PI3K-AKT signaling is a downstream effector of retinoid prevention of murine basal cell carcinogenesis.
ABSTRACT: Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via retinoic acid receptor ?-mediated regulation of tumor cell transcription. Because topical retinoids can cause adverse cutaneous effects and because tumors can develop resistance to retinoids, we have investigated mechanisms downstream of tazarotene's antitumor effect in this model. Specifically we have used (i) global expression profiling to identify and (ii) functional cell-based assays to validate the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway as a downstream target pathway of tazarotene's action. Crucially, we have demonstrated that pharmacologic inhibition of this downstream pathway profoundly reduces murine BCC cell proliferation and tumorigenesis both in vitro and in vivo. These data identify PI3K/AKT/mTOR signaling as a highly attractive target for BCC chemoprevention and indicate more generally that this pathway may be, in some contexts, an important mediator of retinoid anticancer effects.
Project description:Sporadic human basal cell carcinomas (BCC) are generally well managed with current surgical modalities. However, in the subset of high-risk patients predisposed to developing large numbers of BCCs, there is an unmet need for effective, low-morbidity chemoprevention. This population includes fair-skinned patients with extensive sun exposure and those with genodermatoses such as the basal cell nevus (Gorlin) syndrome (BCNS). Tazarotene (Tazorac, Allergan) is a topical retinoid with relative specificity for RAR-? and RAR-? receptors. We previously demonstrated tazarotene's robust anti-BCC efficacy in Ptch1(+/-) mice, a murine equivalent of BCNS, and others have found it to have some efficacy against sporadic human BCCs. We report here results of a randomized, double-blind, vehicle-controlled study in patients with BCNS evaluating the efficacy of topically applied tazarotene for BCC chemoprevention (N = 34 subjects), along with an open-label trial evaluating tazarotene's efficacy for chemotherapy of BCC lesions (N = 36 subjects) for a maximum follow-up period of 3 years. We found that only 6% of patients had a chemopreventive response and that only 6% of treated BCC target lesions were clinically cured. Our studies provide no evidence for either chemopreventive or chemotherapeutic effect of tazarotene against BCCs in patients with BCNS.
Project description:Topical retinoids are effective in retarding skin ageing and restoring homeostasis in skin conditions such as psoriasis. However their adverse effects (AEs), which include irritation (retinoid dermatitis), photosensitivity and teratogenicity, limit their use and patient compliance. Development of retinoid analogues with minimal AEs would allow a broader and more compliant use.To synthesise a novel molecule, bakuchiol salicylate (bakusylan), with a modulatory gene expression profile similar to retinoids, using as reference three prescription retinoids: tretinoin, tazarotene and adapalene.We hypothesized that because bakuchiol salicylate has a structure entirely different from existing retinoids, there would be at least a partial uncoupling of AEs from the skin-normalizing activity of this retinoid. This hypothesis was tested at the transcriptional level in psoriatic cytokine-treated cultures of keratinocytes and organotypic skin substitutes, using DNA microarrays and custom PCR arrays.Evaluation of the gene expression profile of bakuchiol salicylate revealed elimination of several components of the retinoid-like proinflammatory response and teratogenic signature, without a substantial loss of normalizing potential. A possible mechanism of action, consisting of keratinocyte desensitization to psoriatic cytokine signalling through inhibition of the signal transducer and regulator of transcription (STAT)1/3/interferon inflammatory signal transduction axis was also identified.Bipartite materials obtained by merging two skin-active entities with specific, complementary bioactivities, such as bakuchiol and salicylic acid, may yield a new class of functional retinoids.
Project description:Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis. To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, we used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107. Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.
Project description:Background: Topical retinoids are effective in retarding skin aging and restoring homeostasis in skin conditions, such as psoriasis. However their adverse effects, which include irritation (retinoid dermatitis), photosensitivity and teratogenicity, limit their use level and patient compliance. Development of a retinoid analogue with minimal adverse effects would allow a broader and more compliant use. Objective: Here we report the synthesis of a novel molecule - bakuchiol salicylate (bakusylan) with the gene expression modulatory profile similar to retinoids, using as reference 3 prescription retinoids - tretinoin, tazarotene and adapalene. Methods: Having a structure entirely different from existing retinoids, we hypothesized that at least a partial uncoupling of retinoid adverse effects from retinoid skin normalizing activity may be obtained with bakuchiol salicylate. This hypothesis was tested in psoriasiform cultures of keratinocytes and organotypic skin substitutes by DNA microarrays and custom PCR arrays. Results: The evaluation of the bioactivity of bakuchiol salicylate revealed the elimination of several components of the retinoid-like proinflammatory response and teratogenic signature without a substantial loss of normalizing potential. A possible mechanism of action consisting in keratinocyte desensitization to cytokine signaling through the inhibition of the STAT1/3/interferon inflammatory signal transduction axis has also been identified. Conclusion: Bipartite materials obtained by merging two skin-active entities with specific, complementary bioactivities, such as bakuchiol and salicylic acid, may deliver a new class of functional retinoids. Overall design: Psoriasiform epidermal keratinocyte cultures were generated by incubating keratinocytes with cytokines (IL-17A/IL-22/TNFα) for 24 hours (CnT-PCT media). Keratinocytes were then treated with control solvent (CS; 3% dimethyl isosorbide; 40% glycerin; 57% butylene glycol), control solvent supplemented with bakusylan (SE; 10ug/ml), or control solvent supplemented with all-trans-retinoic acid (ATRA; 0.1ug/ml). Two replicates were generated for each treatment group.
Project description:Understanding a drug candidate's pharmacokinetic (PK) parameters is a challenging but essential aspect of drug development. Investigating the penetration and distribution of a topical drug's active pharmaceutical ingredient (API) allows for evaluating drug delivery and efficacy, which is necessary to ensure drug viability. A topical gel (BPX-05) was recently developed to treat moderate to severe acne vulgaris by directly delivering the combination of the topical antibiotic minocycline and the retinoid tazarotene to the pilosebaceous unit of the dermis. In order to evaluate the uptake of APIs within human facial skin and confirm accurate drug delivery, a selective visualization method to monitor and quantify local drug distributions within the skin was developed. This approach uses fluorescence lifetime imaging microscopy (FLIM) paired with a multicomponent phasor analysis algorithm to visualize drug localization. As minocycline and tazarotene have distinct fluorescence lifetimes from the lifetime of the skin's autofluorescence, these two APIs are viable targets for distinct visualization via FLIM. Here, we demonstrate that the analysis of the resulting FLIM output can be used to determine local distributions of minocycline and tazarotene within the skin. This approach is generalizable and can be applied to many multicomponent fluorescence lifetime imaging targets that require cellular resolution and molecular specificity.
Project description:Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified - from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib - most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.
Project description:Psoriasis affects 1-3% of the population, in some people causing changes to the nails and joints in addition to skin lesions.We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of systemic drug treatments, topical drug treatments, and non-drug treatments (other than ultraviolet light) for chronic plaque psoriasis? What are the effects of ultraviolet light treatments for chronic plaque psoriasis? What are the effects of combined treatment with drugs plus ultraviolet light on chronic plaque psoriasis? What are the effects of combined systemic plus topical drug treatments for chronic plaque psoriasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).We found 122 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, adding calcipotriol (topical) to psoralen plus ultraviolet light A or ultraviolet light B, adding oral retinoids to psoralen plus ultraviolet A (PUVA), alefacept, balneotherapy, ciclosporin, dithranol, T cell-targeted therapies, cytokine blocking agents, emollients (alone or plus ultraviolet light B), etanercept, fish oil supplementation, fumaric acid derivatives, Goeckerman treatment, heliotherapy, infliximab, Ingram regimen, keratolytics (salicylic acid, urea), leflunomide, methotrexate, oral pimecrolimus, phototherapy plus balneotherapy, psoralen plus ultraviolet A, psychotherapy, oral retinoids (alone or with ultraviolet light B), systemic drug treatments plus topical vitamin D derivatives, tars, tazarotene, topical corticosteroids (alone or plus oral retinoids), topical Vitamin D derivatives, ultraviolet light A, and ultraviolet light B.
Project description:Currently available smoothened targeted therapies in patients with basal cell nevus syndrome are associated with substantial tumor recurrence and clinical resistance. Strategies bypassing smoothened and/or identifying additional downstream components of the Hedgehog pathway could provide novel antitumor targets with a better therapeutic index. Sry-related high mobility group box 9 (SOX9) is a Hedgehog/glioma-associated oncogene homolog-regulated transcription factor known to be overexpressed in basal cell carcinomas (BCCs). A sequence motif search for SOX9-responsive elements identified three motifs in the promoter region of mammalian target of rapamycin (mTOR). In murine BCC cells, SOX9 occupies the mTOR promoter and induces its transcriptional activity. Short hairpin RNA (shRNA)-mediated knockdown of SOX9, as well as smoothened inhibition by itraconazole and vismodegib, reduces mTOR expression and the phosphorylation of known downstream mTOR targets. These effects culminate in diminishing the proliferative capacity of BCC cells, demonstrating a direct mechanistic link between the Hedgehog and mTOR pathways capable of driving BCC growth. Furthermore, rapamycin, a pharmacologic mTOR inhibitor, suppressed the growth of UV-induced BCCs in Ptch1+/-/SKH-1 mice, a model that closely mimics the accelerated BCC growth pattern of patients with basal cell nevus syndrome. Our data demonstrate that Hedgehog signaling converges on mTOR via SOX9, and highlight the SOX9-mTOR axis as a viable additional target downstream of smoothened that could enhance tumor elimination in patients with BCC.
Project description:Halobetasol propionate and tazarotene lotion 0.01%/0.045% (HP/TAZ) is a topical medication approved for the treatment of plaque psoriasis in adults. As a treatment modality, HP/TAZ has a combinatory therapeutic effect because it contains both a corticosteroid (HP) and a retinoid (TAZ) component. Here, we review the important clinical efficacy and safety data derived from pivotal clinical trials for HP/TAZ in the treatment of plaque psoriasis. We also discuss the mechanism of action, dosage guidelines, pharmacokinetics/pharmacodynamics, and clinical considerations for HP/TAZ, including why HP/TAZ should be avoided in pregnant patients.
Project description:Acne is a chronic inflammatory skin disease that involves the pathogenesis of four major factors, such as androgen-induced increased sebum secretion, altered keratinization, colonization of Propionibacterium acnes, and inflammation. Several acne mono-treatment and combination treatment regimens are available and prescribed in the Indian market, ranging from retinoids, benzoyl peroxide (BPO), anti-infectives, and other miscellaneous agents. Although standard guidelines and recommendations overview the management of mild, moderate, and severe acne, relevance and positioning of each category of pharmacotherapy available in Indian market are still unexplained. The present article discusses the available topical and oral acne therapies and the challenges associated with the overall management of acne in India and suggestions and recommendations by the Indian dermatologists. The experts opined that among topical therapies, the combination therapies are preferred over monotherapy due to associated lower efficacy, poor tolerability, safety issues, adverse effects, and emerging bacterial resistance. Retinoids are preferred in comedonal acne and as maintenance therapy. In case of poor response, combination therapies BPO-retinoid or retinoid-antibacterials in papulopustular acne and retinoid-BPO or BPO-antibacterials in pustular-nodular acne are recommended. Oral agents are generally recommended for severe acne. Low-dose retinoids are economical and have better patient acceptance. Antibiotics should be prescribed till the inflammation is clinically visible. Antiandrogen therapy should be given to women with high androgen levels and are added to regimen to regularize the menstrual cycle. In late-onset hyperandrogenism, oral corticosteroids should be used. The experts recommended that an early initiation of therapy is directly proportional to effective therapeutic outcomes and prevent complications.