The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs

Andreucci, Elena; Biagioni, Alessio; Peri, Sara; Versienti, Giampaolo; Cianchi, Fabio; Staderini, Fabio; Antonuzzo, Lorenzo; Supuran, Claudiu T.; Olivo, Erika; Pasqualini, Elisa; Messerini, Luca; Massi, Daniela; Lulli, Matteo; Ruzzolini, Jessica; Peppicelli, Silvia; Bianchini, Francesca; Schiavone, Nicola; Calorini, Lido; Magnelli, Lucia; Papucci, Laura

doi:10.1016/j.canlet.2023.216338

Cited by 6 publications

(2 citation statements)

References 31 publications

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“…Despite the application of perioperative multimodal chemotherapy, the development of chemoresistance is still an obstacle to the effectiveness of current GC treatment. 22,23 Consequently, the first step toward overcoming drug resistance is to identify the mechanism underlying GC cell drug resistance. A study showed that B7H3 may regulate glucose metabolism and chemotherapy resistance by controlling HK2 expression in CRC F I G U R E 4 (See caption on next page).…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

Gao,

Huang,

Liu

et al. 2024

J of Cellular Biochemistry

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Despite surgical treatment combined with multidrug therapy having made some progress, chemotherapy resistance is the main cause of recurrence and death of gastric cancer (GC). Gastric cancer mesenchymal stem cells (GCMSCs) have been reported to be correlated with the limited efficacy of chemotherapy in GC, but the mechanism of GCMSCs regulating GC resistance needs to be further studied. The gene set enrichment analysis (GSEA) was performed to explore the glycolysis‐related pathways heterogeneity across different cell subpopulations. Glucose uptake and lactate production assays were used to evaluate the importance of B7H3 expression in GCMSCs‐treated GC cells. The therapeutic efficacy of oxaliplatin (OXA) and paclitaxel (PTX) was determined using CCK‐8 and colony formation assays. Signaling pathways altered by GCMSCs‐CM were revealed by immunoblotting. The expression of TNF‐α in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by western blot analysis and qPCR. Our results showed that the OXA and PTX resistance of GC cells were significantly enhanced in the GCMSCs‐CM treated GC cells. Acquired OXA and PTX resistance was characterized by increased cell viability for OXA and PTX, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of cleaved caspase‐3 and Bax expression, and increased levels of Bcl‐2, HK2, MDR1, and B7H3 expression. Blocking TNF‐α in GCMSCs‐CM, B7H3 knockdown or the use of 2‐DG, a key enzyme inhibitor of glycolysis in GC cells suppressed the OXA and PTX resistance of GC cells that had been treated with GCMSCs‐CM. This study shows that GCMSCs‐CM derived TNF‐α could upregulate the expression of B7H3 of GC cells to promote tumor chemoresistance. Our results provide a new basis for the treatment of GC.

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Section: Discussionmentioning

confidence: 99%

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

Gao,

Huang,

Liu

et al. 2024

J of Cellular Biochemistry

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“…Evidence also suggests that combinatorial targeting of CA9 with chemotherapy in chemoresistant tumours may re-sensitize tumour cells to anti-cancer therapy, in part by enhancing ferroptosis. In gastric cancer cells, induction of chemoresistance using standard of care multi-agent perioperative chemotherapy (e.g., FLOT—Leucovorin, 5-Fluorouracil, Docetaxel, Oxaliplatin or FOLFOX—Leucovorin, 5-Fluorouracil, Oxaliplatin) resulted in increased CAIX expression, while combining these chemotherapies with SLC-0111 improved therapeutic efficacy in the drug resistant cells ( Andreucci et al, 2023 ). While this study did not explore the relationship with ferroptosis, studies in gefitinib-resistant lung cancer, in which CAIX is upregulated, have elucidated a role of CAIX in regulating vulnerability to ferroptosis ( Zhang et al, 2023 ).…”

Section: Co-vulnerability Of Iron-sulfur Cluster—xct and Carbonic Anh...mentioning

confidence: 99%

Co-vulnerabilities of inhibiting carbonic anhydrase IX in ferroptosis-mediated tumor cell death

McDonald,

Dedhar

2023

Front. Mol. Biosci.

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The tumour-associated carbonic anhydrases (CA) IX and XII are upregulated by cancer cells to combat cellular and metabolic stress imparted by hypoxia and acidosis in solid tumours. Owing to its tumour-specific expression and function, CAIX is an attractive therapeutic target and this has driven intense efforts to develop pharmacologic agents to target its activity, including small molecule inhibitors. Many studies in multiple solid tumour models have demonstrated that targeting CAIX activity with the selective CAIX/XII inhibitor, SLC-0111, results in anti-tumour efficacy, particularly when used in combination with chemotherapy or immune checkpoint blockade, and has now advanced to the clinic. However, it has been observed that sustainability and durability of CAIX inhibition, even in combination with chemotherapy agents, is limited by the occurrence of adaptive resistance, resulting in tumour recurrence. Importantly, the data from these models demonstrates that CAIX inhibition may sensitize tumour cells to cytotoxic drugs and evidence now points to ferroptosis, an iron-dependent form of regulated cell death (RCD) that results from accumulation of toxic levels of phospholipid peroxidation as a major mechanism involved in CAIX-mediated sensitization to cancer therapy. In this mini-review, we discuss recent advances demonstrating the mechanistic role CAIX plays in sensitizing cancer cells to ferroptosis.

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Carbonic anhydrase IX: An atypical target for innovative therapies in cancer

Ronca,

Supuran

2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs

Cited by 6 publications

References 31 publications

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

Co-vulnerabilities of inhibiting carbonic anhydrase IX in ferroptosis-mediated tumor cell death

Carbonic anhydrase IX: An atypical target for innovative therapies in cancer

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