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

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

doi:10.3389/fonc.2023.1118268

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

Front Oncol. 2023 Jan 26:13:1118268. doi: 10.3389/fonc.2023.1118268. eCollection 2023.

Authors

Katja Eloranta¹, Marjut Pihlajoki¹, Emmi Liljeström¹, Ruth Nousiainen¹, Tea Soini¹, Jouko Lohi², Stefano Cairo^{3

4

5}, David B Wilson^{6

7}, Seppo Parkkila^{8

9

10}, Markku Heikinheimo^{1

6

11}

Affiliations

¹ Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
² Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³ Xentech, Evry, Evry, France.
⁴ Istituto di Ricerca Pediatrica, Padova, Italy.
⁵ Champions Oncology, Hackensack, NJ, United States.
⁶ Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States.
⁷ Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States.
⁸ Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁹ FICAN Mid, Tampere University, Tampere, Finland.
¹⁰ Fimlab Ltd, Tampere University Hospital, Tampere, Finland.
¹¹ Faculty of Medicine and Health Technology, Center for Child, Adolescent, and Maternal Health Research, Tampere University, Tampere, Finland.

Abstract

Background: In response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined.

Methods: We surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions.

Results: CAIX immunoreactivity was detected in 15 out of 21 archival pathology HB specimens. The CAIX-positive cells clustered in the middle of viable tumor tissue or next to necrotic areas. Tissue expression of CAIX mRNA was associated with metastasis and poor clinical outcome of HB. Hypoxia induced a striking upregulation of CAIX mRNA and protein in three HB cell models: the immortalized human HB cell line HUH6 and patient xenograft-derived lines HB-295 and HB-303. Administration of SLC-0111 abrogated the hypoxia-induced upregulation of CAIX and decreased HB cell viability, both in monolayer and spheroid cultures. In addition, SLC-0111 reduced HB cell motility in a wound healing assay. Transcriptomic changes triggered by SLC-0111 administration differed under normoxic vs. hypoxic conditions, although SLC-0111 elicited upregulation of several tumor suppressor genes under both conditions.

Conclusion: Hypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells.

Keywords: carbonic anhydrase IX; hepatoblastoma; pediatric oncology; targeted therapy; tumor hypoxia.

Grants and funding

This study was supported by Doctoral Program in Clinical Research at University of Helsinki Funds, Finska Läkaresällskapet, Helsinki University Central Hospital Research Grants, Päivikki and Sakari Sohlberg Foundation, and Sigrid Jusélius Foundation and Lasten Syöpäsäätiö Väre (Väre Foundation).