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2016 Oct;9(5):453-457. PubMed PMC free article. 9. Filis Kazazi-Hyseni, Jos H. Beijnen,an H. M.. Bevacizumab. Oncologist. 2010 Aug; 15(8): 819–825. back.
Clinical Review

Prevention and Treatment with probiotics, prebiotics and antiangiogenics for triple negative breast cancer. Association between microbiota, chronic inflammation, angiogenesis and cancer Masato Hada, MD, Pharmacist Author information Hada Clinic, [email protected]

Abstract A number of diseases including autoimmune diseases and malignancies including breast cancer are supposed to be caused by imbalance of

microbiota ”dysbiosis”.

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) identifying pathogen-associated molecular patterns (PAMPs) including lipopolysaccharide (LPS) 1 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 breast cancer 2. NF-κB plays a key role between inflammation, angiogensis and cancer at the molecular level. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 3. 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 triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target. But it is possible to prevent and treat the patients with TNBC 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 (IR-1,2,4,6…)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。その結果、血管新生やアルツハイマー病、統合失調症、ベーチェット病といった難 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 receptor:TLR)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 IR, TNF-α、VEGF、COX-2 などです。NF-κB はある文献には” holy grail(渇望の品、至高の 目標)”と記載されています。 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。 癌治療に最も必要なことは病原物質によって活性化または変異活動に陥いた NF-kB を抑制 することが必須です。ハーバード大学の Arvind Panday 先生は私の症例を例に引き明確に 説明しています。 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、バルプロン酸は NF-kB に効果的に作用し強力な抗癌作用を 発揮します。 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 年現 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: Triple-negative breast cancer (TNBC), Gut Microbiota, Toll-like receptors (TLRs), NF-κB, berberine, Thalidomide, Celecoxib, Valproic Acid Introduction It is now widely accepted that treatment options for patients with TNBC are limited due to the lack of a therapeutic target 4. However, this misunderstanding is elicited from inadequately resolved chronic inflammation, angiogenesis and carcinogensis. Triple-negative breast cancer (TNBC) is defined as the absence of the estrogen, progesterone receptor and HER-2 and highly diagnosed among younger and premenopausal African women. This subtype is known to be a poor prognostic factor, associated with a BRCA1 gene mutation, and not effective to specific targeted therapy. Currently TNBC is thought to be a challenge for patients and clinicians due to its poorer prognosis and fewer treatment options, with a lack of targeted agents that reflected with high efficacy 5. Malignant tissue is consisted of malignant and non-transformed cells, which is called tumor microenvironment (TME). More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis. Until recently, the effects of the surrounding stromal tissue (TME) and intracellular signal pathways have been largely ignored 6.

The combination of cytotoxic agents and molecular targeted agents including epidermal growth factor receptor (EGFR), basic fibroblast growth factor receptor (bFGFR), vascular endothelial growth factor (VEGF), and mammalian target of rapamycin (mTOR) could improve the exacerbated state and prolong overall survival. Selected agents working on NF-kB or its downstream factors may show satisfactory therapeutic effects. Higher levels of VEGF correlate with shorter overall survival in patients with TNBC 7. The potential targets for TNBC chemotherapy are VEGF, EGFR, and poly(ADP-ribose) polymerase 1 . Currently bevacizumab and small molecular TKIs have been studied in combination with cytotoxic chemotherapy, but clinical efficacy is modest 8. Monoclonal antibody, bevacizumab work on the VEGFR competitively, and its intracellular pathways are not clearly elucidated. The downstream pathway of small molecular TKIs is not also studied clearly. Available literature about the molecular mechanism of bevacizumab till NF-kB is not reviewed 9. Gut Microbiota The human body harbors anywhere between 10 trillion and 100 trillion microbial cells in a symbiotic relationship as long as the body is in a healthy state from birth. The human microbiota comprises over 1,000 different species of microorganism. The volume of microbiota in gastrointestinal tract amounts to 1-2kg10. The microbiota plays a fundamental role in the host immune system. When the interaction of microbiota and immune system operates optimally, this alliance allows protective responses to pathogens 11. It is implicated that a number of diseases including autoimmune diseases and malignancies including breast cancer are caused by dysbiosis 12. Various pathogenic bacteria contribute to alterations of the tumor microenvironment in the inflammatory tumoral-immune response through interleukins 13. Mucosal dendritic cells play a pivotal role in immune response of gut microbiota especially vigorous immune response to pathogens. It is supposed that during lactation, dendritic cells with gut microbiota translocate from gut to breast tissue via the lymphatic and peripheral blood flow 14. In case of intestinal tumors, infiltration of tumors mediated by commensals through immune cells is believed to be pivotal driving factor in carcinogenesis 11. Gut microbiota plays an important role in the modulation of systemic estrogens through enterohepatic circulation of estrogens in which hepatically conjugated estrogens are excreted in bile and reabsorpted at the intestine 15. An estrobolome, bacterial

composition enriched in enzymes including ß-glucuronidase, promotes deconjugation of conjugated estrogens secreted in bile acid and increase the systemic estrogen burden resulting in the risk of development of breast cancer 16 17. Toll-like receptors (TLRs) TLRs are PRRs identifying PAMPs including LPS1. TLRs are conserved innate receptors expressed in various mammalian immune and non-immune cells. TLRs play a crucial role in the detection of microbial infection through the induction of inflammatory cytokines and type I interferons and also have roles in eliciting pathogen-specific humoral and cellular adaptive immune responses 18 19 20. Activated TLRs promote tumor proliferation, resistance to apoptosis, invasion and metastasis and induce the expression of proinflammatory factors and immunosuppressive molecules 21. It is reported that low TLR9 expression is associated with aggressive and shorted survival caused by hypoxia in TNBC 22. TLR signaling pathways activate NF-κB, which controls the expression of an array of inflammatory cytokine genes 23 24. NF-κB signalings that regulate more than 150 genes, when chronically activated or dysregulated, play the central role of pathogenesis in many diseases including inflammation, immunity, cell proliferation, and differentiation 25. TNBC is one of worst prognosis and treatment option is few. In vascular smooth muscle cell TLRs 4 and 2 respond to Gram-negative and Gram-positive bacteria, respectively resulting in the expression of cyclooxygenase-2(COX-2. However, other pathways may exist, and induce expression of COX-2 responding to whole bacteria 26. Angiogensis and Carcinogenesis There is accumulating evidence that higher malignancy risks exist in many immune-mediated diseases 27. Dysregulated immune response through TRLs cause chronic low grade inflammation. Inflammatory process is defined to be the release of mediators including tumor necrosis factor (TNF)-α, IL-1, IL-6, growth factors including VEGF and COX-2, chemokines, and proteases from macrophages and activated neutrophils. Imbalance of the many mediators between pro-angiogenic 28 and anti-angiogenic cytokines promotes angiogenesis 29.Chronic inflammation and angiogenesis are closely related process exhibiting both pro-inflammatory and pro-angiogenic effects and potentiate each other 30. Inflammatory mediators including COX-2 derived prostaglandins promote cell proliferation, mutagenesis, oncogene activation, and angiogenesis with long term exposure. NF-κB plays a key role between inflammation, angiogensis and cancer at the

molecular level 31. More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis. These proteins include VEGF, bFGF, transforming growth factor (TGF)-α, TGF-β, TNF-α, platelet-derived growth factor (PDGF), EGF 32 and COX-2. 33 VEGF, bFGF and COX-2 are three key mediators of angiogenesis 34. Therapeutic development of antiangioenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 35 36 37.

Prevention and Treatment of TNBC Prevention TNBC A number of diseases including breast cancer are implicated to be caused by dysbiosis. Probiotic and prebiotic therapies have been clinically evaluated and should be taken in as treatment for autoimmune disease and malignancies 38. Probiotics are defined as healthy microbiota that is associated with a beneficial microbial

composition.

Prebiotics

are

roughly

and

typically

defined

as

non-digestible fiber that enhance the growth of gut microbiota and some fibers downregulate COX-2 39. Among various probiotics lactic acid bacteria including Lactobacillus and Bifidobacterium have been known to exert beneficial effects in human. In tumor development there is increasing evidence demonstrating the important role of probiotics in the dysbiotic satate 40. Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea. It is reported that TGF-β1 and TGF-β2 are higher in TNBC cells than in non-TNBC cells. TGF-β are multifunctional cytokines that suppress or induce tumor progression, especially in advanced stage TGF-β promote breast cancer progression and metastasis 41 42. At the level of cell research, berberine suppresses tumor formation of TNBC cells through inhibition of TGF-β1 expression42. Berberine is a multifunctional enzyme inhibitor, attenuating N-acetyltransferase, cyclooxygenase-2, and topoisomerase activities and resulting in inhibitory effects on

certain carcinogenic microorganisms

43. Berberine regulates the dysbitic state, and also prevents the secretion of mucosal immune cytokines 44 Fortunately oral bioavailability of berberine is poor, difficult to be absorbed into the blood stream. So it is possible to use with the combination of other anti-TNBC agents in the blood stream with less side effects.

The combination of berberine with other chemotherapeutics is could be a promising drug for treatment of TNBC. Berberine should be used to suppress interleukins induced by dysbiosis. The combination of berberine and chemotherapeutics suppresses the tumor proliferation and metastasis.

Standard cytotoxic drugs show limited effects. The addition of supplementation of probiotics and prebiotics to TNBC patients from the beginning of chemotherapy may induce more effective treatment. Treatment of TNCB Thalidomide

and Celecoxib

TME and intracellular signal pathways play an important role in the proliferation, development, and metastasis for TNBC. We began the cancer chemotherapy accepting the thought of TME and selected thalidomide and celecoxib that potently block VEGF, bFGF, PDGF, EGF and COX-2 in these pathways and loops of the cell 45 46 47. Pathophysiological chemotherapy with few adverse events should be recommended after first-line and second-line therapy or as first-line treatment. Valproic acid (VPA) Epigenetic modulation of gene expression is regulated by histone deacetylases (HDACs) through methylation, acetylation, phosphorylation. Deacetylation mediate chromatin condensation, and create heterochromatin in which areas, transcription is repressed. HDACs inhibition induces inhibition of tumor growth, and apoptosis of malignant cells 48. VPA induce the differentiation of many malignant cells and suppress tumor development as HDACs inhibitor 49 50. Bisphosphonates The main complication of breast cancer is bone metastases, and 65-70% patients demonstrate this involvement 51. Bone metastases show exacerbating symptoms including severe bone pain, pathogenic fractures, and hypercalcemia, resulting in a short-term prognosis 52. Nitrogen-containing bisphosphonates

(N-BPs) including zolendronate

selectively

inhibit farnesyl pyrophosphate synthase (FPPS) within osteoclasts. FPPS is one of essential enzymes for osteoclast survival and function 51.

Conclusion 1. The tumor microenvironment altered by various pathogenic bacteria should be improved with probiotics, prebiotics (Lactobacillus and Bifidobacterium product) firstly before chemotherapy. To improve dysregulated gut microenvironment more, the combination of berberine may attenuate resistance to the drugs. 2 .Almost antiangiogenic approaches are lead to transient responses and further disease progression. Many trials have been completed trying to target these various pathways but have been unsuccessful, 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 47. Combining low dose cytotoxic agent with thalidomide, celecoxib, bisphoshonates and valproic acid potentiate the efficacy of each agent and could prolong the overall survival. ① Small molecule inhibitors that work between transcriptional factors and various downstream signaling molecules Thalidomide (200mg/day) Celecoxib(400mg/day) ② Epigenetic agents Valproic acid (600mg/day) ③ Cytotoxic agents low dose Paclitaxel, Docetaxel, Doxorubicin, Vinorelbine Gemcitabine ④ Downregulate pro-inflammatory cytokines Berberine ⑤ Farnesyl pyrophosphate synthase (FPPS) inhibitor Bisphoshonates

agent

receptor

Bevacizumab

VEGFR

panitumumab

signal

transcriptional

transduction

factor

chromatin

molecular target

53 no definite

EGFR

target

Lapatinib

EGFR

Palbociclib

CDK4/6 inhibitors

proved

Everolimus

mTOR PD-1

(programmed

54 55 56

estrogen-receptor (ER+)

Pembrolizumab

ref

57 no definite target proved

54

cell death 1) olaparib

poly(ADP-ribose)polymerase:PARP inhibitor

Berberine

JAK/STAT MAPK/ERK

in gut

pathway.

Bisphosphonates

58 COX-2

*FPPS

thalidomide

59 51

NF-kB

VEGF,

NF-κB is a key regulator of

bFGF

inflammatory

COX-2

response,

apoptosis and angiogenesis

61 25

in TNBC 54 celecoxib

NF-kB COX-2

COX-2

61 25

valproic acid

HDACs

APP

62

bFGF

63 64

**cytotoxic

NF-kB

DNA

65

agents *FPPS farnesyl pyrophosphate synthase **Taxanes (paclitaxel, docetaxel), Doxorubicin, Platinum agents (cisplatin, carboplatin) Vinorelbine Capecitabine Gemcitabine Ixabepilone

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