic acid (vitamin C) on the ESR spectra of the red and black hair: pheomelanin free radicals are not always present in red hair.

Increased incidence of melanoma in the population with red hair is conditioned by synthesis of pheomelanin pigments in the skin and their phototoxic properties. The recent research has shown that free radicals of pheomelanin are produced not only by the influence of UV irradiation, but also in UV-independent pathways of oxidative stress. It has been ascertained, that the color of the hair is not always determinant of the amount of pheolemanin radicals in red hair. Therefore, in order to evaluate the risk of melanoma in different individuals, it is necessary to define the amount of free radicals of pheomelanin in red hair using ESR spectroscopy method. Besides, it is very important to find effective antioxidant, capable of neutralizing free radicals of pheomelanin. It was proved that ascorbic acid neutralizes free radicals of pheomelanin very effectively. The main goal of our research was to define the presumably optimal concentration of ascorbic acid as an antioxidant and study the kinetics of the influence of this concentration on red and black hair. It has been found out, that ascorbic acid influences the free radicals of red and black hair, and its appropriate optimal concentration is 10 mM. The obtained results can be considered in dermatology and cosmetology.

Repigmentation of hair following adalimumab therapy.

Repigmentation of canities, or age-related grey or white hair, is a rare occurrence. Generalized repigmentation of grey-white hair has been reported following inflammatory processes, and heterochromia (localized patches of hair repigmentation) is even more unusual, reported in association with medication use and malignancy. Tumor necrosis factor (TNF) inhibitors are increasingly utilized medications for inflammatory disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Hair loss, or alopecia, has been described among the side effects of these medications, but changes in hair pigmentation in association with this class of drugs have not previously been reported. We describe a patient with hair repigmentation associated with adalimumab therapy.

An open-label extension study to evaluate safety and efficacy of pazopanib in patients with advanced renal cell carcinoma.

OBJECTIVES: Evaluation of the safety and efficacy of pazopanib, a multikinase angiogenesis inhibitor, in a single-arm, open-label, extension study (VEG107769/NCT00387764) for placebo-treated patients with advanced renal cell carcinoma (RCC) from a randomized, double-blind, placebo-controlled phase III study (VEG105192/NCT00334282). METHODS: Patients received pazopanib 800 mg/day. The primary endpoint was the safety and tolerability of pazopanib treatment. Secondary endpoints included response rate per Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-nine placebo-treated patients from VEG105192/NCT00334282 who experienced disease progression and one pazopanib-treated patient (an exemption) were enrolled. Forty-one patients (51%) were treatment-naive; 39 (49%) were cytokine-pretreated. Median exposure to pazopanib was 9.7 months. All patients had discontinued pazopanib at the time of analysis. The most common reason for discontinuation was disease progression (61%). The most common adverse events were hypertension (45%), diarrhea (45%), hair color changes (44%), anorexia (30%), and nausea (25%). The response rate was 37.5% [95% confidence interval (CI): 26.9-48.1]; median PFS was 9.2 months (95% CI: 7.3-12.0); median OS was 23.5 months (95% CI: 16.3-28.0). CONCLUSIONS: Efficacy and safety profiles for pazopanib in this extension study of patients with RCC previously treated with placebo were very similar to those observed for pazopanib-treated patients in the pivotal phase III study.