alitretinoin and Melanoma

Topics: Aged; Alitretinoin; Antineoplastic Agents; Female; Forearm; Humans; Indoles; Keratoacanthoma; Melanoma; Proto-Oncogene Proteins B-raf; Retinoids; Skin Neoplasms; Sulfonamides; Tretinoin; Vemurafenib

Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9-cis retinal and its corresponding product 9-cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA and melanin. ALDH1A1 depletion inhibited the ability of 9-cis retinal but not 9-cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalysing the conversion of 9-cis retinal to 9-cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9-cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9-cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Alitretinoin; Cell Line, Tumor; Cells, Cultured; Cyanamide; Humans; Melanins; Melanocytes; Melanoma; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Retinal Dehydrogenase; Skin; Skin Neoplasms; Skin Pigmentation; Tretinoin

Melanoma represents one of the most rapidly metastasizing, hence deadly tumors due to its high proliferation rate and invasiveness, characteristics of undifferentiated embryonic tissues. Given the absence of effective therapy for metastatic melanoma, understanding more fully the molecular mechanisms underlying melanocyte differentiation may provide opportunities for novel therapeutic intervention. Here we show that in mouse melanoma S91 cells activation of the peroxisome proliferator activated receptor (PPAR) gamma induces events resembling differentiation, such as growth arrest accompanied by apoptosis, spindle morphology and enhanced tyrosinase expression. These events are preceded by an initial transient increase in expression from the Microphthalmia-associated transcription factor gene, (MITF) promoter, whereas exposure to a PPAR gamma ligand- ciglitazone that exceeds 8 h, causes a gradual decrease of MITF, until by 48 h MITF expression is substantially reduced. Beta-catenin, an MITF transcriptional activator, shows a similar pattern of decline during ciglitazone treatment, consistent with previous reports that activated PPAR gamma inhibits the Wnt/beta-catenin pathway through induction of beta-catenin proteasomal degradation. We suggest that the PPAR gamma-mediated beta-catenin down-regulation is likely to be responsible for changes in MITF levels. The data suggest that PPAR gamma, besides its well-established role in mesenchymal cell differentiation towards adipocytes, might regulate differentiation in the melanocytic lineage.

Topics: Alitretinoin; Animals; Antigens, Differentiation; Antineoplastic Agents; beta Catenin; Blotting, Western; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Shape; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Melanocytes; Melanoma; Mice; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Phenotype; PPAR gamma; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Thiazolidinediones; Tretinoin; Up-Regulation

Two new canine melanoma cell lines (CMM1 and CMM2) were established from the patients with oral malignant melanomas. Histopathological type of both CMM1 and CMM2 was a mixed cell type consisted of spindle-shaped cells, polygonal cells, and oval cells. Doubling time of CMMI and CMM2 were 18.4 +/- 1.96 hr and 21.0 +/- 0.73 hr, respectively. The effect of two kinds of retinoids (all-trans retinoic acid and 9-cis retinoic acid) on the proliferation of these cells were examined by morphological changes, proliferation assay and apoptosis assay. However, the retinoids did not suppress growth rate of these cells. This result suggests that retinoids used in this study did not induce differentiation, apoptosis, and growth inhibition of the canine melanoma cell lines.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Apoptosis; Cell Division; Dog Diseases; Dogs; Melanoma; Mouth Neoplasms; Retinoids; Tretinoin; Tumor Cells, Cultured