Enhanced interleukin-2 diphtheria toxin conjugate-induced growth suppression in retinoic acid-treated hypoxic hepatocellular carcinoma cells

Hypoxia induces survival signals in hepatocellular carcinoma (HCC). Hypoxia and retinoic acid (RA) may also induce interleukin-2 (IL-2) receptor expression, and thus we evaluated if RA and IL-2 receptor-targeted therapy are indicated in hypoxic HCCs. RA induced IL-2 receptor expression (R alpha, R beta, R gamma) in HCC cells, whereas hypoxia specifically induced IL-2 R gamma expression. IL-2 stimulated hypoxic HCC cell growth via p42/44 MAPK activation. Combination of denileukin diftitox and RA significantly suppressed hypoxic HCC cell growth compared to single agent-treated or normoxic cells. Therefore, denileukin diftitox and RA may be therapeutically implicated in infiltrative HCCs which are exposed to hypoxic environments.     

p-Dodecylaminophenol derived from the synthetic retinoid, fenretinide: antitumor efficacy in vitro and in vivo against human prostate cancer and mechanism of action

Fenretinide, N-(4-hydroxyphenyl)retinamide (4-HPR) is an aminophenol-containing synthetic retinoid derivative of all-trans-retinoic acid, which is a potent chemopreventive and antiproliferative agent against various cancers. Clinical studies of 4-HPR have shown side effects consisting of night blindness and ocular toxicity. To maintain potent anticancer activity without side effects, p-dodecylaminophenol (p-DDAP) was designed based on structure-activity relationships of 4-HPR. In our study, we investigate whether p-DDAP shows anticancer activity against human prostate cancer cell line PC-3 when compared with 4-HPR. p-DDAP inhibited PC-3 cell growth progressively from low to high concentration in a dose-dependent manner. p-DDAP was the most potent antiproliferative agent in vitro among 6 p-alkylaminophenols and 3 4-hydroxyphenyl analogs examined including 4-HPR. Cells treated with p-DDAP were shown to undergo apoptosis, based on condensation nuclei, cytofluorimetric analysis, propidium iodide staining and the expression of bcl-2 and caspase 3. p-DDAP arrested the S phase of the cell cycle, while 4-HPR arrested the G(0)/G(1) phase. In addition, both the i.v. and i.p. administration of p-DDAP suppressed tumor growth in PC-3-implanted mice in vivo. p-DDAP showed no effects on blood retinol concentrations, in contrast to reductions after 4-HPR administration. These results indicate that p-DDAP exhibits excellent anticancer efficacy against hormonal independent prostate cancer in vitro and in vivo, and it may have great potential for clinical use in the treatment of prostate cancer with reduced side effects.     

Retinoid processing in cone and Müller cell lines

To determine whether cones and Müller cells in the rod dominated retina cooperate to regenerate the 11-cis retinal chromophore via the retinoid cycle, two cell lines from the rod dominated retinas of Murine were used for this study: 661W, a mouse cell line derived from cones, and rMC-1, a rat Müller cell line. Retinoid cycle enzymes were analyzed by RT-PCR, and their catalytic activity was detected by incubation with retinoids and analyzed by HPLC. We found that 661W cells are capable of reducing all-trans retinal to all-trans retinol due to the presence of multiple dehydrogenases and to generate minor amounts of retinyl-ester. The rMC-1 cells take up all-trans retinol and oxidize it to all-trans retinal or esterify it to retinyl-ester, but are incapable of isomerizing all-trans retinoids to 11-cis retinoids. This could be a reflection of lack of necessary activities in Müller cells in vivo, which suggests that Müller cells do not contribute to retinoid cycling by regenerating 11-cis retinoids. Alternatively, this could be due to the potential that rMC-1, as a transformed cell line, has stopped expressing the proteins needed for the regeneration of 11-cis retinoids.     

Tazarotene foam, 0.1%, for the treatment of acne

Introduction: Acne is a common skin condition of the pilosebaceous units that affects the young and old, ranges from moderate to severe and can be treated with an array of options. Topical retinoids are the initial treatment for acne due to their ability to treat comedones, the starting point of acne.

Areas covered: Tazarotene is a topical retinoid available as a cream, gel and foam. Tazarotene 0.1% foam was FDA approved in 2012 for the treatment of acne in patients ages ≥12 and is the first foam topical retinoid on the market. Phase I and III trials support the efficacy and safety of tazarotene foam for acne.

Expert opinion: The foam vehicles may increase compliance and satisfaction in some patients and as retinoids are commonly first line acne treatments, this new topical retinoid foam may be a useful option for some acne patients.     

Treating acne vulgaris: systemic,local and combination therapy

Optimizing the management of acne vulgaris corresponds with improved outcomes, reduced scarring and a positive influence on the profound psychosocial disability that frequently accompanies this debilitating skin condition. Many effective, cost-effective therapies are widely available, but significant improvement or clearance can only be achieved if these agents are employed with a logical approach. Patient variability makes the definition of optimum treatment strategies difficult, but with due consideration of the pathological mechanisms driving acne in each individual patient, an appropriate combination of topical, systemic and localized therapies can be prescribed that will yield a favorable outcome. In recent years, a range of physical techniques have emerged as an adjunct to conventional treatments, and with increasing patient interest and expectation, extensive research is underway into these and novel medical therapies that may further broaden our therapeutic armamentarium. This article provides details of currently available therapies, reviews the published evidence on efficacy and considers how best to optimize outcomes with a focus on acne pathogenesis.     

Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma

Retinoids, natural and synthetic derivatives of vitamin A, are biological regulators of differentiation, proliferation, apoptosis, and immune response. Retinoic-acid-receptor-selective retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphoma (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid-X-receptor retinoid to be approved by the FDA for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Bexarotene treatment induces apoptosis of CTCL cells with down-regulation of its receptors and of survivin, an inhibitor of apoptosis. Identification of new receptor subtype-selective retinoids, combination of various receptor-selective retinoids or other agents, and a new drug delivery system may improve the clinical efficacy of retinoids in the future.