hadaclinic web journal: Thalidomide & Celecoxib,mCRC

 

Metastatic Colorectal CancerFAntiangiogenic Chemotherapy@ with thalidomide, celecoxib and valproic acid

Linkage between chronic inflammation, angiogenesis and carcinogenesis

 

Masato Hada, MD, Pharmacist

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

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Abstract

Oxaliplatin, when combined with fluorouracil and leucovorin, was among the most effective chemotherapy for metastatic colorectal cancer (mCRC). Combination therapy with fluorouracil/leucovorin, irinotecan, oxaliplatin and bevacizumab has increased survival rates of patients with mCRC 1.@Despite these improvements, relapse is almost inevitable, and therefore, there is a urgent need for alternative agents.

New therapeutic strategies incorporating pathophysiology and tumor microenvironment (TME) of mCRC are much needed. Cancer is tightly linked to chronic inflammation and angiogenesis. Angiogenesis is pathophysiological bridge between inflammation and cancer. Angiogenesis occurs during the interactions between angiogenic endothelial cells and the other components of the stroma - fibroblasts, pericytes and extracellular matrix in TME.@Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops.

However, the combination with antiangiogenic agents is not associated with treatment benefits. The cause of this failure is the choice of the agents that act on receptors and signaling pathways, not on transcriptional factors or chromatin.

Here we review the treatment of mCRC with thalidomide, celecoxib, valproic acid that act on transcriptional factors or their downstream signaling molecules.

Keywords: metastatic colorectal cancer, angiogenesis, thalidomide, celecoxib, valproic acid, transcriptional factors

Introduction

Colorectal cancer (CRC) is the most common cancer and common cause of cancer-related death, increasing year by year 2.@Nowadays overall survival in metastatic patients has largely improved thanks to the introduction of targeted agents with standard chemotherapy including oxaliplatin, irinotecan and 5-FU.

Unfortunately, the prognosis of mCRC still remains poor even after standard chemotherapy or /with target agents 3. Epidermal growth factor receptor (EGFR) cascade and the vascular endothelial growth factor (VEGF) signaling are two major cancer promoting pathways in mCRC.

 Until recently, the mechanism of carcinogenesis including the microbiota that is linked to initiation and progression of CRC4, pathophysiology of mCRC, TME and the mechanism of anti-cancer agents have been largely ignored.

The precise mechanism of action may help to overcome tumor escape mechanisms to standard mCRC treatment.

Chronic Inflammation and Colorectal Cancer

Infection

It has been reviewed that molecular mechanism between infection, inflammation and cancer is tightly connected through nuclear factor-ƒÈB (NF-ƒÈB) 5. Angiogenesis is complicated   molecular events bridging the gap between inflammation and cancer 6. The important risk factors that are confirmed in the carcinogenesis of CRC are chronic inflammation 7. There is accumulating evidence that gut microbiota may drive CRC.

Fusobacterium nucleatum is researched most in gut microbiota 8. Microbiota may activate Toll-like receptors (TLRs), NF-ƒÈB and signal transducer and activator of transcription (STAT)3 that promote carcinogenesis 9. A high level of fusobacterium gradually trigger normal tissue to adenoma tissue and finally to adenocarcinoma in CRC 10.@CRC patients with a high level of Fusobacterium in their cancer tissues have a high degree of CpG methylation and a high rate of mutations. CpG islands, rich in cytosine-guanosine dinucleotide repeats,@repress@transcription by methylation of cytosine residues in promoter regions and proximal exons 11.Reducing fusobacterium in gut of colorectal cancer patients may modulate their response to chemotherapy and reduce cancer recurrence 10.

Based on the retrospective cohort study, periodontal disease (PD) severity is associated with an increase in the risk of CRC 12. Periodontal disease and tooth loss caused by oral bacterial infection potentially alter gut microbiota by pathogens and increase systemic inflammation resulting in aggressive dysirregulated immunological response 13. The relationship between periodontal disease or tooth loss and risk of oral, upper gastrointestinal, lung, and pancreatic cancer in different populations has also reported 14 15.

Obesity

Adipose tissue is an important source of cytokines which are called adipokines including TNFƒ¿, leptin, plasminogen activator inhibitor-1 (PAI-1), IL-6, resistin, and angiotensinogen. Therefore, adipose tissue produces inflammatory factors mediating cancer progression like TNFƒ¿, PAI-1, and IL-6 16. Adipokines trigger inflammatory signaling pathways, most commonly the NF-ƒÈB, MAPK, and Janus kinase (JAK) JAK/STAT pathways.17

 

Tumor Microenvironment and Angiogenesis

Malignant tissue is consisted of malignant and non-transformed cells, which is called@tumor microenvironment (TME).@The non-malignant cells have tumor-promoting@function@at all stages of carcinogenesis. Especially, tumor-associated macrophages (TAMs) are abundant and usually activate tumor development. Macrophages are major triggers to tumor angiogenesis 18.@The interaction between tumor cells and the associated stroma (TME) is one of the key determinants that influences disease initiation, progression and metastasis 19. The mutual interactions between tumor cells and surrounding nonmalignant cells, soluble inflammatory proteins, and components of the extracellular matrix (ECM) eventually promote tumor development and progression.

More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis. These proteins include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-ƒ¿, TGF-ƒÀ, tumor necrosis factor (TNF)-ƒ¿, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) 20and cyclooxygenase-2 (COX-2) 21VEGF, bFGF and COX-2 are three key mediators of angiogenesis 22. 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@25.

Until recently, the effects of the surrounding stromal tissue have been largely ignored 26. 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 27@28@29.

Pathophysiological chemotherapy with few adverse events should be recommended after first-line and second-line therapy or as first-line treatment

Liver Metastasis

The liver is the most common site of CRC metastasis anatomically because the majority venous drainage enters the hepatic portal venous system. More than half of patients with CRC will develop metastasis to their liver and ultimately results in death for more than two thirds of these patients 30.

Signal pathways from malignant cells to recipient cells are efficiently mediated by extracellular vesicles (EVs) locally or systemically. Among EVs, exosomes play an important role in cancer progression and drug resistance. Exosomes contain all known molecular constituents of a cell, including proteins, RNA, and DNA that regulate numerous biological activities including angiogenesis, immunity, and metastasis 31@32@33.

The dominant metastatic site of pancreatic cancer is liver (85%) 18. Liver metastases are a major cause of death. Premetastatic niche in the liver is a liver microenvironment permissive to render cancer cell entry through the growth factors from the primary tumor 19.

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. TGF-ƒÀ secretion and upregulation of fibronectin production are caused by uptake of exosomes by Kupffer cells. In this course macrophage migration inhibitory factor (MIF) is highly expressed in exosomes 34.@MIF is a pleiotropic cytokine and present in the tissue of healthy liver microenvironment to prepare favorable conditions for future metastasis 35.@MIF also plays a key role in angiogenesis and neovascularization, upregulating hypoxia-inducible factor 1-alpha (HIF-1ƒ¿), VEGF, matrix metalloproteinases (MMPs) TNF-ƒ¿, prostaglandin E2 and others. Liver microenvironment consists of these protein factors and cells of the immune system 36. Over-expression of EGFR plays important roles in metastasis, especially liver metastasis and malignant transformation of pancreatic cancer37. High MIF levels may promote pre-metastatic niche formation and liver metastasis in other gastrointestinal tract tumors, such as colorectal and gastric cancer 38.

The only option for effective cure is the resection of liver metastasis with isolated liver metastasis. However, even combined with current adjuvant chemotherapy, with cytotoxic or with targeted agents, curative rate is very low. This is because target agents chosen do no target transcriptional factor or its downstream molecules in the TME cells.

 

Treatment

Prevention of Carcinogenesis and Development of Adenoma to Adenocarcinoma.

Probiotics

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[a].1359

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[b].1589

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-ƒ¿ signaling in the rat liver 39.

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, e.g, TNF-ƒ¿, IL-1ƒÀ, IL-6, monocyte chemo-attractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and COX-2 [c]. 1541 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[d] 1542

Systematic Treatment

The choice of drugs is important for effective mCRC treatment. Moreover, it is necessary to select drugs considering the pathophysiology of the disease. We would like to classify antiangiogenic drugs according to the pathophysiological mechanism as shown in the Figure. Cellular proliferation, migration and invasion are activated by multiple pathways with aberrant autocrine and paracrine signaling. Main signaling molecules in mCRC are EGFR cascade and VEGF@signaling. Many trials have been completed trying to target these various pathways but have been unsuccessful 40, because they choose the drugs that work on receptors or signal transduction in multiple pathways, not act on molecular targets between transcriptional factors and their downstream signaling molecules directly.

 

Figure

receptor

signal transduction

transcriptional factor

chromatin

molecular target

ref

Bevacizumab

VEGFR

 

 

 

no definite target proved

 

 

 

 

41

Cetuximab

EGFR

 

 

42

Panitumumab

EGFR

 

 

 

1

Ramucirumab

VEGFR

 

 

 

43

Ziv-aflibercept

VEGFR

 

 

44

Regorafenib

RET,VEGFR1, VEGFR2, VEGFR3,KIT,

PDGFR-ƒ¿, PDGFR-ƒÀ,FGFR1, FGFR2,

 

 

 

45

46

Berberine

in gut

JAK/STAT MAPK/ERK pathway.

 

 

COX-2

47

thalidomide

 

 

NF-kB @@@@@

@@@@@@@@@

@@@@@@@@@

VEGF, bFGF

COX-2

48

49

50

celecoxib

 

 

NF-kB COX-2 @@@

@@@@@@@@@@

COX-2

51

50

valproic acid

 

 

 

HDACs

@

 

APP

bFGF

52

53

54

*cytotoxic agents

 

 

NF-kB

DNA

 

 

55

*5-Fluorouracil (5-FU) Capecitabine, Irinotecan Oxaliplatin

 

 

Conclusion

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

To improve dysirregulated gut microenvironment, the combination of probiotics, prebiotics and berberine may attenuate resistance to the drugs.

 

1. small molecule inhibitors that work between transcriptional factors and various downstream signaling molecules

thalidomide(200mg/day)  celecoxib(400mg/day)

2. epigenetic agents 1088 11

   valproic acid (600mg/day)

3. cytotoxic agents low dose

  irinotecan

4. downregulate pro-inflammatory cytokines

berberine

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