Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis

Andreucci, Elena; Peppicelli, Silvia; Carta, Fabrizio; Brisotto, Giulia; Biscontin, Eva; Ruzzolini, Jessica; Bianchini, Francesca; Biagioni, Alessio; Supuran, Claudiu T.; Calorini, Lido

doi:10.1007/s00109-017-1590-9

Cited by 79 publications

(71 citation statements)

References 36 publications

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“…In this study, we provide a prospective combination of treatment that includes an inhibitor of histone deacetylases (HDACs), as their dysregulation is associated with many forms of cancers [29][30][31][32][33][34][35][36] , and an inhibitor of CA IX, as its overexpression in various tumours is correlated with cancer progression and poor survival 17,52 . We have previously reported that melanoma, breast and colorectal cancer cell lines, express high levels of CA IX in normoxia whereas the transiently and chronically exposure to extracellular acidic microenvironment (pH 6.7 ± 0.1) induces CA IX overexpression 53 . Moreover, we demonstrated that SLC-0111, a novel CA IX inhibitor, is able to synergize with cytotoxic drugs such as Dacarbazine, Doxorubicine and 5-Fluorouracil 26 .…”

Section: Discussionmentioning

confidence: 98%

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

Ruzzolini

Laurenzana

Andreucci

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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& Lido Calorini (2020) A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer, ABSTRACTThe emergence of tumour recurrence and resistance limits the survival rate for most tumour-bearing patients. Only, combination therapies targeting pathways involved in the induction and in the maintenance of cancer growth and progression might potentially result in an enhanced therapeutic efficacy. Herein, we provided a prospective combination treatment that includes suberoylanilide hydroxamic acid (SAHA), a well-known inhibitor of histone deacetylases (HDACs), and SLC-0111, a novel inhibitor of carbonic anhydrase (CA) IX. We proved that HDAC inhibition with SAHA in combination with SLC-0111 affects cell viability and colony forming capability to greater extent than either treatment alone of breast, colorectal and melanoma cancer cells. At the molecular level, this therapeutic regimen resulted in a synergistically increase of histone H4 and p53 acetylation in all tested cell lines. Overall, our findings showed that SAHA and SLC-0111 can be regarded as very attractive combination providing a potential therapeutic strategy against different cancer models. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 98%

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

Ruzzolini

Laurenzana

Andreucci

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…However, to prevent intracellular H þ accumulation cancer cells upregulates proton exchangers that extrude protons in excess contributing to acidify extracellular tumour microenvironment 9,11,12 . Among these proton exchangers, a primary role is played by CA IX, an enzyme overexpressed in many types of cancers, including prostate cancer, with the potential to represent both a promising tumour biomarker and a specific target for future cancer therapies 13,[30][31][32][33][37][38][39][40][41]44 . Under the pressure of the acidic microenvironment, CA IX expression and activity are upregulated in both tumour cells 30,44 and the exosomes released extracellularly 30 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed CA IX is the most widely expressed gene in response to hypoxia, playing a pivotal role in tumour pH regulation 13,30,37,41 ; thus conferring to cancer cells a survival advantage in hypoxic and acidic microenvironments 43 . Thus, it is clear that the acidic microenvironment induces the up-regulation of the CA IX expression and activity in both tumour cells 30,44 and tumour released exosomes 30 . However, the possibility that CA IX expression and activity in cancer cell-derived exosomes could represent a new valuable tumour marker has not yet been tested in clinical samples.…”

Section: Introductionmentioning

confidence: 99%

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

Logozzi

Mizzoni

Capasso

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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2020) Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 280-288, ABSTRACT Acidity, hypoxia and increased release of exosomes are severe phenotypes of tumours. The regulation of pH in tumours involves the interaction of several proteins, including the carbonic anhydrases which catalyze the formation of bicarbonate and protons from carbon dioxide and water. Among CA isoforms, CA IX is over-expressed in a large number of solid tumours, conferring to cancer cells a survival advantage in hypoxic and acidic microenvironment, but there isn't evidence that CA IX expression could have a real clinical impact. Therefore, in this study for the first time the expression and activity of CA IX have been investigated in the plasmatic exosomes obtained from patients with prostate carcinoma (PCa). For this purpose, the study was performed through different methodological approaches, such as NTA, western blot analysis, enzyme activity assay, Nanoscale flow cytometry, ELISA, confocal microscopy. The results showed that PCa exosomes significantly overexpressed CA IX levels and related activity as compared to healthy donors. Furthermore, CA IX expression and activity were correlated to the exosome intraluminal pH, demonstrating for the first time that PCa exosomes are acidic. Our data suggest the possible use of the exosomal CA IX expression and activity as a biomarker of cancer progression in PCa.

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“…Recent studies support SFN as a potent antitumor agent against multiple signaling pathways in diverse cancers and targeting of mitochondrial functions where normal cells are protected [45][46][47][48][49][50]. Expression of carbonic anhydrase IX (CAIX) is highly relevant to rapidly growing and aggressive tumor cells adapting to the acidic microenvironment in rapidly growing tumors in order to maintain a more intracellular physiological pH, and thus inhibitors of CAIX can potently inhibit tumor cell viability [51,52]. Here we show that AZ alone is an effective but more modest growth inhibitory agent.…”

Section: Discussionmentioning

confidence: 99%

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

et al. 2019

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Background Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. Methods Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. Results Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. Conclusions Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

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Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis

Abstract: Cancer cells overexpress CAIX under transient and chronic extracellular acidosis. Acidosis-induced CAIX overexpression is NF-κB mediated and HIF-1α independent. FC16-670A prevents CAIX overexpression and induces acidified cancer cell death.

Cited by 79 publications

References 36 publications

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

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