HadaClinic Web Journal: Thalidomide & CelecoxibBladder  Cancer


Clinical Review


Prevention with Probiotics and Treatment with Thalidomide, Celecoxib and  Valproic  Acid  for Bladder  Cancer.


Association between microbiota, chronic inflammation, angiogenesis and cancer


Masato Hada, MD, Pharmacist

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


More than 90% of muscle invasive bladder cancer is high grade urothelial cell carcinoma (UCC). The carcinogenic mechanisms of urothelial carcinoma are various and complex and not clarified fully, however several mechanisms are elucidated. The various initiating and promoting factors of UCC involve urinary tract infection, cigarette smoking and chemicals concerning the occupational risk factors1.

UCC emerges as noninvasive and invasive pathways independently. FGFR3 and TP53 mutations might define this difference 2 3 4.

The 25 % of patients with bladder cancer are muscle invasive on a biopsy specimen and have more aggressive progression with a worse prognosis. Half of the patients progress to metastatic state and the 5-year survival rate is approximately 5% 3. Malignant tumors are encircled by stromal cells and extracellular matrix (ECM) that create the tumor microenvironment (TME), which develops carcinogenesis, proliferation, and metastases interacting between malignant cells and non-malignant components 5 6 7 8

New therapeutic strategies incorporating pathophysiology UCC are much needed. Cancer is tightly linked to chronic inflammation and angiogenesis. Angiogenesis is pathophysiological bridge between inflammation and cancer 9 10. 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 UCC with thalidomide, celecoxib, valproic acid that act on transcriptional factors or their downstream signaling molecules.


Key words : thalidomide, celecoxib, valproic acid, probiotics urothelial cell carcinoma


Microbiota, comprising bacteria, virus, and fungi, plays an important role in health and disease, especially the development and progression of cancer 11 12. Microbes reside in human body, mainly on the external and internal surfaces, including the gastrointestinal tract, skin, and oral mucosa. The amount of microorganism is about 1.0-1.8kg, 1.0- 3.8 × 1013  in number, 1000species13 14. Fusobacterium nucleatum (F. nucleatum) is a common constituent of the oral microbiome residing in healthy or diseased host. It is implicated to be associated with periodontal diseases in young age and it expresses carcinogenic potential gradually in getting older. F. nucleatum plays a key role in carcinogenesis of colorectal cancer. Moreover, F. nucleatum may be the cause of oral infections, gastrointestinal disorders including appendicitis, inflammatory bowel disease and colorectal cancer 15 16 Although the limited number of participants, Fusobacterium nucleatum has been reported to be associated with the development of bladder cancer15.

TME which promotes the development of UCC is associated with proinflammatory cells and cytokines. TP53 and FGFR3 mutations play a significant role in the proliferation of UCC. FGFR3 and TP53 are the most common mutations which define two distinct pathways in superficial papillary and invasive UCC disease in bladder cancer 17 18.


Innate immune response that drives inflammation could be triggerd by pathgens, damaged cells and toxic chemicals. Therefore inflammation is triggerd through inflammatory signaling pathways including NF-κB pathway 19. Microbiota could be the pathogenesis of chronic diseases, including intractable diseases and cancers. Some carcinogenic mechanisms of microbiota are suggested.

Innate immunity, genotoxicity, bacterial virulence is studied as the carcinogenic mechanism of microbiota. Chronic inflammation is the most studied area of innate immunity and directly associated with the treatment 20.

 F. nucleatum has been reported to be associated with the development of bladder cancer 15. Mechanism of carcinogenesis by F. nucleatum on colorectal cancer could also be applied to the preventive and immunotherapeutic strategies of bladder cancer.

Pathogenic factors and receptors triggered by F. nucleatum in TME are NF-kB, Toll-like receptors (TLRs) and inflammatory cytokines including IL-6, IL-8, IL-10, IL-18, TNF-α  21.

The main carcinogenic glycosidases produced by intestinal flora are β-glucuronidase and β-glucosidase. Bifidobacteria and lactobacilli have been described in a number of studies to be probiotics with cancer protective effects. These organisms possess low activities of carcinogenic enzymes resulting in low production of carcinogenic compounds such as IL-6, IL-8 and NF-κB 22 23.

FGFR3 and p53 mutations

FGFR3 mutation has been described that this mutation is associated with lower histological and clinical grade in a number of studies. Mutant FGFR3 as tumor maker predicts better prognosis. However, p53 mutations have been shown to be high grade, late stage, and poor clinical outcome 24. FGFRs are crucial for not only tumor cell growth, survival, migration but also tumor angiogenesis. Overactivation or aberration of FGFR exerts malignancies 25. Binding of FGFs with FGFR3 activates downstream signal pathways that regulate cellular functions including reduction of cell–cell adhesion. Activated FGFR3 induces urothelial cell to epithelial spread and development of tumor outward proliferation 26.

FGF signaling pathways transmit their stimuli through multiple pathways. Therefore, it is difficult to clarify the transmission of stimuli to transcriptional factor such as NF-kB. NF-kB plays a pivotal role in the chemotherapeutic strategy, and it is important to suppress or regulate the aberrant NF-kB.

Currently, inhibitory agents such as brivanib, nintedanib, dovitinib, lenvatinib and ponatinib are investigated as FGFR-targeted agents 27. However, it may be difficult to expect its efficacy because these agents could not block multiple signaling pathways and their interactive loops.

p53 is a tumor suppressor protein encoded by the p53 gene which is easy to mutate. p53 is attenuated by complicated pathways such as directly by mutation and indirectly by hypermethylation 28 29 30 31. VEGF, bFGF and COX-2 are three key mediators of angiogenesis that activate oncogenes 32. p53 and NF-kB work cooperatively for the upregulation of COX-2 that promote cell survival 33 34.

Tumor Microenvironment and Angiogenesis

The tumor microenvironment (TME) is a dynamic interaction network between malignant and non-malignant cells and the extracellular matrix (ECM) through cytokines, growth factors, and inflammatory and matrix remodeling enzymes 35 36. Malignant cells proliferate and invade into TME regulated by a variety of oncogens and tumor suppressor genes such as p53, c-Myc and transforming growth factor-β (TGF-β) that are mutated in TME.

P53 is a transcription factor and mutated p53 is contained in more than half of human tumors and are associated with muscle-invasive UCC. DNA damage, hypoxia, oncogenic stresses activate p53 response 37. P53 mutations associated with late stage muscle-invasive bladder tumors 38. Emerging data have demonstrated that p53 exerts its effects for not only suppression of metastasis but also anti-angiogenesis 39. p53 alterations predicts poor prognosis in UCC 38.

 c-Myc oncogene regulates cellular growth regulation and cellular metabolism. c-Myc plays important roles in transformational changes 40.Hypoxia in TME affects tumor progression and hypoxia-inducible transcription factors (HIFs), particularly HIF-1 plays a key role in angiogenesis with c-Myc 41.

Cytokine IL-37 is fundamentally an inhibitor of inflammation (inhibitor of innate immunity) 42 43. TGF-β is a cytokine that predominantly affects epithelial cells 44. IL-37 potently activates endothelial cells and pathological angiogenesis   through TGF-β which mediates IL-37 binding to the TGF-β receptor complex 45.

More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 32. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 46 47 48. We selected thalidomide and celecoxib that potently block VEGF, bFGF, PDGF, EGF and COX-2 in these pathways and loops of the cell 49 50 51.  Pathophysiological chemotherapy with few adverse events should be recommended after first-line and second-line therapy based on the 2016 ASCO guidelines 52 or as first-line treatment for UCC.


Systemic chemotherapy for patients with metastatic UCC with first line treatment show high initial response rates, however , the duration is approximately 15 months 53.

First-Line Treatment

Gemcitabine-cisplatin (GC) regimen has been commonly used as the first-line chemotherapy for mUCC.

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 disrupting signaling 54. However, 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 have median overall survival (OS) was 8.0-9.0 months, progression-free survival (PFS) is about 2 month 55. The response rate after first line chemotherapy remains under 30% 55 56. At present we could not benefit from using the drugs.

Second-Line Treatment

HIF family (transcription factors) activate proangiogenic factors such as VEGF, FGF, COX-2, and interleukin-8 53 57. 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.




signal transduction

transcriptional factor


molecular target
















NF-kB COX-2    





valproic acid












*cytotoxic agents









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 66.



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 anticancer effects with prebiotics 67.



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 67.



Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea. The anti-inflammatory activity of berberine is induced via AMP-activated protein kinase (AMPK) activation, NF-kB inhibition and AP-1 pathway inhibition.1541 1823 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 68.



Thalidomide is an immunomodulatory agent with strong antiangiogenic properties with COX-2 inhibitor celecoxib. Thalidomide inhibits the mRNA encoding such as TNF-α and VEGF 69.In addition, thalidomide modulates activated or irregulated NF-κB, resulting in suppressing malignant cell proliferation and angiogenesis as well as invasion and metastasis 70.



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-κB 69 71.


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 anticancer agents   72.

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 73 74.

VPA inhibits endothelial function and angiogenesis 75.


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-kB.

1. thalidomide celecoxib low dose

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 with low dose

Gemcitabine, Irinotecan,


4. Downregulate pro-inflammatory cytokines

Berberine 100-300mg/day p.o


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Shizuoka Concentration Camp Cancer Center ( SCCCC)

Director of the SCCCC Ken-ichi Tobisu Urologist


The Director of the Shizuoka Cancer Center who prides himself as an oncologist who explains molecular targeted agents erroneously

on television broadcasting


When I began the chemotherapy in Feb. 2009, I asked Shizuoka Cancer Center for pathological finding. The finding replied was poorly differentiated urothelial carcinoma G3.(December,2008)

In order to write this case report, I asked for optical microscope photograph with pathological finding.

The reply was small cell carcinoma or neuroendocrine tumor with the copy of photos(below).


From Shizuoka Cancer Center

Niwakawa, Masashi. Vice President and Director of Department of Urology 

静岡県立静岡がんセンター副院長兼泌尿器科部長 庭川 (Masashi Niwakawa,)