HadaClinic Web Journal: Thalidomide & CelecoxibFGallbladder Cancer

 

 

Clinical Review

 

Chemotherapeutic Strategy with the Interaction of Gut-Organs Axis and Tumor Microenvironment for Gallbladder Cancer.

 

Association between microbiota, chronic inflammation, angiogenesis and cancer

 

Masato Hada, MD, Pharmacist

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

Abstract

The incidence of gallbladder cancer (GBC) is generally considered rare, however there are prominent geographic and ethnic variabilities and also correlates with the   prevalence of cholelithiasis and gut microbiota including Salmonella and Helicobacter species. Biliary cholesterol homeostasis depends on synthesis of biliary cholesterol in the liver and absorption of cholesterol through enterohepatic circulation 1. Bile salts are antibacterial components that trigger oxidative damage to DNA and control host defense and immunity. Some bacterial species are able to endure the antibacterial activities of bile salts leading to cholelithiasis and carcinogensis 2.

NF-ƒΘB plays a pivotal role in resistance of gut microbiota and in chronic inflammation leading carcinogenesis.

@

Key words :@Thalidomide, Celecoxib, Valproic Acid, Probiotics, Gallbladder  Cancer, Gut-Organs Axis

@@@@@@@@@

 


 

Introduction

Mean overall survival of patients with advanced GBC is 6 months and 5-year survival rate is 5% 3.@The incidence rate shows regional and ethnic differences. The prevalence is higher in American Indians in Chile, Indian and Pakistani in Southeast Asia, Japanese, and Korean, however, quite lower elsewhere in the Americas and the world 3 4 5. Biliary lipids consist of mainly four kinds of lipid including bile salts, phospholipids, cholesterol, and bilirubin conjugates 6. Bile salts, phospholipids, and cholesterol combine to form mixed micelles through hydrophobic interactions.

Hepatic hypersecretion of cholesterol forms supersaturated state transiently in gallbladder bile. Supersaturated state cause solid cholesterol crystals.

Moreover, gallbladder hypomotility and mucin gel promote cholesterol crystallization.

Emerging data have demonstrated that a variety of microbes are associated with solid tumors. Epidemiological studies have demonstrated the relation between gallbladder cancer and chronic inflammation caused by Salmonella typhi, S. paratyphi, Helicobacter bilis, and H. pylori 7 8. Moreover, there is considerable evidence showing that Salmonella typhi infection causes gallbladder cancer as H. pylori induces gastric cancer 9. GBC shows a marked geographic variation with high incidence in Chile, Poland, India, Japan and Israel. Ethnic variation may also be another GBC risk factor which could cause gallstones, obesity, female hormone imbalance and chronic infections 7.@@

 Lipopolysaccharide (LPS) from Salmonella enterica can activate NF-ƒΘB through both classical and alternative pathways 10 11.

Pathogenesis of GC

Cholesterol homeostasis is maintained by cholesterol biosynthesis mainly in the liver and intestinal absorption with biliary cholesterol and bile salts 12. Cholesterol is synthesized in almost all cells, however, predominantly in the liver, intestine, adrenal cortex, and reproductive tissues. The liver in humans synthesizes 10–15% of cholesterol in the body. Minor imbalances caused by certain pathological conditions induce increase of plasma cholesterol concentration and increase hepatic secretion of biliary cholesterol 2. Hypersecreted biliary cholesterol triggers atherosclerosis and cholelithiasis 13. The blood levels of triglycerides, cholesterol, glucose, and energy homeostasis are regulated by bile acids 14.

The strong risk factors for GBC are gallstones, gallbladder polyps, pancreaticobiliary maljunction (PBM) and chronic infections including Salmonella and Helicobacter 5.

The most important risk factor for carcinogenesis of gallbladder is gallstones, which cause chronic inflammation leading to dysplasia and carcinoma in situ. This process is modulated with P53 mutations, mDNA mutations, COX-2 overexpression and methylation of tumor suppressor genes (TSGs) promotors 5 15.

Gallbladder polyps are consistent of pseudotumors and tumorous polyps.@Pseudotumors include cholesterol polyps, adenomyomatosis, and inflammatory polyps. Tumorous polyps include adenoma, adenocarcinoma and benign mesenchymal tumors, such as leiomyomas, lipomas, neurofibromas, and neuroendocrine tumors 16.

PBM is defined as anomalous pancreaticobiliary duct, with the junction outside of duodenal wall without a sphincter system 17. Currently it is believed that the reflux of pancreatic juice into biliary duct might induce the insult to biliary epithelium, which trigger carcinogenesis within the biliary tract 18. However,@it is now widely  accepted that invasion of microbes into biliary tract due to small intestinal microbial dysbiosis underlies carcinogenesis 19 20.

Microbiota and transcription factor NF-ƒΘB

It is now widely accepted that biofilm is intricate and sessile communities of microbes that are attached to the surface of extracellular matrix@(ECM) or as aggregates buried in ECM. ECM surrounds the biofilms making resistant to antibacterial treatments, moreover, biofilms are associated with chronic inflammation that cause chronic disorders 21. Host-adapted strains of Salmonella typhi cause systematic infections, and thereafter reside chronically modulating host innate and adaptive immune responses through macrophage without symptoms 22.

Activated Toll-like receptor (TLR) signaling by pathogens induces the production of NF-ƒΘB and cytokines such as inflammatory cytokines such as IL-6, IL-8 23 24 25. TLR4 is expressed on immune cells and epithelial cells, and its activation triggers NF-ƒΘB and MAP kinase pathways through myeloid differentiation factor 88(MyD88) and partly through COX-2. Aberrantly activated TLR4 with pathogens plays a critical role in the initiation and progression of tumors 26.

NF-ƒΘB

The nuclear factor (NF)-ƒΘB family is ubiquitous transcription factor and functions to regulate the expression of more than 150 genes defensing cellular processes including  inflammation, immunity, cell proliferation, differentiation, and survival 27 28 29. The irregulated or activated of NF-ƒΘB are associated with various pathological conditions especially included in infections and malignancies. Two major signaling pathways, canonical and noncanonical (or alternative) pathways are crucial for activation of NF-ƒΘB 30. The canonical pathway is the main pathway for inflammation and innate immunity. The non-canonical pathway is essential in lymphoid organ development and adaptive immunity 31

NF-ƒΘB pathway is activated by pathogens including bacteria and parasites, and most carcinogens including cigarette smoke, alcohol, and UV light 10 31.

Tumor homeostasis is maintained by the dynamic balance between cell survival and apoptosis. Insufficient apoptosis induce tumor formation and progression. The inhibitor of apoptosis proteins (IAP) were originally identified as an inhibitor of apoptosis.  However, IAP also have a variety of functions, such as regulation of tumor migration and metastasis through tumor necrosis factor (TNF)-ƒΏ-induced NF-ƒΘB activation 32 33.        Lymphangiogenesis and lymph node metastasis of GBC are promoted by vascular endothelial growth factor C (VEGF-C) through NF-kB 33.

Cytokines and growth factors which induce chronic inflammation promote the malignant transformation of cholangiocytes through the production of reactive nitrogen oxide species that interact with DNA 34.

Gut-Organs Axis and Probiotics

The so-called gut-brain axis is interactions between enteric microbiota, central and enteric nervous systems, however, a number of hormones secreted by gastro-intestinal enteroendocrine cells work on whole body organs.  For that reason, this mechanism should be designated gut-organs axis. Physiological balance of gut microbiota indicates the homeostatic state of microbes in the gut. Dysbiosis correlates with pathogensis of a variety of diseases@35. A probiotic is defined as an oral supplement or a food product containing a sufficient number of viable microorganisms to alter the microflora of the host with the potential for health benefits with low or no pathogenicity 36. Probiotics including Lactobacillus and Bifidobacterium species show an anti-tumor activity by secreting active molecules such as short chain fatty acids (SCFAs: acetate, propionate, butyrate)@37. Probiotic Lactobacilli might inhibit the biofilm formation and may be a potent therapeutic approach 38. Up to 70% of the acetate is transported to the liver not only for energy source but also for the substrate of a variety of metabolites 39. Butyrate and valerate play an outstanding role as a histone deacetylase (HDAC) inhibitor, however propionate plays a much smaller role 40. Glucagon-like peptide-1 (GLP-1) and PYY are secreted from enteroendocrine cells by the ingestion of meals. Acetate and butyrate significantly drive colonic GLP-1 secretion, and also PYY secretion to a lesser extent 41. Blood glucose level is regulated by GLP-1 and PYY, mainly inhibiting glucagon and stimulating insulin secretion. Moreover activated GLP-1 reduces growth and survival of colon cancer cells 42.

Tumor Microenvironment and Angiogenesis

The tumor microenvironment consists not only of cancer cells but also more than 50% of non-malignant cells and extracellular matrix (ECM) 43. Tumor proliferation is profoundly influenced by interactions of cancer cells and non-cancer cells through cytokines, growth factors, and hormones secreted by stromal and tumor cells in ECM 44. IAP is overexpressed in GBC tumor microenvironment and enhances tumor proliferation and promotes metastasis by TNF-ƒΏ activation that inhibits apoptosis through NF-ƒΘB pathway 45 46. The non-malignant cellular components include fibroblasts, myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells,@vascular endothelial cells, pericytes and lymphatic endothelial cells 47. Inflammatory cytokines drive COX2 overexpression and epigenetic suppression of tumor suppressor genes. Mutations of TP53 and mitochondrial DNA are also associated in this early stage. These molecular changes transform the normal epithelium into metaplastic cells 48. Angiogenesis, pathological angiogenic process, plays a major role in tumor proliferation and metastasis in TME. Fibroblasts and myofibroblasts which secrete growth factors and cytokines recruiting endothelial cells represent the majority of the stromal cells 49.

These angiogenic proteins include VEGF, basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-ƒΏ, TGF-ƒΐ, TNF-ƒΏ, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) 50 and cyclooxygenase-2 (COX-2) 51. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 52. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 53 54 55. Until recently, the effects of the surrounding stromal tissue have been largely ignored 56. However, we began the cancer chemotherapy accepting the thought of TME since 2000. We selected thalidomide and celecoxib that potently block VEGF, bFGF, PDGF, EGF and COX-2 in these pathways and loops of the cell 57 58 59. Pathophysiological chemotherapy with few adverse events should be recommended after first-line and second-line therapy based on the 2016 ASCO guidelines 60, or as first-line treatment for GBC.

Treatment

There is no established standard chemotherapy for patients with advanced biliary tract cancer. Fluoropyrimidines, cisplatin, and gemcitabine are thought to show activity. The report (Juan Valle, M.D.) shows a significant survival advantage for cisplatin plus gemcitabine, with the median overall survival was 11.7 months in the cisplatin–gemcitabine group and 8.1 months in the gemcitabine group 61. This overall survival might be statistically significant, however clinical benefits of this combination appear to be less than hoped for the patients. Signalling pathways VEGF, PDGF and FGF pathways could be the targets of valid anti-cancer drug targets 62. However many agents, including monoclonal antibodies (ending –mab like nivolumabCbevacizumab), and inhibitory agents(ending –ib like solafenib) have failed to show clinically meaningful benefits 63. The carcinogenic signals pass through complicated and loop pathways. Carcinogenesis may be attained in more than 10-30 years with weak signals.

Immunotherapy

Immune checkpoint inhibitors that are currently used clinically are monoclonal antibodies. They work on receptors outside of the cells preventing the receptors and ligands from binding to each other, thereby only disrupting the signal between receptors and ligands 64. Moreover, no growing body of evidence supports the signal pathways till transcriptional factors that modulate the proliferation or apoptosis of malignant cells. Patients treated with immune checkpoint inhibitors seems not to have an apparent effect on progression-free survival (PFS) 14. At present we could not benefit from using the drugs.@

Second-Line Treatment

Transcription factor HIF family activates proangiogenic factors such as VEGF, FGF, COX-2, and interleukin-8 65. These factors are produced through activated or irrgulated NF-kB. It is important to use the agents that act on transcriptional factors or their downstream factors.

 

Figure

 

receptor

signal transduction

transcriptional factor

chromatin

molecular target

ref

Sorafenib

 

Raf Kinase

 

 

 

66

PD-1 inhibitors

 

 

 

 

Nivolumab

PD-1

 

 

 

14

Berberine

in gut@

 

 

JAK/STAT MAPK/ERK pathway

 

COX-2

 

14

67

68

 

limited intestinal absorption

thalidomide

 

 

NF-kB

HIF

TNF-ƒΏ,

IL-6

IL-12

69

70

71

72

73

74

VEGF,

bFGF

COX-2

celecoxib

 

 

NF-kB COX-2

COX-2

valproic acid

 

 

 

HDACs

 

APP

bFGF

75

*cytotoxic agents

 

 

NF-kB

DNA

 

 

*  The active agents are: Gemcitabine, Irinotecan

 

The exciting findings in the past decade are that the gut microbiota may act as a regulator of the malignant cell resistance to cytotoxic agents. At least it is important to maintain the homeostasis of gut microbiota with probiotics, prebiotics and berberine 76.

Probiotics and Prebiotics

Probiotics and prebiotics (symbiotics) play an important role in the cross-talk of Gut-organs axis and TME 37 77. The potential natural products are whole grains, fruits, vegetables, and nuts. SCFAs are known as HDAC inhibitors, especially butyrate shows significant response and modulates cancer and immunological stability 78. Symbiotics improve dysbiosis that underlies the development of inflammatory diseases in the intestine and distant organ systems. In addition, it is reported that gallbladder-derived surfactant protein D also contributes to maintain intestinal homeostasis 79. Therefore, it may improve the efficacy of agents for GBC by bile acids, bile acid derivatives, and bile acid sequestrants such as cholestyramine 79 80 81.

Berberine

Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea. Bile acids secreted into the gut are regulated through the enterohepatic circulation. About 5 % of bile acids in the gut are excreted into feces. Berberine modulates this circulation and lower the blood-lipid 14 67 68. The nuclear receptor superfamily, farnesoid X receptor (FXR)Cplay a key role in multiple metabolic pathways, especially in regulating bile acid metabolism on its activation by bile acids 82. Berberine affects microbes directly and regulates bile acid metabolism through activating FXR signaling 83.@As the oral bioavailability of berberine is poor, it is possible to use with the combination of other chemotherapeutics with less side effects 84.

Thalidomide

Thalidomide is an immunomodulatory agent with strong antiangiogenic properties with COX-2 inhibitor celecoxib. Thalidomide inhibits the mRNA encoding such as TNF-ƒΏ and VEGF 85 86. In addition, thalidomide modulates activated or irregulated NF-ƒΘB, resulting in suppressing malignant cell proliferation and angiogenesis as well as invasion and metastasis 87.

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 and proinflammatory cytokines by COX-2 cause angiogenesis with subsequent carcinogenesis, tumor proliferation and metastasis, especially through NF-ƒΘB 88.

Valproic acid

VPA is a short chain 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 anticancer agents 89.

Genetic and epigenetic alterations promote carcinogenesis. Acetylation and deacetylation of histones plays a key role in epigenetic regulation through HDAC and histone acetyltransferases (HAT). VPA induce cell cycle arrest, apoptosis, and modulation of immune response 90 91. VPA also inhibits endothelial function and angiogenesis 92.

Conclusion

The ultimate goal of Cancer Prevention and Treatment is to mediate pathogens binding to Toll-like receptors and to select the agents that act on transcriptional factors such as NF-ƒΘB.

1. Thalidomide, Celecoxibc low dose

Small-molecule inhibitors that work between transcriptional factors and various downstream signaling molecules.

Thalidomidec200mg/day 

Celecoxibc400mg/day

2. Epigenetic agents

   Valproic acidc600mg/dayclow dose

3. Cytotoxic agentsclow dose

Gemcitabine, Irinotecan

4. Downregulate pro-inflammatory cytokines

Berberinec 100-300mg/day( p.o.)

 

 

 

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Osaka City University Hospital

Center for Clinical Research and Innovation

Senior Executive Director

Tetsuya Kusakabe “ϊ‰Ί•”“N–η

Thalidomide Scandal

 

A former bureaucrat ,Tetsuya Kusakabe, of the Ministry of Health and Welfare who forced each Prefectural Pharmaceutical Affairs officials to hoax a violation of the Pharmaceutical Affairs Act in thalidomide synthesis.

His Words of Greeting:

"The one who controls regulation controls innovation."

It is far from the past words and actions he did.

The reality is that The Minister of Health, Labor and Welfare Chikara Sakaguchi(βŒϋ—Ν)supported and cooperated the counterfeit at the request of the patient group, and in response he carried out the fabrication. He ordered not to treat cancer patients with thalidomide by recalling our thalidomide.

His first words:

"The one who controls regulation controls innovation."

This phrase means

"If you have the power to twist the rules, you can do wrong reforms, not for people, not for life, not for the future"@