Rationale for NanoStilbene/EGCg Conjugate in Endothelial Dysfunction

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TimGDixon
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Rationale for NanoStilbene/EGCg Conjugate in Endothelial Dysfunction

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Rationale for NanoStilbene/EGCg Conjugate in Endothelial Dysfunction
Augmentation of Stem Cell Activity using Pterostilbene and Epigallocatechingallate

Discussed are means of augmenting circulating endogenous stem cells through administration of an effective amount of pterostilbene and epigallocatechingallate (EGCg). In one application a patient with reduced levels of circulating endothelial progenitor cells can be supplemented with NanoStilbene alone, at a concentration and frequency sufficient to restore, and/or enhance levels of circulating endothelial progenitor cells (EPC). In another application endogenous levels of stem cells are restored or enhanced by administration of NanoStilbene and EGCg. Cells may include endogenous stem cells comprised of the dentate gyrus, subventricular zone, hepatic stem cells, cardiac stem cells, and hematopoietic stem cells.

Pterostilbene is a phenolic compound biologically classified as a phytoalexin, which is an antimicrobial substance that is part of a plant’s defense system and is synthesized in response to pathogen infection, as well as to excessive ultraviolet exposure.

Pterostilbene is known to have diverse benefits for the prevention and treatment of wide variety of diseases, including cancer, diabetes, cardiovascular disease and cognitive function degeneration.

Accordingly, the use of pterostilbene for acceleration of healing and revascularization by augmentation of EPC numbers and/or potentiation of activity is discussed.

One of the first targets of atherosclerotic disease is the penile vasculature [1]. Accordingly, the use of pterostilbene, and analogues thereof, to augment vascular function, and through this to augment health and prevention of vascular associated diseases is reviewed.

In general, atherosclerotic disease is correlated with decreased levels of circulating EPC. One study assessed patients without cardiovascular disease having varying scores on the Framingham risk questionnaire. A correlation between higher risk scores and low EPC numbers was found [2]. Another study assessed the preclinical atherosclerosis marker of carotid intima-media thickness (IMT) measured by ultrasound. The investigators found a correlation between IMT and low levels of CD34+, KDR+ circulating EPC.

Patients with atherosclerosis have been described by numerous studies as having reduced numbers of EPC compared to healthy controls [3,4,5,6]. Additionally, correlations between stenosis and reduced circulating EPC numbers have also been made [4]. Thus, given the hypothesis that ED is caused in many cases by atherosclerotic disease, it should not be surprising that several studies have found patients with ED as having suppressed numbers of circulating EPC. Accordingly, we teach here, the use of pterostilbene alone, or in combination with other therapeutic modalities, as a treatment for erectile dysfunction.

Foresta et al reported lower number of cells capable of forming CFU-E in circulation of men with ED as compared with healthy controls. Their rationale was based on previous reports of cardiovascular disease affecting the penile circulation first, and given that cardiovascular disease correlates with lower EPC, they sought to verify if ED was an early manifestation of cardiovascular disease [7].

A subsequent study of 119 patients with coronary artery disease found that almost 60% had ED. Presence of ED correlated with known cardiovascular risk factors such as age, hypertension, reduced left ventricular ejection fraction (LVEF) and diabetes. Importantly, ED correlated with reduction in circulating EPC [8]. A similar correlation was found in a study comparing 30 healthy overweight men with 30 overweight men suffering from ED. Severity of ED according to the IIEF score correlated with lower numbers of EPC [9].

Chronic inflammation has been associated with ED and with a variety of chronic degenerative diseases. Assessment of inflammatory markers followed by modification of pterostilbene dosage after identifying to what extent modulation of inflammatory markers has occurred should be determined.

In the case of ED, a study of 137 men with ED found significant association between the levels of the inflammatory marker C-reactive protein (CRP) and severity of penile vascular disease as measured by penile Doppler [10]. In obese men, presence of ED was also associated with increased CRP-levels [11]. Oxidative stress plays a known component in numerous inflammatory conditions. In ED, salivary 8-hydroxy-2′-deoxyguanosine, a known marker of oxidative stress, has been shown to correlate with severity of dysfunction [12].

Numerous other markers of oxidative stress have been associated with ED including upregulation of the hypoxia inducible factor-1alpha (HIF-1alpha), superoxide dismutase (SOD), aldose reductase (AR) and nerve growth factor (NGF) genes [13]. Other inflammatory mediators such as TNF-alpha are associated with ED [14]. Interestingly mice lacking TNF have increased erectile ability [15], whereas administration of TNF to corpora cavernosa tissue ex vivo results in decreased reactivity [16].

Additionally, increased systemic levels of TNF are observed in a form of inflammatory arthritis called ankylosing spondylitis. Treating these patients with TNF inhibitors results in increased erectile function [17]. The detection of these types of inflammatory markers may be used to titrate the dose of NanoStilbene.

Thus, it appears that underlying chronic inflammation associated with atherosclerotic disease has a negative effect on circulating EPC, which may account for impaired endothelial repair and poor vascular function associated with ED. Supporting the inflammatory cause of EPC decrease are studies in which anti-inflammatory agents partially, or fully restore EPC numbers similar to healthy controls.

For example, Grisar et al demonstrated in 28 patients with rheumatoid arthritis that a 7-day course of treatment resulted in restoration of circulating EPC to values comparable to healthy age-matched controls [18].

Green tea has been reported to contain numerous antioxidants [19]. Given the known component of oxidative stress on inflammation, as well as the direct anti-inflammatory role of components in green tea, an investigation was conducted in 20 young smokers to determine whether green tea administration altered circulating EPC [20]. Consumption of green tea daily for 2 weeks resulted in an increase in circulating EPC, as well as improvement in endothelial function as measured by the flow mediated dilation assay (FMD).

In the specific case of ED, administration of the antioxidant vitamin alpha-tocophenol resulted in IIEF improvement in a pilot group of patients resistant to PDE5 inhibitors [21].

Other antioxidants have displayed benefit in ED including folic acid [22], Korean ginseng [23], and propionyl L-carnitine [24].

Thus, it appears that in ED a low grade, underlying inflammation, associated with markers such as CRP, TNF-alpha, as well as oxidative stress, are associated with reduction in EPC numbers and possibly causative of pathology.

The bone marrow is recognized as a major source of EPC. Suggestive of the angiogenic potential of bone marrow was an early clinical study by Tateishi-Yuyama et al, in which 22 patients with bilateral critical limb ischemia were treated intramuscularly with autologous bone marrow mononuclear cells in randomly chosen legs, with control leg receiving peripheral blood derived mononuclear cells [25]. Improvement in the treated legs was observed in terms of ankle brachial index, pain-free walking and ulcer healing. One of the primary characteristics of endothelial dysfunction is reduction in the flow mediated dilation assay. In an attempt to induce neo-angiogenesis through stimulation of circulating EPC numbers, mobilization of bone marrow progenitors was performed by 2-week administration of GM-CSF in 45 patients with peripheral arterial disease [26].

At 12 weeks not only was improvement in exercise capacity noted (as compared to pre-treatment levels), but also systemic augmentation of the flow mediated dilation assay was reported. These data suggest the possibility that administration of cells containing EPC, such as bone marrow, as well as mobilization of endogenous bone marrow EPC may be useful in repairing/improving endothelial function.

Unfortunately, autologous bone marrow therapy and mobilization by agents such as GM-CSF is cost-prohibitive and possesses possibility of undue pain to the patient. In the case of autologous bone marrow, the need to perform iliac crest extraction to collect sufficient cell numbers is difficult to perform in patients that numerous times have a variety of comorbidity conditions.

The use of cytokine-based mobilization, if used chronically, can lead to splenomegaly, bone marrow hyperplasia, and other adverse effects. The use of pterostilbene together with mobilizers of bone marrow stem cells is may be considered. In animal models, administration of agents capable of inducing endothelial cell proliferation, and/or neoangiogenesis, induces inhibition of ED progression or reversion of ED.

For example, basic fibroblast growth factor (bFGF) is a known inducer of angiogenesis in ischemic situations, and its exogenous administration is therapeutic in models of stroke [27], angina [28], and peripheral limb ischemia [29]. The administration of two 2.5 microgram doses of bFGF, at 3-week intervals into corporal tissue of hypercholesterolemic rabbits was shown to increase corporal relaxation in response to chemical stimuli, as well as ability to generate NO [30].

In another study, intracavernous administration of bFGF into diabetic rats by means of gelatin microbeads resulted in protection of erectile function [31]. Additionally, another study demonstrated that systemic basic fibroblast growth factor induces favorable histological changes in the corpus cavernosum of hypercholesterolemic rabbits [32].

The use of pterostilbene, in one manner, may also comprise of augmentation of activity of known agents that stimulate EPC numbers, said agents include: Testosterone administration to hypogonadal men increases erectile function while simultaneously stimulating numbers of circulating EPC [33]. Interventions such as exercise [34], and smoking cessation [35], which have demonstrated improvement in erectile function are also associated with augmentation of circulating EPC [36, 37, 38].

Green Tea Extracts – (trihydroxyphenolic units)

EGCG (epigallocatechin gallate) is a major polyphenol found in green tea, along with ellagic acid, epicatechin gallate, epigallocatechin, gallocatechin, epicatechin, and catechin.

The biological pathway identified here involves trihydroxy- containing polyphenols at concentrations achievable by dietary ingestion. Indeed, foods rich in this class of compounds, such as EGCG, have been consumed as therapeutics for decades [39].

A large number of clinical trials have demonstrated that tea is good for health in terms of the prevention and treatment for a range of diseases, such as cardiovascular disease [40], lung cancer [41], breast cancer [42], prostate cancer [43] and pathogenic microorganisms, etc. For example, tea consumption may be able to interrupt the chronic progress of atherosclerosis and thus prevent or delay the onset of ischemic stroke. Tea may also protect the artery wall by reducing blood pressure, inhibiting the migration of monocytes and smooth muscle cells to the atherosclerotic lesion, inhibiting proliferation of smooth muscles cells, and by improving endothelial function [44].

One cup of tea provides 150-300 mg flavonoids [45]. The mounting evidence that tea flavonoids can improve endothelial function and lower blood pressure has emerged in recent years. A report in 2006 showed that short-term administration of green tea in 20 young healthy smokers induced a rapid improvement of endothelial progenitor cell levels and flow-mediated endothelium dependent vasodilation.

Green tea consumption may be effective in preventing future cardiovascular events in chronic smokers [46]. A Japanese study found that green tea consumption over short and long periods appeared to ameliorate endothelial dysfunction by scavenging free radicals with anti-inflammatory and anti-apoptotic properties in healthy male smokers [47].

Endothelial dysfunction has been associated with coronary artery disease and increased oxidative stress. Duffy et al [48] randomized 66 patients with proven coronary artery disease to consume black tea and water in a crossover design; they found that short- and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Some antioxidants have been shown to reverse endothelial dysfunction and tea contains antioxidant flavonoids.

A proposed mechanism by which dietary flavonoids could affect flow-mediated endothelium dependent vasodilation is that they improve the bioactivity of the endothelium derived vasodilator nitric oxide (NO) [49] by enhancing NO synthesis or by decreasing superoxide-mediated NO breakdown. Flavonoids may increase endothelial NO production by stimulating Akt-mediated endothelial-derived NO synthase activity and additionally decrease levels of the vasoconstrictor endothelin-1[50,51].

A study recently reported the vasoconstrictor actions of exogenous endothelin-1 and methoxamine to be mediated by the RhoA/Rho-kinase pathway in the cavernosal circulation. While it is widely recognized that the nitric oxide-cyclic GMP-protein kinase G pathway mediates vasorelaxation and penile erection, the interaction between this pathway and the vasoconstrictor process remains to be fully elucidated. During erection, the vasoconstrictor action of methoxamine and endothelin -1 are inhibited and NO is likely to be responsible for this inhibition [52].

Erectile dysfunction in men over 40 years of age is usually of vascular (endothelial dysfunction) origin [53].

In other words, endothelial dysfunction is a causative factor in the development of erectile dysfunction. As flavonoids of tea may decrease erectile dysfunction occurrence as it may ameliorate endothelial dysfunction, we therefore hypothesize that the conjugate of NanoStilbene and our proprietary Green Tea Extract may play a role in erectile dysfunction prevention.

NanoStilbene

Pterostilbene, being extracted from many plants, has significant biological activities in preventing cancer, diabetes, and cardiovascular diseases so as to have great potential applications in pharmaceutical fields. But the poor solubility and stability of pterostilbene strictly restrained its applications. As a good protection and oral delivery system, an optimal nanoemulsion for pterostilbene was developed by using a low-energy emulsification method.

Nanoemulsions are non-equilibrium systems and possess kinetic stability in a long period with a remarkable small droplet size (below 200 nm).

The pterostilbene placed in a nanoemulsion droplet is free from air, light, and hard environment; therefore, as a delivery system, nanoemulsion can not only improve the bioavailability of pterostilbene but also protect it from oxidation and hydrolysis, while it possesses an ability of sustained release at the same time.

The “NanoStilbene” is prepared by method of low-energy emulsification which includes a phase inversion composition (PIC). The low-energy emulsifying method possesses great advantages of lesser physical destruction of active agents, smaller size of droplets, better phase behavior, and more convenient industrial scale-up than high-energy emulsifying methods.

In the PIC process, the stability and droplet size are greatly influenced by oil/surfactant ratio, hydrophile-lipophile balance (HLB) of surfactants.

We therefore aimed at developing an optimal oil/water (O/W) pterostilbene nanoemulsion by the PIC method on the basis of minimum surfactant concentration with increases in the solubility, stability, and the release performance of pterostilbene.

Nanotechnology

Therapeutic uses of nanotechnology typically involve the delivery of small-molecule drugs, peptides, proteins, and nucleic acids. Nanoparticles have advanced pharmacological effects compared with the therapeutic entities they contain. Active intracellular delivery and improved pharmacokinetics and pharmacodynamics of drug nanoparticles depend on various factors, including their size and surface properties.

Nanoparticle therapeutics is an emerging treatment modality in cancer and other inflammatory disorders. The National Cancer Institute has recognized nanotechnology as an emerging field with the potential to revolutionize modern medicine for detection, treatment, and prevention of cancer.

On May 15, 2018 TSI announced Institutional Review Board (IRB) clearance to initiate a pilot pharmacokinetic trial of “NanoStilbeneÔ.” Then on July 02, 2018 the Company announced receiving pilot clinical data providing proof of concept that NanoStilbene more effectively increases blood levels of the molecule as compared to conventional formulations. The clinical trial involved the administration of NanoStilbene in comparison to powder in capsule form pterostilbene with healthy volunteers, whom underwent a series of blood draws to determine the concentration of the compound.

Blood was collected in EDTA tubes and plasma collected subsequent to centrifugation at 700g for 10 minutes. Collection time points were prior to administration of test compound, as well as at times 2hr, 4hr, 6hr, 8hr, 10hr, and 12 hrs. Test compounds were 10 ml of NanoStilbene (provided by Therapeutic Solutions International) and 6 capsules of 50 mg pterostilbene (VitaMonk). A wash out period of 3 days was allowed between two test compound administration.

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The results were that at peak concentration NanoStilbene (Square) had a 55% increase in serum levels over the traditional powder (Triangle) form of pterostilbene. The data also shows the half-life to be double to that of the powder form.

The data in Granted U.S. Patent No.: 9,682,047 strongly suggest that pterostilbene administration may be an inexpensive and safe method of augmenting the efficacy of numerous immunotherapeutic drugs. Although cancer immunotherapy has revolutionized the prognosis of many patients, the majority of patients still possess poor or suboptimal responses to this approach.

Quantification of Pterostilbene

Plasma levels of pterostilbene was measured using a tandem mass spectrometer (API 3000; Applied Biosystems/MDS Sciex, Foster City, CA) equipped with a high performance liquid chromatograph (Agilent 1200; Agilent Technologies, Wilmington, DE). For pterostilbene determination, a 100 μL aliquot of plasma was mixed with 1 mL of acetonitrile (ACN; Sigma–Aldrich, St. Louis, MO). After vortex mixing for 1 min, the sample was centrifuged at 7,000 RPM at 4°C for 10 min to remove precipitated proteins; the supernatant was transferred to a clean tube and dried under nitrogen at room temperature (approximately 25°C). After the evaporation was completed, the residue was reconstituted in 100 μL of methanol with 5 min of sonication, added to 400 μL of water, vortex mixed, and centrifuged again. The resulting supernatant was transferred to a sample vial for instrumental analysis. All sample preparations were conducted under yellow light and using opaque plastic ware to avoid light exposure of the agent.

Freshly prepared pterostilbene standard curves were analyzed along with samples on each day of analysis. Instrument calibrators and quality control (QC) samples were prepared by adding 10 μL of a stock pterostilbene solution (in a methanol/water mixture [v/v 50:50] to 100 μL of rat plasma (Bioreclamation Inc., Westbury, NY). Target calibrator concentrations were 5, 10, 20, 50, 100, 200, 500, and 1,000 ng/mL. QC samples were prepared at approximately 12, 400, and 800 ng/mL. Calibrators and QC samples were processed for analysis using the procedure described earlier. The concentration of conjugated metabolites for both agents was estimated using the calibration curve for each parent compound.

Chromatography was performed using a Luna 3μC18, 30 × 2.0 mm column (Phenomenex, Torrance, CA) maintained at a temperature of 25°C. A flow rate of 0.25 mL/min was used. Mobile phase (MP) A consisted of 5 mM ammonium acetate in water:isopropanol (98:2, v/v); and MP B consisted of methanol:isopropanol (98:2, v/v). The MP gradient was as follows: after injection, initial conditions with MP A at 90% were held for 0.5 min, decreased to 5% in 3.5 min and held constant for 5 min, returning to initial conditions for another 3 min of re-equilibration time. Retention times for the target analytes were: pterostilbene, 6.3 min; pterostilbene glucuronide, 5.4 min; and pterostilbene sulfate, 5.5 min. Total run time was 12 min.

A turbo ion spray interface was used as the ion source operating in negative ion mode. Acquisition was performed in multiple reaction monitoring mode using the following ions: pterostilbene, 255.1 → 197.5; pterostilbene glucuronide, 431.1 → 255.1; and pterostilbene sulfate, 335.1 → 255.1. Ion spray voltage was −3,000 V; ion source temperature was 450°C; and collision energy was −30, −35, or 45 V.

The selectivity of the method was assessed by analyzing plasma extracts from different lots for the presence of analytical interferences and comparing the results to those obtained from spiking the blank plasma sources with analytes at the lower limit of quantitation (LLOQ; 5 ng/mL). Linearity was assessed using external standard method (pterostilbene) and up to eight calibrators with analyte concentrations in the 5–1,000 ng/mL range. The curves were built from peak areas using least-squares linear regression with (1/x) weighting factor. The weighting factor was chosen based on goodness-of-fit criteria including coefficient of determination (r2), the back-calculated concentration of individual calibrators, and minimizing intercept value. Precision and accuracy of the method were determined from QC sample results. Within-run precision and accuracy were assessed from the results from a single
day, while between-run precision and accuracy were determined from the results from multiple runs.

No significant peaks interfering with the quantitation of the agents were detected in the chromatograms of blank plasma. Calibration curves for both agents were linear from 5 to 1,000 ng/mL. The r2values were greater than 0.995. The back-calculated concentration of individual calibrators used to determine the calibration curve ranged from 90 to 100% of the true value. The method’s precision (CV%) was less than 10% and within-run accuracy ranged from 92 to 109% for both agents.

Clinical Trial of NanoStilbene™️ for Immune Derepression in Advanced Cancer

Pterostilbene, being a methyl ether of resveratrol, is known to possess anti-inflammatory and anticancer activity in various model systems. It is known that in advanced cancer, excess inflammatory signaling may be associated with reduction in CD3 zeta chain signaling and inhibited function of natural killer (NK) cells.

Given the importance of NK cells in the activity of various Immunotherapeutics, we sought to determine whether administration of a nanoparticle formulation of pterostilbene may reverse cancer associated suppression of NK activity. An initial study in heathy volunteers was performed to elucidate amount of NanoStilbene needed to be administered to achieve sufficient plasma concentration for induction of anti-inflammatory activity.

Subsequent to this, the selected NanoStilbene dose was administered to twelve patients with advanced solid cancers for 3 weeks. Daily treatment with 300mg of NanoStilbene caused reduction in serum levels of inflammatory markers TNF-alpha, IL-6, and CRP. Assessment of peripheral blood mononuclear cell ability to generate IFN-gamma subsequent to stimulation with anti-CD3 and anti-CD28 was increased.

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TNF-a what is it?
Tumour Necrosis Factor alpha (TNF alpha)
, is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signaling events within cells, leading to necrosis or apoptosis. The protein is also important for resistance to infection and cancers.

TNF inhibitors are drugs that help stop inflammation. They’re used to treat diseases like rheumatoid arthritis (RA), juvenile arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, ulcerative colitis (UC), and Crohn’s disease. They’re also called TNF blockers, biologic therapies, or anti-TNF drugs.
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IL-6 what is it?
IL-6
or Interleukin 6, is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation.

Interleukin inhibitors are immunosuppressive agents that inhibit the action of interleukins. Interleukins are a group of cytokines that are synthesized by lymphocytes, monocytes, macrophages, and certain other cells. They function especially in the regulation of the immune system.

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CRP what is it?
CRP
or C-reactive Protein is an annular, pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells.

Lowering of CRP may be seen with the use of statin drugs even without significant improvement of the cholesterol profile. Reduction of CRP level has also been noted in individuals with known cardiovascular disease who begin aspirin therapy.

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IFN-gamma what is it?

IFN-gamma
(IFNγ), or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoal infections. IFNγ is an important activator of macrophages and inducer of Class II major histocompatibility complex (MHC) molecule expression.

IFN–gamma has long been recognized as a signature proinflammatory cytokine that plays a central role in inflammation and autoimmune disease. There is now emerging evidence indicating that IFN–gamma possesses unexpected properties as a master regulator of immune responses and inflammation.

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NK cell what is it?
Natural killer cells
(also known as NK cells, K cells, and killer cells) are a type of lymphocyte (a white blood cell) and a component of the innate immune system. NK cells play a major role in the host-rejection of both tumors and virally infected cells.

NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection. NK cells work to control viral infections by secreting IFNγ and TNFα.

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Additionally, NK cytotoxicity was augmented. These results suggest that NanoStilbene may be a useful adjuvant to immunotherapy of cancer rescuing T cell and NK cell activities.

Augmentation of NK cell function may stimulate efficacy of approved therapies that depend on an active NK compartment such as Herceptin, Rituximab, and Cetuximab.

*The data provided here is partial and does not contain all materials submitted for publication and is preliminary until peer review is complete. These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.

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Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling

Post by curncman »

Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling

https://www.sciencedirect.com/science/a ... 9X22000499

Inflammation has been found to promote cancer initiation and progression by facilitating the development of a TME.


Phytochemicals and small molecules targeted inflammatory signaling can be helpful in cancer management.


Nanoparticles targeting inflammatory signaling serve as an avenue in cancer management.


Nanoparticles conjugated phytochemicals can be used in cancer treatment.


Unfavorable interactions of nanoparticles with biological entities are one of the major challenges in drug delivery which leads to unwanted toxicity.

Abstract
Recent mounting evidence has revealed extensive genetic heterogeneity within tumors that drive phenotypic variation affecting key cancer pathways, making cancer treatment extremely challenging. Diverse cancer types display resistance to treatment and show patterns of relapse following therapy. Therefore, efforts are required to address tumor heterogeneity by developing a broad-spectrum therapeutic approach that combines targeted therapies. Inflammation has been progressively documented as a vital factor in tumor advancement and has consequences in epigenetic variations that support tumor instigation, encouraging all the tumorigenesis phases. Increased DNA damage, disrupted DNA repair mechanisms, cellular proliferation, apoptosis, angiogenesis, and its incursion are a few pro-cancerous outcomes of chronic inflammation. A clear understanding of the cellular and molecular signaling mechanisms of tumor-endorsing inflammation is necessary for further expansion of anti-cancer therapeutics targeting the crosstalk between tumor development and inflammatory processes. Multiple inflammatory signaling pathways, such as the NF-κB signaling pathway, JAK-STAT signaling pathway, MAPK signaling, PI3K/AKT/mTOR signaling, Wnt signaling cascade, and TGF-β/Smad signaling, have been found to regulate inflammation, which can be modulated using various factors such as small molecule inhibitors, phytochemicals, recombinant cytokines, and nanoparticles (NPs) in conjugation to phytochemicals to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy to restrict malignant progression and improve the efficacy of cancer therapy. siRNA-and shRNA-loaded NPs have been observed to downregulate STAT3 signaling pathways and have been employed in studies to target tumor malignancies. This review highlights the pathways involved in the interaction between tumor advancement and inflammatory progression, along with the novel approaches of nanotechnology-based drug delivery systems currently used to target inflammatory signaling pathways to combat cancer.

Keywords
NanomedicinePhytomedicineCancer therapeuticsInflammationCancer signaling
1. Introduction
Novel advancements in the treatment of cancer, which is a leading cause of morbidity and mortality worldwide, have resulted in modest impacts on patient survival. Determinants of cancer progression and survival are of increasing interest to researchers working to develop effective cancer therapies. Research in the recent decades has highlighted the importance of inflammatory responses in determining disease progression in patients with cancer [1]. Studies support the impact of inflammation on every step of tumor development, including initiation, promotion, metastasis, and recurrence. Inflammation caused by autoimmune diseases, infections, and other factors that increase the risk of cancer and accelerate malignant progression, such as obesity, smoking, and alcohol consumption, termed as tumor-extrinsic and tumor-intrinsic inflammation, initiate mutations and provide a preferred background for tumor progression. The occurrence of genetic mutations increases in an inflamed microenvironment, promoting genetic instability, which further paves the way for cancer initiation [2]. Inflammation regulates cancer development and may have antagonistic effects on therapeutic outcomes by facilitating resistance to treatment [3]. Crosstalk between cancer cells and immune cells is either directly or indirectly through cytokine and chemokine signaling molecules. Pro-tumorigenic effects of inflammation, mediated by signaling pathways, often consist of feed forward loops. For instance, the cytokines produced by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in immune cells induce chemokines, which further results in an increased inflow of inflammatory cells into the tumor [4]. In certain cases, therapy-induced inflammation may lead to immune-mediated tumor eradication to enhance antigen presentation. Thus, understanding the contribution of inflammation in various phases of tumor growth will assist in developing approaches to exploit the inflammatory pathways and selectively target the tumor-associated microenvironment for therapeutic and diagnostic purposes.

The pharmacological success of chemotherapeutics in cancer therapy is limited owing to a reduction in their efficacy due to degradation by specific enzymes and poor biodistribution, which increases extensive off-target effects [5]. These effects are responsible for drug resistance and poor patient survival. With advancements in nanotechnology, we could expand the physicochemical features of chemotherapeutics, diminishing their overall toxicity while sustaining their pharmacological activities, and enhancing their therapeutic index and accretion at the disease site. A variety of nanomaterials have been utilized for the development and improvement of new cancer therapeutics. In this review, we will further discuss the role of nanoparticles (NPs) in cancer treatment by targeting different inflammatory signaling pathways for cancer therapy.

2. Revisiting inflammatory signaling in cancer
Inflammation is an evolutionarily conserved phenomenon that results in the activation of cells from both immune and non-immune compartments. The goal of the inflammatory process is to protect the host body from bacteria, viruses, toxins, and a multitude of infections, while simultaneously facilitating damaged tissue repair. Depending on the intensity and extent (systemic or local) of a particular immune response, several neuroendocrine and metabolic changes may occur in the host to channelize the energy and nutrient supply to the activated immune system. Although a sporadic rise in inflammation is critical for endurance during physical injury and infection, recent studies have demonstrated that specific social, environmental, and lifestyle factors can promote systemic chronic inflammation (SCI). SCI itself is detrimental to the body and can lead to diseases such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative disorders [6]. In fact, SCI is a leading cause of disability and mortality in patients around the globe.

Regarding cancer, SCI promotes its initiation and progression by facilitating the development of a tumor-supportive microenvironment (Fig. 1). Furthermore, SCI triggers tumor progression by inducing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are typically associated with DNA mutations. As chronic inflammation persists, mutations tend to accumulate, and some of these mutations can drive cell growth, survival, or even reduce cellular apoptosis [7]. A key hallmark of chronic inflammatory conditions in the host body is the activation of inflammatory signaling pathways, such as Wnt/β-catenin, Janus-activated kinase (JAK)-signal transducers and activators 3 (STAT3), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/ mammalian target of rapamycin (PI3K/AKT/mTOR), NF-κB, mitogen-activated protein kinase (MAPK), and transforming growth factor (TGF)-β/Smad. Consequently, to prevent or limit SCI-induced tumor progression, it is imperative to understand the interaction between these signaling prototypes and their associated proteins at a molecular level.

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Table 1. List of naturally occurring and synthetic small molecules used to target inflammatory signaling pathways in cancer treatment.

Compounds Compound class Targeted inflammatory signaling pathways Mechanism of action Cancer type References
Naturally occurring small molecules
6-Shogaol Phenylpropanoid Inhibits AKT and JAK/STAT signaling pathway, and
inhibits NF-κB activity Reduces expression of Ki-67, cyclin D1, c-myc, inhibits phosphorylation of STAT3 and AKT, induces cell cycle arrest and apoptosis NSCLC, and prostate cancer [119,120]
Alicin Organosulfur Reduces the activity of PI3K/AKT signaling pathway and downregulates STAT3 activity Suppresses AKT phosphorylation, alters TIMP/MMP balance, inhibits adhesion, invasion, and migration, and upregulates Bax proteins inducing apoptosis Lung adenocarcinoma cells and
cholangiocarcinoma [121,122]
Alpinumisoflavone Flavonoid,
pyranoisoflavone Represses ERK/MAPK and NF-κB pathways Modulates miR-101/RLIP76 signaling, suppresses Nrf2 expression and induces cell death Renal cell carcinoma and ESCC [123,124]
Andrographolide Phytomolecule, diterpenoid Inhibits upstream PI3K/AKT pathway Suppresses expression of HIF-1α and VEGF protein, dephosphorylates AKT, mTOR and its downstream effector P70S6K Breast cancer [125]
Apigenin Flavonoid Inhibits PI3K/AKT signaling pathway Suppresses the SNAIL/SLUG-mediated EMT and Cd26 expression NSCLC [111]
Baicalein Flavonoid, trihydroxyflavone Activates MAPK, ERK and p38 signaling pathway Enhances phosphorylation of ERK1/2 and p38, RAS-induced senescence Regulates colon cancer cell apoptosis and senescence and ESCC [126]
Baicalin Flavonoid, flavone glycoside Modulates PI3K/AKT, mTOR and
NF-κB signaling pathway Inhibits hTERT and SLUG- mediated EMT Breast cancer [127]
Curcumin Phytopolyphenol Disrupts NF-κB signaling, inhibits COX-2, CD-31, VEGF, IL-8, JAK2/STAT3, PI3K/AKT/mTOR signaling pathway and suppresses Notch1 signaling Suppresses p65 and p50 genes, C-MET, survivin, Bcl-2 and cyclin D1 Colon, gastric, pancreatic, breast, ovarian cancer and multiple myeloma [113,129]
Emodin Small molecule, natural anthraquinone Inhibits JAK/STAT,
MAPK, PI3K/AKT, a
nd NF-κB signaling Inhibits JAK activity and IRF4, STAT6 and C/EBPb signaling Breast, colorectal, lung cancer and hepatocellular carcinoma [130,131]
Entrectinib Rozlytrek Modulates RAS/MAPK/ERK, PI3K/AKT and PLCγ Tyrosine kinase inhibitor CNS cancer, colorectal cancer and NSCLC [132]
Fedratinib Brand Name- INREBIC® Modulates JAK/STAT pathway Inhibits JAK, downregulates the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin NSCLC [133]
Genistein Isoflavonoid Modulates Wnt/β-catenin signaling pathway Inhibits cyclin D1 and c-myc, reduces nuclear β-catenin expression and upregulates Wnt1 Colon cancer [134]
Glycyrrhizin Triterpenes Modulates NF-κB signaling Activates TLR4, inhibits TxA2-related pathway and HMGB1 Lung cancer [135]
Luteolin Flavonoid Inhibits PI3K/AKT pathway Induces caspase-3, -7, and -9, ERK, IGF, β-catenin, GSK-3β, MMP-2 and -9, iNOS, COX-2, Bcl-2, Bax, CDK2, and cyclin D and damages DNA Breast cancer [138]
Licochalcone A Estrogenic flavonoid, natural phenol, chalcone Inhibits PI3K/AKT/mTOR activation Targets cyclins and CDKs, promotes autophagy and apoptosis Breast cancer [139]
Nimbolide Triterpene Reduces PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signaling Reduces AKT, mTOR and, p70S6 Kinase, phosphorylates ERK and blocks EMT Pancreatic cancer [116]
Pterostilbene Polyphenol Modulates JAK/STAT3, MAPK/ERK and PI3K/AKT pathway Upregulates p-p38MAPK and downregulates p-ERK1/2 Bladder, lung, gastric, endometrial cancer and NHL [141,142]
Thymoquinone Phytochemical, quinone Inhibits STAT3 phosphorylation Reduces JAK2 and c-Src activity Gastric cancer [143]
Withaferin-A Phytosterol, steroidal lactone Modulates AKT signaling Targets FOXO3a-Par-4 cell death pathway, increases phosphorylation of ERK and p38 pathway HCC [144]
Synthetic small molecules
Capmatinib Brand name-Tabrecta Modulates PI3K/AKT, MAPK, STAT, NF-κB pathway Inhibits C-MET NSCLC, thyroid cancer and renal carcinoma [128]
Dabrafenib Brand name-Tafinlar Modulates RAS/RAF/MEK/ERK signaling Modulates BRAF/CRAF Melanoma, NSCLC and ATC [92]
Everolimus Brand Name-Afinitor Inhibits PI3K/AKT Inhibits mTOR RCC,
Pancreatic
and breast cancer [97]
Quizartinib Brand Name-Vanflyta Modulates PI3K/AKT/mTOR, RAS/RAF/MAPK and JAK/STAT Targets FLT3 AML [87]
Idelalisib Brand Name-Zydelig Modulates PI3K/AKT pathway Inhibits PI3Kδ CLL and
follicular lymphoma [94]
Larotrectinib Brand Name-Vitrakvi Modulates RAS/MAPK/ERK, PI3K/AKT and PLCγ Inhibits tropomyosin receptor kinase- A/B/C Breast cancer [136]
Lestaurtinib Semi synthetic derivative of indolocarbazole Modulates JAK/STAT signaling Inhibits JAK2, FLT3, and neurotropin receptor TrkA AML [137]
Buparlisib NVP-BKM120 Inhibits PI3Kα and mTOR Blocks NF-κB expression, activates caspase-9 and caspase-3/7 and reduces AKT phosphorylation Breast cancer [140]
Temsirolimus Brand Name-Torisel Inhibits PI3K/AKT Modulates mTOR RCC
I am well wisher of everyone! GOD will pardon all your sins but not your Central Nervous System! Think Positive!
curncman
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Quadrame Vs ELYSIUM

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QUADRAMUNE Vs Elysium

QUADRAMUNE is far superior and has multiple health benefits in treating Rhemeutoid Arthrithis, Diabetes, Parkinsons and above all COVID-19 variants
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I am well wisher of everyone! GOD will pardon all your sins but not your Central Nervous System! Think Positive!
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