SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration

Eloranta, Katja; Pihlajoki, Marjut; Liljeström, Emmi; Nousiainen, Ruth; Soini, Tea; Cairo, Stefano; Wilson, David B.; Parkkila, Seppo; Heikinheimo, Markku

doi:10.3389/fonc.2023.1118268

Cited by 12 publications

(5 citation statements)

References 78 publications

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“…Previously it has been shown that CA inhibitor SLC-0111/U-104 downregulates CA9 expression at both protein and transcript levels in hepatoblastoma cell lines [46]. Similarly, following compound S4 treatment, levels of CA9 protein and mRNA were significantly decreased in both LCLs (Fig.…”

Section: Resultsmentioning

confidence: 64%

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Malik,

Biswas,

Sarkar

et al. 2023

Preprint

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Epstein-Barr virus (EBV) contributes to ∼1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.

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Section: Resultsmentioning

confidence: 64%

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Malik,

Biswas,

Sarkar

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Previously it has been shown that CA inhibitor SLC-0111/U-104 downregulates CA9 expression at both protein and transcript levels in hepatoblastoma cell lines [47]. Similarly, following compound S4 treatment, levels of CA9 protein and mRNA were significantly decreased in both LCLs (Fig 6C and 6D).…”

Section: Plos Pathogensmentioning

confidence: 53%

Differential carbonic anhydrase activities control EBV-induced B-cell transformation and lytic cycle reactivation

Malik,

Biswas,

Sarkar

et al. 2024

PLoS Pathog

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Epstein-Barr virus (EBV) contributes to ~1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus, ectopic expression of EBNA2 and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.

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“…[29,30] The tail approach proved to be an exploitable tactic for designing compounds 1-5 (Figure 1) which demonstrated remarkable inhibition potential against hCA IX, making them promising candidates for treating human malignancies characterized by the overexpression of hCA IX in hypoxic tumors. [31] The increased expression of hCA IX in hypoxic tumors has a critical role in cancer cell survival, proliferation, and metastasis by decreasing the pH of the extracellular matrix. [32,33] More importantly, hCA IX overexpression enhances the chemoresistance of anticancer drugs that are weakly alkaline in nature.…”

mentioning

confidence: 99%

In‐vitro and in‐silico investigations of SLC‐0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors

Sharma,

Vats,

Giovannuzzi

et al. 2024

Archiv der Pharmazie

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Two novel series of hydrazinyl‐based benzenesulfonamides 9a–j and 10a–j were designed and synthesized using SLC‐0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off‐target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5–176.6 nM and 6.0–127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC‐0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off‐target hCA I and II.

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SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration

Cited by 12 publications

References 78 publications

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Differential carbonic anhydrase activities control EBV-induced B-cell transformation and lytic cycle reactivation

In‐vitro and in‐silico investigations of SLC‐0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors

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