HadaClinic Web Journal: Thalidomide & CelecoxibOvarian Cancer

 

Chemotherapeutic Strategy with Probiotics, Thalidomide, Celecoxib and Valproic Acid for Ovarian Cancer.

 

Linkage between dysbiosis, chronic inflammation, angiogenesis and cancer

 

Masato Hada, MD, Pharmacist

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

 

 

Abstract

A number of diseases including autoimmune diseases and malignancies are supposed to be caused by dysbiosis, imbalance of microbiota. Tumor microbiome may be associated with ovarian cancer (OC). However tumor microbiome is complex and difficult to clarify the mechanism. Utilization of microbiota as a potential therapeutic option may be effective without prominent adverse effects 1 2.

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) identifying pathogen-associated molecular patterns (PAMPs) including lipopolysaccharide (LPS). Dendritic cells are main antigen-presenting cells that express a wide variety of PRRs. TLR signaling pathways activate transcription factor nuclear factor-kappaB (NF-κB). NF-κB is a major therapeutic target to suppress the production of exacerbating interleukins for OC. NF-κB plays a key role between inflammation, angiogenesis and cancer at the molecular level 3. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 4. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops.

It is now widely accepted that prevention and treatment options for patients with OC are limited due to the lack of a therapeutic target. But it is possible to prevent and treat the patients with OC with chemotherapeutic agents including thalidomide, celecoxib and valproic acid. These agents also blocks dysregulated or activated NF-kB in immune and malignant cells.

 

要約

近年多くの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。体内細菌叢によって排出された病原体は免疫細胞を刺激してインターロイキン(IL-1,246…)という細胞間免疫物質を放出し、慢性炎症(微弱な炎症)を引き起こします。自己免疫疾患といった難治性の疾患を引き起こします。この現象で重要な働きをなすのが、トル様受容体(Toll like receptorTLR)とNF-kBといった因子です。トル様受容体が病原体の刺激を感受してその情報をNF-kBに伝え各種疾患を引き起こす免疫物質を作り出します。具体的にはIL, TNF-α、VEGFCOX-2などです。これらの因子が複雑に絡み合い難病を引き起こし、最終的には癌を引き起こします。

現在の分子標的薬は受容体やNF-kB到達前までの蛋白に作用するもので、NF-kBに直接作用する薬剤は存在しません。それゆえ辛くて効果が少ない癌治療といわれている所以です。サリドマイド、セレコキシブはNF-kBに効果的に作用し強力な抗癌作用を発揮します。バルプロン酸はこれらの作用を補助する役目で抗癌作用を増強します。

卵巣癌治療の場合は女性ホルモンが大きな作用をはたしていると考えられています。あまりに複雑すぎて明確な結論は出ていませんが、腸内の細菌叢を安定した状態に整えることは治療効果を上げると考えられます。腫瘍内微生物が抗癌剤たとえば卵巣癌に効果があるゲムシタビンを代謝して無毒化してしまうということも報告されています2 。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や藤本製薬 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、抗癌剤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癌患者さんは死に追い込まれています。

 

Key Words: Ovarian Cancer, Gut Microbiota, Toll-like receptors (TLRs), NF-κB, Berberine, Thalidomide, Celecoxib, Valproic Acid

 

Introduction

More than half of the patients with OC are diagnosed in metastatic state with the dissemination of cancer cells into abdominal cavity and ascites. Pathophysiological understanding is significantly important for therapeutic modalities 5.

Neutrophils (also called polymorphonuclear leukocytes, PMNs) are the most abundant white blood cells with short lifespan within less than 24hours. 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 6. Aggressive OC often correlates with PMNs that suppress the innate immune system. The starting processes to carcinogenesis are the first stimuli of pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide (LPS) or viral RNA that ligate with pattern-recognition receptors (PRRs) 7.

TLRs play an important role in the innate immune system, detecting specific microbial motif, defending against pathogens and finally triggering an inflammatory response 8.

Circulating estrogens are regulated by β-glucuronidase that modulates inactive conjugated estrogen altered in the liver into the active form. The gut microbiota plays an important role in expression of β-glucuronidase. Dysbiosis of gut microbiota alters the level of circulating estrogens and possibly leads to OC 9.

The molecular cross-talk signaling between OC cells and various stromal cells play crucial roles in OC proliferation, progression and metastasis. The potential targets that offer a significant survival advantage are targets of TLRs and angiogenic pathways that cause chronic inflammation, angiogenesis and malignancies.

 

The Estrobolome and Circulation of Estrogens.

Estrobolome is defined as the aggregate of enteric bacterial genes whose constituents are bacterial species in the gut with β-glucuronidase activity. The estrobolome can regulate both the excretion and circulation of estrogens via conjugation and deconjugation 10. Low levels of circulating estrogens of post-menopausal women adversely effect on clinical state including female reproductive systems and women’s health. Dysbiosis of gut microbiota reduce circulating estrogens, as a result various gynecological malaise including ovarian cancer can develop 10 11 12.

 

Toll-like Receptors (TRLs)

About 90% of tumor initiation is linked to somatic mutations and environmental factors. To date, inflammation induced by bacterial and viral infections increases cancer risk 13.  TRLs expressed in leukocytes play an important role in initiation of immune response, activating pro-inflammatory pathways that express cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α) 14 15. The subsequent factor that induce proangiogenic stimuli is NF-κB. NF-κB regulates the expression of more than 150 genes that lead to a broad range of production of various cytokines, chemokines and antiapoptotic and stress-response factors 15 16. TLR2, TLR3, TLR4, and TLR5 are shown to be highly expressed in the normal ovarian epithelium, as well as in neoplastic ovarian epithelial cells. These TRLs are also expressed in vascular endothelial cells, macrophages, and occasional fibroblasts in tumors 17. Recognizing LPS by TRL-4 that recruites MyD88 induce the production of proinflammatory cytokines including IL-6, TNF-α, and IL-12 and activate NF-κB 18. OC microenvironment is consistent of these cytokines and immune cells with complex nature and shows strong immunosuppression 15.

 

Ascites and Peritonitis Carcinomatosa

Advanced OC may cause ascites retention and peritonitis carcinomatosa that express various symptoms such as abdominal bloating, weight loss, constipation and so on. Malignant ascites of OC develops more common than other cancer types because ovary resides intraperitoneal cavity and contact with peritoneum 19.

The accumulation of ascites are associated with various factors including  increased vascular permeability with vascular endothelial growth factor (VEGF), mechanical obstruction with malignant cells on the peritoneal surface, and inhibited reabsorption of ascites into bloodstream by low osmotic pressure due to hypoalbuminemia. In case of malignant ascites, it may be possible to control ascitic fluid only with suppression of VEGF activity and production of VEGF. However, without overall treatment of angiogenesis induced by malignancy, using intracellular acting agents that cease production of angiogenic growth factors, it is impossible to control malignant ascites. Without the treatment of primary/metastatic lesions, VEGF is continued to be supplied.

 

Contraindication: Use of CART

Cell-free and concentrated ascites reinfusion therapy (CART) is approved only in Japan for the management of malignant ascites. CART is one of the types of apheresis therapy, by which filtered and concentrated ascites containing albumin and globulin is reinfused intravenously to patients. VEGF also pass through the filter. Concentrated VEGF exacerbates the accumulation of ascites 20 21 CART has been a promising strategy for Equipment Maker Asahikasei Medical with massive income but has been annoying the patients with more massive peritoneal fluid. In case of malignant ascites, it may be possible to control ascitic fluid only with suppression of VEGF production, not with antiangiogenic monoclonal antibody like bevacizumab (Avastin).

 

Angiogenesis

Angiogenesis is a multi-step process essential for tumor growth and metastasis, which involves endothelial cell proliferation, migration and capillary formation. Hypoxic state induces proangiogenic signaling by activating a protein called hypoxia-inducible factor (HIF) -1α which enters the nucleus and forms a complex with another protein, the HIF-1β. HIF-1 complex plays as a transcription factor targeting many genes responsible of upregulation of growth factors 22 23 24. More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis.  These proteins include VEGF, basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-α, TGF-β, TNF-α, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) 25 and cyclooxygenase-2 (COX-2) 26 VEGF, bFGF and COX-2 are three key mediators of angiogenesis. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 23 24 27.

 

Treatment

Women with estrogen replacement therapy for more than 10 years were at significantly increased risk of OC. The exciting findings in the past decade that the gut microbiota may act as a regulator of the estrogen level in the bloodstream. At least it is important to maintain the homeostasis of gut microbiota with probiotics, prebiotics and berberine 2.

 

Probiotics

More than 60% of primary ovarian and breast tumors express estrogen receptor α (ERα) and thought to promote tumor proliferation, however therapeutic effect with antiestrogens is disappointing 28 29. The microorganism that exert beneficial effects in human health are known as probiotics which are defined as  live microbial feed supplements including the genus Lactobacillus and Bifidobacterium. Probiotics have been shown to have anti-cancer effects with prebiotics 30.

The role of gut microbiota in estrogen deconjugation will be explored in the future.

 

Prebiotics

The fermentation may lead to the increased production of short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate. The potential natural products are whole grains, fruits, vegetables, and nuts. SCFAs are known as HDAC inhibitors, especially butyrate possesses significant response and modulate cancer and immunological stability 31.

 

Berberine

Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea. Berberine modulates gut microbiota and reduces significantly fasting blood glucose, triglyceride, low-density lipoprotein-cholesterol and insulin resistance through inhibition of LPS/TLR4/TNF-α signaling in the rat liver 32.

The anti-inflammatory activity of berberine is induced via AMAK activation, NF-kB inhibition and AP-1 pathway inhibition. The inhibition of these pathways by berberine plays a critical role in inflammation and carcinogenesis resulting in down-regulating the expression of cytokines,including TNF-α, IL-1β, IL-6, monocyte chemo-attractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and COX-2 33. Neutrophils generate antimicrobial ROS (oxidative burst) and release of proteolytic peptides. The inhibitory effect of berberine on ROS production is prominent, that is, berberine shows more profound anti-inflammatory effect via neutrophil-derived ROS 34.

 

Chemotherapy

Chemotherapy for OC is usually a combination of platinum and 1 or more agents. Many patients with OC respond to first-line platinum-based therapy, however most of patients experience the disease recurrence in less than 6 months after treatment was finished 35.

Chemotherapy with targeted agents that act on transcriptional factors should be given with cytotoxic agents including taxanes (docetaxel, paclitaxel), gemcitabine, irinotecan, and vinorelbine.

 

Thalidomide

Thalidomide is an immunomodulatory agent with strong anti-angiogenic properties with COX-2 inhibitor celecoxib. Thalidomide inhibits the mRNA encoding such as TNF-α and VEGF 36. In addition, thalidomide modulates activated or irregulated NF-κB, resulting in suppressing malignant cell proliferation and angiogenesis as well as invasion and metastasis37.

 

Celecoxib

COX-2 is constitutively overexpressed in chronic inflammation including premalignant, malignant, and metastatic tumors. Chronic inflammation induced by pathogens and metabolic state such as obesity leads to express COX-2. Produced prostaglandin (PG) and pro-inflammatory cytokines by COX-2 cause angiogenesis with subsequent ovarian carcinogenesis, tumor proliferation and metastasis, especially through NF-κB 36 38 .

 

Valproic acid

VPA is a short fatty acid and has been used as an anti-convulsant agent. In recent years, VPA is used as HDAC inhibitor alone or in combination with other anti-cancer agents 39.

The induction of cell cycle arrest and apoptosis by VPA are associated with increased expression of E-cadherin and decreased expression of VGF and MMP-9 40 41.

 

Conclusion

Combining low dose cytotoxic agent with thalidomide, celecoxib, and valproic acid has the potential to improve efficacy and attenuate resistance to OC.

Before the start of chemotherapy, it is important to modulate irregulated immune system by dysbiosis with the use of probiotics, prebiotics, and berberine.

1. Inactivation of NF-kB

There are various reviews assessing the safety and efficacy of antiangiogenic agents including monoclonal antibodies (ending –mab like nivolumabbevacizumab), and inhibitory agents(ending –ib like solafenib). These agents could not block multiple angiogenic signaling pathways and their interactive loops. To date, prolongation of overall survival is not ascertained 42. This is caused by the improper combination of agents without celecoxib. Small molecule inhibitors that work inside the malignant cells and also work between transcriptional factors and various downstream signaling molecules should be selected.

Thalidomide (200mg/day)  Celecoxib (400mg/day)

 

2. Epigenetic agents

   Valproic acid (600mg/day)

 

3. Cytotoxic agents with low dose

 Taxanes (docetaxel, paclitaxel), Gemcitabine, Irinotecan, and Vinorelbine

 

4. Downregulate pro-inflammatory cytokines

Berberine 100-300mg/day p.o

 

 

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忖度・癒着・天下り

藤本製薬のサリドマイド認可

大阪市立大学   医学研究科   臨床医科学専攻   教授

日下部 哲也 (クサカベ テツヤKUSAKABE Tetsuya)

医薬品行政:薬事法違反立案を地方薬務課に強制した教授(元厚生官僚)

藤本製薬

(Fujimoto Pharmaceutical Co.)

山下治夫と森和彦が天下りと癒着で目指す千円企業

サリドマイド治験開始へ

記者会見する藤本製薬山下治夫薬事法規部長(元大阪府保健衛生部薬務課長)

 

藤本製薬

癒着と天下りで利益を目指す千円企業

 

森和彦大臣官房審議官(医薬担当)

医薬食品局審査管理課長

厚生労働省と藤本製薬との癒着でサリドマイドは認可されました。