HadaClinic Web Journal: Thalidomide & CelecoxibFlung adenocarcinoma

 

Clinical Review

 

Chemotherapeutic Strategy with the Interaction of Gut-Organs Axis and Tumor microenvironment for Lung Adenocarcinoma

 

Association between microbiota, chronic inflammation, angiogenesis and cancer

 

Masato Hada, MD, Pharmacist

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

Abstract

40% of lung cancer is adenocarcinoma and is aggressive and fatal 1. At present, correlations between salivary microbiota and lung cancer could be predicted to be proved 2.  Probiotics, orally administered, may reduce periodontal pathogens in the subgingival microbiota 3.

Lung adenocarcinoma is regulated by a variety of oncogenic factors that are effective therapeutic targets for targeted therapies 4. Immune system is significantly relevant to gut and salivary microbiota, which is also associated with gut and salivary lung axis in tumor microenvironment (TME). NF-ƒÈB plays pivotal role in gut-organs axis and tumor cells in TME. It might be possible to prevent carcinogenesis, proliferation, and metastasis by modulating irregulated or activated NF-ƒÈB.

 

Key words :@ gut-organs axis, thalidomide, celecoxib, valproic acid, probiotics, NF-ƒÈB

Introduction

Microbiota comprising bacteria, virus, and fungi plays an important role in health and   carcinogenesis 5 6. More than 600 bacterial species are known to reside in oral cavity. These microorganisms play an important role in maintaining not only oral health but also systemic health including lung, digestive tract and cardiovascular system. Therefore, dysbiosis in oral microbiota triggers local and systematic diseases 7. Microbiota gut-lung axis is the bi-directional cross-talk between gut and lung and dysbiosis drives allergy, asthma and cystic fibrosis 8

Numerous studies may help to predict the possibility that cystic fibrosis might increase the risk of cancers 9 10.

Multiple angiogenic signaling pathways and their interactive loops drive@chronic@inflammation that induce carcinogenesis, proliferation, and metastasis through@angiogensis in more than 20-30 years.11

Lung adenocarcinoma is regulated by oncogenic factors including EGFR, ALK, ROS1, BRAF, MET, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2), RET, and NTRK that are effective therapeutic targets for chemotherapies12.

Microbiota

Oral bacteria are important to maintain oral health. However, dysbiosis induces periodontitis especially in cigarette smokers. Oral dysbiosis also increases systemic diseases including lung, digestive tract and cardiovascular system 13 14 15.

Gut, brain, and lung are intimately linked organs and they maintain homeostasis through cross-talks, e.g. microbiota gut-brain axis and gut-lung axis. The metabolites produced by gut microbiota cross-talk with lung through lymph or blood stream (gut-lung axis) 8. Two Firmicutes and Bacteroidetes reside predominantly in the   respiratory airways, however, the lower respiratory tract is one of the least habitat 16. Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, and Proteobacteria are demonatrated to relevant to carcinogenesis, and Fusobacterium may contribute to the development of lung cancer 17 18. Smoking promotes chronic inflammation which triggers increased macrophage recruitment, delayed neutrophil clearance, and increase in reactive oxygen species (ROS). This pulmonary microenvironment is seemed to be induced by pulmonary and gut microbiota 15 19. Chronic inflammation induced by infections and non-infectious agents including smoking promotes the release of cytokines and growth factors by alveolar macrophages, lymphocytes, neutrophils, endothelial cells, and fibroblasts 20. These factors including P-53, NF-kB, VEGF, FGF,  and COX-2 drive epithelial dysfunction, carcinogenesis and malignant progression 19.

Oncogenic factors

p-53

p53 is a major tumor suppressor, mutant p-53 in tumors promotes tumor progression and resistance to anticancer agents when losing the tumor suppressor functions of wild-type p53, this function is referred to mutant p53 gain-of-function 21. COX-2 regulates P-53, and inhibition of COX-2 may be a proper option for treatment, however inhibition of COX-2 with celecoxib may increase chemoresistance in lung cancer cells 22.

 

NF-ƒÈB

The nuclear factor (NF)-ƒÈB 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 23 24. The irregulated or activated of NF-ƒÈB 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-ƒÈB 25.

Pathogens including bacteria and parasites activate the NF-ƒÈB signalling pathway for tumor cell proliferation, survival, migration, inflammation, and angiogenesis 26.

Immune homeostasis in epithelial tissues such as the skin and the intestine are maintained by NF-ƒÈB signaling pathways. Deregulated NF-ƒÈB triggers severe TNF-dependent skin inflammation and epidermal hyperplasia in keratinocytes and also triggers severe chronic colon inflammation disturbing the intestinal barrier in intestinal epithelial tissues 27.    

Various carcinogens including cigarette smoking cause DNA damage in lung epithelial cells and simultaneously during damaged DNA repair, chronic inflammation in lung tissue is induced by activated NF-ƒÈB through the canonical pathway. Deregulated NF-ƒÈB causes cancer by producing cytokines including a variety of interleukins and TNF-ƒ¿ 28. Hypoxia-inducible factor (HIF) family upregulates the angiogenic growth factors that stimulate angiogenesis in response to hypoxia 29. Angiogenesis drives tumor growth, metastasis and is related to poor prognosis. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 30 31. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 32 33.  

Treatment with antiangiogenic agents, especially targeting VEGF have advanced recently. Targeting angiogenesis, however, has not proven to be as efficacious as originally hoped 32. The significant effect could not be expected because the drugs are not selected according to the following mechanism of action. Antiangiogenic pathways are significantly complicated with a variety of factors. Moreover, the agents now used target the receptors and factors of upstream pathways till transcriptional factors, not pivotal transcriptional factor NF-ƒÈB.

The NF-ƒÈB signalling pathways are attractive targets for the treatment of malignancies by anti-NF-ƒÈB agents such as thalidomide and celecoxib.

Tumor microenvironment and angiogenesis

Tumor microenvironment (TME) is the functional malignant tissue in which malignant and non-malignant cells communicates via a complex and dynamic network. This network is driven via cytokines, chemokines, growth factors, and inflammatory and matrix remodeling enzymes 34.

Tumor associated fibroblasts play a critical role in the network. The fibroblasts secrete growth factors and chemokines such as altered extracellular matrix (ECM) enhancing cancer-cell proliferation and invasion. The other cells composing of TME are immune and inflammatory cells, blood and lymph vessels, and nerves 35. The VEGF family consists of five members (VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and platelet derived growth factor (PDGF) and they bind with three receptor tyrosine kinases (VEGFR-1, -2 and -3).  After the link inducing endothelial cell migration, proliferation, vascular permeability, and tube formation are induced after the link between VEGFA and VEGFR. Bevacizumab, humanized monoclonal antibody to VEGF-A, has been described in a number of studies that this agent has provided significant benefit to cancer patients 36. But this agent only inhibits VEGFR-1 andVEGF-2 and also cannot control the complex network of signaling cascades and cannot transmit signals to NF-ƒÈB that drive angiogenesis and lymphangiogenesis.

FGFs are pleiotropic molecules that can act on a variety of cell types. Different from VEGF, FGFs induce angiogenesis and arteriogenesis with other growth factors such as VEGF, PDGF, and FGF in cardiomyocyte, stromal cells and endothelial cells 37. COX-2 expression is induced in a variety of cells including the neoplastic cells, endothelial cells, immune cells, and stromal fibroblasts within malignant tumors. COX-2 triggers the production of thromboxane A2 (TXA2), prostaglandin E2 (PGE2), and prostaglandin I2 (PGI2) through arachidonic metabolism.  These eicosanoid products promote angiogensis with other growth factors such as VEGF, Bcl-2, and matrix metalloproteinases 38.

Treatment

Cisplatin based doublet chemotherapy is effective as first-line chemotherapy providing a survival benefit and symptom relief in patients with inoperable non-small-cell lung cancer (NSCLC). Currently anticancer agents including irinotecan, paclitaxel, docetaxel, gemcitabine, and vinorelbine are considered standard chemotherapy regimens for advanced NSCLC 39.

Signalling pathways VEGF, PDGF and FGF pathways could be the targets of valid anti-cancer drug targets. 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 40. The carcinogenic signals pass through complicated and loop pathways. Carcinogenesis may be attained in more than 10-30 years with weak signals.

 

Monoclonal antibody: Nivolumab

Monoclonal antibody nivolumab is an immune checkpoint inhibitor blocks PD-1 and promotes antitumor response and is thought to be clinically meaningful agent with   median overall survival (mOS) 9.6 months for SCLC. However, the intracellular signal pathways after docking nivolumab with extracellular receptors till transcriptional factors are not elucidated.

The CheckMate 057 trial demonstrated improved OS compared with docetaxel: a median OS of 12.2 months in patients treated with nivolumab compared with 9.4 months with docetaxel 41. This OS is statistically significant improvement but not clinically meaningful benefits for the patients. Microbiota improves anti-tumor immune response and promotes the efficacy of immune checkpoint inhibitors 42. This may be supposed to be caused by the suppression of activated NF-kB in macrophage 43.

 

Sorafenib

Sorafenib is a multitargeted signal transduction inhibitor that inhibits Raf-Kinase, VEGF receptor-2, PDGF receptor-B, and c-kit. Clinical benefits of the combination of sorafenib and cytotoxic agents have been studied, however no benefit was demonstrated from adding sorafenib to cytotoxic regimens for NSCLC 44.

 

Toll-like receptors and NF-kB

Toll-like receptors and NF-kB play a crucial role in the progress of inflammation and cancer such as carcinogenesis, proliferation, and metastasis. Molecular targeted anticancer agents targeting these two factors make the regimen more effective with cytotoxic agents.

Cytotoxic chemotherapy, either as a platinum-based doublet or as a single agent, remains the standard therapeutic approach with metastatic NSCLC. There are no statistically significant differences and benefits among these regimens 45.

Other approaches with new agents that have different mechanism from standard chemotherapy must be warranted.

Transcription factor HIF family activates proangiogenic factors such as VEGF, FGF, COX-2, and interleukin-8 46. 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 47.

 

 

Figure

 

receptor

signal transduction

transcriptional factor

chromatin

molecular target

ref

Sorafenib

 

Raf Kinase

 

 

 

44

PD-1 inhibitors

 

 

 

 

Nivolumab

PD-1

 

 

 

41

Berberine

in gut@

 

 

JAK/STAT MAPK/ERK pathway

 

COX-2

 

48

49

 

limited intestinal absorption

thalidomide

 

 

NF-kB

HIF

TNF-ƒ¿,

IL-6

IL-12

50

51

52

53

54

VEGF,

bFGF

COX-2

celecoxib

 

 

NF-kB COX-2

COX-2

valproic acid

 

 

 

HDACs

 

APP

bFGF

55

*cytotoxic agents

 

 

NF-kB

DNA

 

 

*  The most active agents are: Texans, Gemcitabine, Vinorelbine, 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 56. The key factor that acts and promotes the secretions of cytokines in macrophage and angiogenic factors in tumor cells is NF-ƒÈB. This factor is the pivotal chemotherapeutic target.

 

Probiotics

The fermentation 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 anticancer effects with prebiotics 57.

 

Prebiotics

The microbial fermentation of dietary fiber@may lead to the increased production of short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate. The potential natural products containing dietary fiber are whole grains, fruits, vegetables, and nuts. SCFAs contribute to energy consumption and mucosal protection against pathogens through enteroendocrine L cells that secrete GLP-1 and PYY 58. SCFAs are known as histone deacetylas (HDAC) inhibitors, especially butyrate possesses significant response and modulates cancer and immunological stability57.

 

Berberine

Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea damaging the structure of bacterial cell membrane 48. The antiinflammatory activity of berberine is induced via AMP-activated protein kinase (AMPK) activation, NF-kB inhibition and AP-1 pathway inhibition 59. 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-ƒ¿, IL-1ƒÀ, IL-6, monocyte chemo-attractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and COX-2 60. Berberine is an agent with little side effects, becasue it is hard to be absorbed from gut. Various studies have demonstrated that berberine modulate the gut microbiota through short chain fatty acids(SCFAs) production and SCFSs work as gut-organs axis with various organs through peptides including GLP-1, GLP-2, and PYY after the damage of bacterial cell membrane 61.

 

Thalidomide

Thalidomide is an immunomodulatory agent with strong antiangiogenic properties with COX-2 inhibitor celecoxib 62. Thalidomide inhibits the mRNA encoding such as TNF-ƒ¿ and VEGF 63. In addition, thalidomide modulates activated or irregulated NF-ƒÈB, resulting in suppressing malignant cell proliferation and angiogenesis as well as invasion and metastasis 64.

 

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-ƒÈB 65 66.

 

Valproic acid

VPA is a short fatty acid and has been used as an anticonvulsant agent. In recent years, VPA is used as HDAC inhibitor alone or in combination with other anticancer agents   67. The structural change of histone by methylation or acetylation facilitates or inhibits the access of transcriptional factors. HDAC inhibitors have been used for cancer therapy and the combination of epigenetic agents and other anticancer agents may increase the efficacy 68 69.

The induction of cell cycle arrest and apoptosis by VPA are associated with increased expression of E-cadherin and decreased expression of VEGF and MMP-9 70. VPA inhibits endothelial function and angiogenesis 71.

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-ƒÈB.

1. Thalidomide Celecoxib

Small molecular inhibitors that work between transcriptional factors and various downstream signaling molecules

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

 

2. Epigenetic agent

   Valproic acid (600mg/day)

 

3. Cytotoxic agents with low dose

Texans, Gemcitabine, Vinorelbine, Irinotecan

 

4. Downregulate pro-inflammatory cytokines

Berberine 100-300mg/day p.o

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