The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

Psoriasis is a chronic immune-mediated skin disease that involves the interaction of immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation, and angiogenesis. Because the available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can repair the molecular defects associated with psoriasis and could possibly be developed for its management. Fisetin (3,7,3′,4′-tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables, has demonstrated proapoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological, and tissue engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC), and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose- and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α stimulated NHEKs also significantly inhibited the activation of p38 and JNK, but had enhanced effect on ERK1/2 (MAPK). In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFN-γ and IL-17A by 12-O-tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in vivo human psoriatic skin lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify the prodifferentiative, antiproliferative, and anti-inflammatory effects of fisetin, via modulation of the PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin models of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.

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This article contains supplemental datasets of the recently published related research article “Synthesis, Inverse Docking-Assisted Identification and in vitro Biological Characterization of Flavonol-based Analogs of Fisetin as c-Kit, CDK2 and mTOR Inhibitors against Melanoma and Non-melanoma Skin Cancers” by Roy et al., [1] . It provides in-depth data not included in the original co-submission on the biophysical, molecular docking, and biological characterization of newly synthesized flavonol-based analogs of fisetin, a natural dietary small molecule with anticancer and anti-inflammatory properties. These synthetic small molecules were investigated as new, potential single and/or multi-kinase inhibitors of the cyclin-dependent kinase-2 (CDK2), receptor tyrosine kinases (c-KITs), and mammalian targets of rapamycin (mTOR) targets, potentially active against melanoma or non-melanoma skin cancers. Furthermore, this data-in-brief article comprises additional sets of results on several aspects of the properties of the dual and multiple kinase inhibitor compounds’ effects that were not presented in the associated article, including the activated targets that are dysregulated in skin cancers; the effects on markers of apoptosis; on colony formation; and in scratch wound healing assays. The study has identified a panel of novel fisetin analogs that are either single- or multi-kinase inhibitors, which may be further developed as active for the treatment of melanoma and non-melanoma skin cancers. The dataset presented herein will be utilized for additional studies aiming to establish a biological platform to steer for predictive and experimental screening of novel flavonoids and analogs in relevant organoids, humanized animal models and in vivo disease models. The present results should also serve as a key stepping-stone towards enabling target-structure-based design, synthesis and initial testing of novel analogs or derivatives of fisetin. The current study may eventually lead to the development of safe, promising and preclinical candidate entities for treatment of skin and other forms of cancers as well as various other human diseases, which can possibly add to the general armamentarium of promising and safe drugs for health promotion.

Inflammatory skin diseases (ISDs) such as psoriasis and allergic contact dermatitis affects millions of people and poses a major public health burden. Aberrant cytokine production is a prominent characteristic of ISDs, although the molecular mechanisms underlying the imbalance between pro-and anti-inflammatory gene expression remain underexplored. Cterminal-binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Our recently studies have uncovered a previously unrecognized proinflammatory role of CtBP in skin inflammation. CtBP1 overexpression in transgenic mouse keratinocytes causes a psoriasis-like phenotype including increased epidermal proliferation, immunocyte infiltration and proinflammatory cytokine expression in skin. Expression of the CtBPs is elevated in both human psoriatic skin lesions and the inflamed skin of two mouse ISD models, the imiquimod-induced psoriasis and the DNFB-induced contact hypersensitivity. Keratinocytes stimulated by imiquimod or DNFB exhibit transactivation of CtBP2 and CtBP-controlled proinflammatory genes that is accompanied by increased recruitment of CtBPs to the target promoters. Furthermore, we demonstrate that distinct CtBP-specific inhibitors can effectively suppress the expression of the CtBP target genes by evicting CtBPs from their target promoters and relieve symptoms of skin inflammation with topical treatment in both mouse ISD models. Together, these findings indicate that the CtBPs can promote skin inflammation by transactivating a select set of proinflammatory genes and suggest new avenues for therapeutic modulation of inflammation and immune responses in ISDs.

Chronic metabolic acidosis (CMA) can be a consequence of persistent hypertension but could potentially play a role in invoking hypertension. Currently, there is a scarcity of studies examining the outcome of induced chronic acidosis on blood pressure regulation. This study investigates CMA as a cause of hypertension. Chronic acidosis was induced in Sprague Dawley rats (100–150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4Cl) in tap water for 8 weeks. To determine whether the rats were acidotic, blood pH was measured, while blood pressure (BP) was monitored by tail-cuff plethysmography weekly. Rats were divided into five groups: control, CMA, CMA ± spironolactone, captopril, and tempol. Serum sodium and potassium; renal interstitial fluid (for Angiotensin II concentration); and kidney proximal tubules (for Na+/K+ ATPase- α1 concentration) were analyzed. Reactive oxygen species (ROS) were detected in renal cortical homogenates using electron paramagnetic resonance (EPR). In the CMA rats, a sustained elevation in mean arterial pressure (MAP) associated with a significant decrease in blood pH was observed compared to that of control over the 8 weeks. A significant decrease in MAP was observed in acidotic rats treated with captopril/tempol, whereas spironolactone treatment caused no decrease in MAP as compared to that of the CMA group. The interstitial angiotensin II was increased in the CMA group but decreased in the CMA with captopril and tempol groups. In addition, the urinary sodium was decreased, and the serum sodium levels increased significantly in the CMA groups as compared to that of control. However, the acidotic groups with captopril and tempol showed reduced levels of serum sodium and an elevation in urinary sodium as compared to that of the CMA group. In addition, there was a significant increase in plasma renin and no change in plasma aldosterone in the CMA group with no significant differences in plasma renin or aldosterone observed during spironolactone, captopril, or tempol treatments. The increased expression of Na+/K+ ATPase-α1 in the CMA group suggests that active transport of Na+ to the blood could be causative of the observed hypertension. Furthermore, the EPR analysis confirmed an elevation in superoxide (O2-) radical levels in the CMA group, but the tempol/captopril treated acidotic groups showed less (O2-) compared to that of either the CMA group or control. Taken together, our data suggest that induction of CMA could potentially be causative of hypertension, while the mechanisms underlying the increased BP could be through the activation of intrarenal Ang II and induction of oxidative stress.

The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders.

Melanoma and nonmelanoma skin cancer are the most lethal and commonest forms of skin cancers affecting one fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL28, A431, SCC12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, CC and CN linked biphenyls, and substituted methyl gallate or aniline derivatives, displayed low micromolar range activities, primarily against the A431 and SCC12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 lower case Greek muM, SCC12: IC50 = 2.9 lower case Greek muM, SKMEL-28: IC50 = 4.9 lower case Greek muM, A375: IC50 = 6.7 lower case Greek muM) and 13 (A431: IC50 = 5.0 lower case Greek muM, SCC-12: IC50 = 3.3 lower case Greek muM, SKMEL-28: IC50 = 13.8 lower case Greek muM, A375: IC50 = 17.1 lower case Greek muM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose dependently induced apoptosis of SCC12 and SKMEL28 cells as evidenced by the downregulation of Bcl2 and upregulation of Bax protein expression levels, and by cleaved caspase 3, caspase 9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and nonmelanoma skin cancers.