Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma

Kawamoto, Makoto; Umebayashi, Masayo; Tanaka, Hiroto; Koya, Norihiro; Nakagawa, Shino; Kawabe, Ken; Onishi, Hideya; Nakamura, Masafumi; Morisaki, T.

doi:10.21873/anticanres.12516

Cited by 13 publications

(13 citation statements)

References 28 publications

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“…Moreover, Kawamoto et al [193] demonstrated for the first time that metronidazole (MNZ) reduces cancer stemness by reducing ALDH activity and promoting MET, resulting decreased invasive potential and enhanced gemcitabine (GEM) chemosensitivity by enhancing equilibrative nucleoside transporter 1 (ENT1) and diminishing ribonucleotide reductase M1 (RRM1) in CCA cells. Therefore, this combination therapy has the potential to improve the prognosis of CCA patients [193].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

Chu

2019

IJMS

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Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed ‘CSC niche’, where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

Chu

2019

IJMS

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“…In cholangiocarcinoma cell lines, gemcitabine-resistant cells show CSC-like phenotype, such as high ALDH activity and high CD44 expression ( Kawamoto et al, 2018 ). Metronidazole is effective for gemcitabine-resistant cells but not normal cells, although the underlying mechanism is not clear.…”

Section: Application To Diagnosis and Treatmentmentioning

confidence: 99%

Cancer Stem Cells in Intrahepatic Cholangiocarcinoma; Their Molecular Basis, and Therapeutic Implications

Tamai

Fujimori²,

Mochizuki³

et al. 2022

Front. Physiol.

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Cancer tissue consists of heterogenous cell types, and cancer stem cells (CSCs) are a subpopulation of the tissue which possess therapy resistance, tumor reconstruction capability, and are responsible for metastasis. Intrahepatic cholangiocarcinoma (iCCA) is one of the most common type of liver cancer that is highly aggressive with poor prognosis. Since no target therapy is efficient in improving patient outcomes, new therapeutic approaches need to be developed. CSC is thought to be a promising therapeutic target because of its resistance to therapy. Accumulating evidences suggests that there are many factors (surface marker, stemness-related genes, etc.) and mechanisms (epithelial-mesenchymal transition, mitochondria activity, etc.) which are linked to CSC-like phenotypes. Nevertheless, limited studies are reported about the application of therapy using these mechanisms, suggesting that more precise understandings are still needed. In this review, we overview the molecular mechanisms which modulate CSC-like phenotypes, and discuss the future perspective for targeting CSC in iCCA.

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“…The pattern of protein expression in two eCCA cell lines (Mz-ChA-1 and SK-ChA-1) undergoing spheroid formation has been recently investigated [121]. Compared to 2D cultures, eCCA spheroids showed an increased expression of several enzymes involved in glycolysis, hypoxia signaling, the protein ubiquitination pathway, the NADH repair pathway, and the degradation of superoxide radicals [72]. In another study, spheroids were established from the iCCA cell lines SG231, HUCCT1, CCLP1, and CCA4; their molecular characterization revealed an increased expression of key genes involved in pluripotency, self-renewal, drug-resistance, and survival, as well as stem-like surface markers [122].…”

Section: Spheroidsmentioning

confidence: 99%

“…For instance, Kawamoto et al developed spheroids from an eCCA GEM-resistant cell line (TFK-1) and from iCCA cells established from a patient with a GEM-resistant tumor. They observed that Metronidazole reduced cancer stemness features in both types of GEM-resistant CCA spheroids [72]. Cholangiosphere models were also useful for studying tumor-stroma interactions by using either direct or indirect co-culture systems.…”

Section: Spheroidsmentioning

confidence: 99%

Evolution of the Experimental Models of Cholangiocarcinoma

Massa

Varamo

Vita

et al. 2020

Cancers

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Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA molecular pathogenesis, highlighting its extreme heterogeneity and high frequency of genetic and molecular aberrations. Effective preclinical models, therefore, should be based on a comparable level of complexity. In the past years, there has been a consistent increase in the number of available CCA models. The exploitation of even more complex CCA models is rising. Examples are the use of CRISPR/Cas9 or stabilized organoids for in vitro studies, as well as patient-derived xenografts or transgenic mouse models for in vivo applications. Here, we examine the available preclinical CCA models exploited to investigate: (i) carcinogenesis processes from initiation to progression; and (ii) tools for personalized therapy and innovative therapeutic approaches, including chemotherapy and immune/targeted therapies. For each model, we describe the potential applications, highlighting both its advantages and limits.

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Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma

Abstract: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.

Cited by 13 publications

References 28 publications

Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

Cancer Stem Cells in Intrahepatic Cholangiocarcinoma; Their Molecular Basis, and Therapeutic Implications

Evolution of the Experimental Models of Cholangiocarcinoma

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