HadaClinic Web Journal: Thalidomide & CelecoxibChronic Granulomatous Disease.

 

Chemotherapeutic Prevention and Treatment with Thalidomide, Celecoxib, and Valproic Acid for Chronic Granulomatous Disease.

 

Linkage Between Pathogens, Chronic Inflammation, and Angiogenesis

 

Masato Hada, MD, Pharmacist

Author information Hada Clinic, clinichada@cy.tnc.ne.jp

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Abstract

Chronic granulomatous disease (CGD) is a rare, inherited immunodeficiency disease. Patients with this disorder have aberrant immune systems, leaving the body vulnerable to chronic inflammation and frequent bacterial and fungal infections. Hyperinflammatory reactions such as reduced neutrophil apoptosis, dysbalanced innate immune receptors, induction of Th17 cells, and impaired Nrf2 activity become more prominent.

Thalidomide, celecoxib and valproic acid (VPA) have pleiotropic immunomodulatory and antiangiogenic effects. In addition to their effects these agents also exhibit therapeutic effects in CGD and malignancies.

 

要約

 近年多くの難治性疾患や癌は体内細菌叢のアンバランスによって引き起こされることがわかってきました。体内には約1-2kgの微生物が住み着いています。

生後3年間は母親から引き継いだビフィズス菌を主とする腸内細菌叢が優位を占めますが、その徐々に成人型の細菌叢に変化していきます。この変化の大きな原因は日常の食生活環境に関係してきます。腸内細菌叢の乱れをdysbiosisといいますがこの乱れが各種疾患の原因になると考えらており成人型細菌叢に移行する際に起こり難治性疾患、癌の原因になります。癌の20%は細菌に、30%は喫煙、35%は食生活を含む生活環境によると考えられていますが,これらがdysbiosisを起こすと考えられます。

慢性肉芽腫症も癌に至る前段階の疾患と考えることが適当と考えます。癌治療と同様に細かい病態生理学を取り入れた治療が必要と考えます。難治性疾患や癌の治療においては病態を引き起こす重要因子を抑えることです。慢性肉芽腫症でも他の疾患と同様にトル様受容体とNF-kBといった因子です。サリドマイド、セレコキシブは数多くの作用点を持っており、相乗効果でNF-kBに作用し強力な抗炎症作用を発揮します。さらにバルプロ酸を併用することで効果的な治療が可能となります。上記3種類の薬剤を単独に使用してもある程度の効果を得られますが、相乗効果を期待した有効な治療法が患者さんにとっては有益と考えます。

しかしながら日本では、厚生官僚の無知、保身で上記の薬剤は使用できません。2002現大阪市立大学教授、元監視指導課課長日下部哲也氏の不法サリドマイド回収命令や、森和彦厚生労働省大臣官房審議官のサリドマイド治験拒否藤本製薬 山下 治夫部長との癒着と天下りでサリドマイドを認可させ、医薬品としての使用を制限してしまいました。その結果助かるべき難病や癌患者さんは辛い闘病生活や死に追い込まれています。厚生官僚の忖度、医学的能力の低さ、出世主義、製薬会社保護は余りにもひどいものがあります。

 

Key words: Chronic granulomatous disease, gut microbiota, IL-23/IL-17, Nrf2, neutrophil apoptosis, berberine, thalidomide, celecoxib

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OVCAR-3 cells were sensitized to paclitaxel-induced apoptosis by celecoxib through downregulation of NF-κB and Akt activation, suggesting that celecoxib may work synergistically with paclitaxel to inhibit different targets and ultimately produce anticancer effects. Combining celecoxib with paclitaxel may prove beneficial in the clinical treatment of ovarian cancer.

Keywords: Ovarian neoplasms, Celecoxib, Paclitaxel, Apoptosis, NF-kappa B, Akt

Introduction

CGD is an inherited primary immunodeficiency resulting in severe recurrent infection and inflammatory complications characterized by the dysfunction of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytic cells1 2. NADPH oxidase is associated with the production of bactericidal reactive oxygen species (ROS) in phagocytes.  As a result, the dysfunction of NADPH oxidase of CGD patients increases the susceptibility to certain catalase-positive bacteria and fungi, and Aspergillus species3 4. With the use of antibiotics and antimycotics, the prevention and treatment of severe infections have been achieved. However, hyperinflammatory reactions such as reduced neutrophil apoptosis, dysbalanced innate immune receptors which cause complicated interleukin reaction loops, induction of Th17 cells, and impaired Nrf2 activity become more prominent 5.

Neutrophil Apoptosis

Neutrophils (also called polymorphonuclear leukocytes, PMNs) are the most abundant white blood cells with short lifespan within less than 24 hours. PMNs play a pivotal role in innate immunological defense. Neutrophil apoptosis is regulated by intracellular signal pathways and changes in gene expression. PMNs apoptosis associate with pathogenesis of infections and inflammatory diseases. PMNs play an important role in defending against infections recruiting NADPH oxidase-derived ROS 6. However, if recovery process from infection including neutrophil apoptosis is not properly progressed, inflammation leads to persistent tissue damage by leukocytes, lymphocytes or collagen7. Neutrophil apoptosis possesses a complex network of intracellular signaling pathways and is profoundly affected by signals from the inflammatory microenvironment. Transcription factor NF-κB regulates the expression of more than 150 genes including inflammation, immunity, cell proliferation, differentiation, and survival 8. Neutrophil apoptosis triggered by LPS or TNF-α can be regulated with small molecular-pharmacological agents that act directly on NF-κB 9. 

Dysbalanced Innate Immune Receptors

Innate immune receptors regulate the function of neutrophils through such as Toll-like receptors (TLRs) and complement receptors that play critical role in first-line host defense10 11. The signal pathways of TLRs involve the activation of mitogen-activated protein kinases (MAPK) and NF-κB. TLRs play an important role in the innate immune system, detecting specific microbial motif, defending against pathogens and finally triggering an inflammatory response12. Although in bacterial infection neutrophils are triggered to the inflammatory site through the IL-8 receptors CXCR1 and CXCR2, TLR5 and TLR9 expression is reduced in CGD through a mechanism associated with the deficient ROS production10 13. TLR5 is a   pleiotropic receptor that are implicated in the protection such as microbial infections and inflammation14.

TLR5 is expressed in many tissues including lung, intestinal epithelial cells and react on recognition of the flagellin, component of bacterial flagella12.

 

dysbalanced innate immune receptors

dendritic cell

monocyte

macrophage

Th17cell

fibroblast

macrophage

endothelial cell

epithelial cell

inflammation

Ref 7 11 12 13 14 15

 

 

IL-17A,17B

IL-26

IL-23

 

IL-6,21, IL-1β,

TGF-β

IFN-γ,TNF-α

IL-6,22

IL-1,6

TNF-α

 

 

Gut Microbiota and IL-23/IL-17 Immune Pathway

The IL-23/IL-17 pathway plays an important role in the pathogenesis of CGD and targeting this pathway may be beneficial in the treatment of CGD 15. IL-23 is a member of the IL-6/IL-12 family of cytokines and IL-12 and IL-23 are produced by activated antigen-presenting cells including dendritic cells (DC).Detecting the pathogens of microorganism, IL-23activates DC and mediate T cell via TLRs to produce IL-17 that has a crucial role in pathogenesis of CGD.16 IL-17 receptors activate NF-κB and MAP kinases for the induction of proinflammatory mediators such as IL-6, IL-8 independent of toll-like receptor15.

 

Impaired Nrf2 Activity

The Keap1-Nrf2 pathway is the major cytoprotective regulator against overproduction of oxidative stress including ROS and electrophiles 20 21.  The key factors within the pathway are the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2).  Together with small musculoaponeurotic fibrosarcoma proteins (sMafs) Nrf2 binds to the antioxidant response element (ARE). A repressor protein Kelch ECH associating protein 1 (Keap1) binds to Nrf2 and promotes its degradation by the ubiquitin proteasome pathway that degrades diverse cellular proteins with their specificity22 20. Nrf2 prevents initiation and progression of transformation in non-malignant tissues, however Nrf2 promotes tumor cell growth increasing chemoresistance20 23. Nrf2 expression in gastric cancer can be a potential tumor marker for prognosis 24.

 

Treatment

A possible role of Probiotics and Prebiotics against Dysbiosis

Probiotics are defined as healthy microbiota that promotes benefits to host health. Prebiotics are roughly and typically defined as non-digestible fiber that enhance the growth of gut microbiota and some non-digestible fiber compounds downregulate COX-2 25.

Among various probiotics lactic acid bacteria including Lactobacillus and Bifidobacterium have been known to exert beneficial effects in human26.

There are data that gut microbiota established at birth play a more significant role in the development and maintenance of colitis than phagocyte-derived ROS in mice27 28.

The cell deaths of bifidobacteria are caused by ROS mainly hydrogen peroxide (H2O2).Some strains of bifidobacterial species are cross-protected with gut catalase-positive bacteria. Many kinds of bacteria are defended by catalase that detoxicates H2O229.  Specific Bifidobacteria and Bacteroides produce acidic fermentation products, short chain fatty acids (SCFA), including acetate, propionate and butyrate30. These degradation products have been implicated in anti-inflammatory effect via inhibition of activated NF-κB 31 and play a beneficial role in human gut health32.

Prebiotics

  Almost polysaccharides which generate short-chain fatty acids, including acetate, propionate and butyrate are non-digestible by human intestinal enzymes 34. 33

 Fibers that possess high solubility and viscosity include β-glucan and pectins are highly fermentable.

Berberine

Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea.

The anti-inflammatory activity of berberine is induced via AMAK activation, NF-kB inhibition and AP-1pathway inhibition. The inhibition of these pathways by berberine plays a critical role in inflammation and carcinogenesis resulting in down-regulating the expression of cytokines, eg, . TNF-α, IL-1β, IL-6, monocyte chemo-attractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) 35 By production of antimicrobial ROS (oxidative burst) and release of proteolytic peptides neutrophils act. The inhibitory effect of berberine on ROS production is prominent, that is, berberine shows more profound anti-inflammatory effect via neutrophil-derived ROS 36.

Thalidomide

Currently, thalidomide is clinically most favorable agent as novel antiangiogenic and immunomodulatory drug in combination with other anti-inflammatory agents for the treatment of various diseases, including lupus erythematosis, Behcet's disease, inflammatory bowel disease, solid tumors37 38, hematologic malignancies, and heart failure. Thalidomide has broad spectrum of activities and classified as immunomodulatory and non-immunomodulatory activities. Immunomodulatory activities are exerted through the inhibition of NF-kB that causes such as adjustment of secretion of interleukins, stimulation of Th1 immunity. Non-immunomodulatory activities are antiangiogenic, anti-proliferative and pro-apoptotic activity, and COX-2 inhibition 39.Theprominent effects of thalidomide are immune cell regulation, chronic inflammation and angigensis38 41.

Celecoxib

Apoptosis can take place mainly by cross-talks between the intrinsic and extrinsic pathways. Damage stresses activate intrinsic pathway.

The extrinsic apoptotic pathway is activated upon binding of specific ligands including cytokines, such as TNFα, to death receptors. Celecoxib modulates stress-induced apoptosis and promotes extrinsic apoptosis 41 42.

Valproic Acid

Histone is the main components of chromatin playing a role in gene regulation with histone modification including methylation, acetylation,and phosphorulation. HDAC inhibitors such as valproic acid show powerful anti-inflammatory and immunomodulatory activities 43. However, there are reports that HDAC inhibitors down-regulated the expression of numerous host defense genes and compromise host defence44 45.

 

Conclusion

It is very effective to inhibit the expression of interleukins with the use of probiotics, prebiotics and berberine with very few side effects from the beginning of the treatment. Chronic inflammation which is caused by interleukins must be repressed by anti-inflammatory agents such as thalidomide, celecoxib, and VPA to treat CGD. It is important to select the agents that act on NF-kB or its downstream factors. Mechanism of action of monoclonal antibodies (ending-mab agents) or inhibitory agents (ending –ib agents) that work on receptors or its downstream factors (between receptors and NF-kB) are not elucidated clearly.

In clinical appliance of thalidomide regimen, it is important to combine probiotics (including berberine), and celecoxib to get potent anti-inflammatory effects.

1. Probiotics

Lactic acid bacteria including the genus Lactobacillus and Bifidobacterium enforce immunity in human health.

Prebiotics

Almost polysaccharides which generate short-chain fatty acid are non-digestible by human intestinal enzymes. Fibers that possess high solubility and viscosity including β-glucan and pectins are highly fermentable.

Berberine

100-300mg/day according to the fecal fermentative end products.

2. Thalidomide and Celecoxib

The combination of thalidomide 200mg/day and celecoxib 400mg/day is important for suppression of dysirregulated or activated NF-kB.

3. Valproic acid

depending upon the patient state.

Valproic acid 600mg/day (three times a day)

 

 

maternal neonate interface

infant

adult

disease

Delayed Neutrophil Apoptosis

abortion, preeclampsia

intrauterine growth restriction

preterm birth 46

neutrophil activation

 

chronic inflammatory disorders 47 48

 

 

Oxidative stress

interaction with placenta.    ROS activates NF-kB.

cell homeostasis

cell death

miscarriage, pre-eclampsia 49

 

 

 

 

Nrf2

fetal growth and survival  50

 

 

elimination of oxidative stress

cytokines

 

fetal inflammatory response syndrome (FIRS) 51 52 53

L-17R mediates signal via downstream NF-κB Granuloma Formation 54

autism, schizophrenia, multiple sclerosis 52

thalidomide

× contraindication

Post-conception 20-36days

antiangiogenic, anti-inflammatory via  NF-kB

thalidomide embryopathy 56

celecoxib

use of early antiangiogenic and anti-inflammatory agents improves preeclampsia 57

Immunomodulation 58

 

valproic acid

neural tube malformations 59

antimicrobial defense 60

Autism Spectrum Disorder

Berberine

alleviates preeclampsia in rats 61

 

treatment of T-cell–mediated autoimmune diseases 62

probiotics prebiotics

modulation of intestinal microbiota, strengthening of the epithelial barrier, and immunomodulation  63 64 65

 

 

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