New and emerging drugs for the treatment of acne vulgaris in adolescents

Introduction: Acne vulgaris is the most common skin disease worldwide, yet current treatment options, although effective, are associated with unwanted side effects, chronicity, relapses and recurrences. The adequate control of the four pathogenic mechanisms involved in the appearance of acne lesions is key to treatment success. This paper aims to discuss the novel treatment modalities that have surfaced in consequence of new knowledge obtained in acne pathogenesis.

Areas covered: Pathogenic pathways are evaluated and discussed throughout the paper in relation to the mechanisms of action of novel molecules being investigated for the treatment of acne vulgaris. A comprehensive search was made in PubMed and Clinicaltrial.gov using a different combination of keywords, which included acne vulgaris, treatment, therapy, and therapeutic.

Expert opinion: In the near future, more effective treatments with less side effects are expected. The use of topical anti-androgens, coenzyme-A carboxylase inhibitors, and insulin growth factor-1inhibitors to control sebum production seem promising. Selective RAR-agonists have the potential of becoming an alternative to the currently available retinoid therapy in the management of infundibular dyskeratosis with a better safety profile. Antibiotic use will probably decline as more effective options for controlling Cutinebacterium acnes colonization and the inflammation cascade emerge.     

Design,synthesis, and biological characterization of tamibarotene analogs as anticancer agents

In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn²⁺‐binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC₅₀ of 1.8 ± 0.1 μm , thus suggesting that this could contribute to the improved antiproliferative activities of 7b . Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.     

Recent developments of retinoids as therapeutic agents

Retinoids, a group of natural and synthetic retinol (vitamin A) analogues, play an important role in regulating pleiotropic biological events, including growth, differentiation and death of normal, premalignant and malignant cell types, which appears to account for their therapeutic or preventive effects in acne, psoriasis, photoageing, cancer and other diseases. Nuclear retinoic acid receptors and retinoid X receptors are thought to mediate the majority of retinoid biological effects. One effective strategy is to design and synthesise retinoids with receptor selectivity restricted to specific retinoic acid receptors or retinoid X receptor subtypes (α, β and γ) in order to develop novel retinoids with a more favourable therapeutic index and with reduced adverse effects and teratogenic risk. Indeed, retinoid medicinal chemistry has identified ligands that include highly specific antagonists for one of the three RAR subtypes and for retinoid X receptors. Since the retinoid X receptors also serve as heterodimer partners for several other nuclear receptors, including thyroid hormone receptors, vitamin D receptors, peroxisomal proliferator-activator receptors, Farnesoid X receptors and liver X receptors, retinoid X receptor-selective retinoids may have clinical applications for the prevention and treatment of diseases other than dermatological diseases and cancer, such as diabetes, obesity and atherosclerosis.     

The Pregastrulation Rat Embryo: A Possible Object for Studies of Retinoid-Associated Teratogenicity

The study examined whether pregastrulation rat embryos can be used as a model for demonstrating in vivo the toxic and teratogenic effects of all-trans retinoic acid (tRA). The tRA was administered per os to Wistar rats on day 6 of gestation (the presence of sperm was taken as day 1) in a single dose of 120 mg/kg body weight. In the litters examined on days 9 and 14 of gestation, tRA significantly increased the number of resorbed embryos. Examination on day 14 of pregnancy revealed that tRA also caused a high proportion of embryos to be growth-retarded (with CR length at least 20% less than that of controls). Growth retardation was found in 6 of 7 tested litters. Both external and skeletal malformations were observed in 20 day fetuses when tRA was administered on day 6 of gestation. Rats receiving tRA on days 11 or 14 of gestation served as positive controls, and also showed malformations. These results indicate that pregastrulation rat embryo can be used for assessing the pathways contributing to the teratogenic effect of tRA.     

Retinoids in the prevention of bladder cancer

Superficial bladder cancer has an unpredictable natural history but in many patients it has a tendency for multiple recurrences over many years. Chemoprevention approaches are ideally tested in this type of tumor and may delay or prevent recurrences of superficial bladder cancer or prevent progression to invasive disease. Vitamin A and its derivatives, the retinoids, have been studied in detail in this disease. This article reviews the data on this subject and includes in vitro and in vivo preclinical studies as well as the clinical studies performed in the secondary prevention of this disease.     

The novel atypical retinoid ST5589 down‐regulates Aurora Kinase A and has anti‐tumour activity in lymphoma pre‐clinical models

Despite the marked improvements in the treatment of lymphomas, there is still a need for new therapeutic agents. Synthetic retinoids represent a class of compounds with anti‐cancer activity. Here, we report the preclinical activity of a new member of this class, the ST1926‐derivative ST5589, in lymphomas. ST5589 presented a dose‐dependent anti‐proliferative activity in almost all of the 25 lymphoma cell lines analysed, with a median 50% inhibitory concentration of 433 nM. Apoptosis was observed in 8/11 cell lines. ST5589 induced changes in the gene expression profiles of the cell lines, including the down‐regulation of Aurora Kinase A (AURKA). Specific gene expression signatures were associated with a higher sensitivity to the compound and combination of ST5589 with carfilzomib revealed the importance of proteasome activity in mediating the anti‐tumour activity of ST5589. In conclusion, we have identified a new mechanism of action of atypical retinoids as anti‐cancer compounds, and the encouraging results obtained with the new ST1926‐derivative ST5589 provide the basis for further developments of the compound.     

Solid Tumor Differentiation Therapy – Is It Possible?

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiationbased therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors.