Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

McDonald, Paul C.; Chafe, Shawn C.; Supuran, Claudiu T.; Dedhar, Shoukat

doi:10.3390/cancers14143297

Cited by 69 publications

(40 citation statements)

References 53 publications

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“…The cooperative use of MCT1/MCT4 inhibitors or nonspecific MCT inhibitors has good therapeutic potential ( 125 , 132 , 134 , 135 ). Also of great importance to decrease pHi values is the pharmacological inhibition of the proton pump H + -ATPase ( 136 ), sodium-hydrogen antiporter 1 (NHE1) ( 137 ), and carbonic anhydrase IX (CAIX) ( 138 ). For example, according to the results of a phase III clinical trial (NCT01069081), intermittent use of a high dose of the proton pump inhibitor esomeprazole potentiates the effects of docetaxel and cisplatin chemotherapy in metastatic breast cancer without causing further toxicity ( 139 ).…”

Section: Tumor Acidity As a Target Of Treatmentmentioning

confidence: 99%

Tumor acidity: From hallmark of cancer to target of treatment

et al. 2022

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Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid–base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to “ion trapping”. Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.

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Section: Tumor Acidity As a Target Of Treatmentmentioning

confidence: 99%

Tumor acidity: From hallmark of cancer to target of treatment

et al. 2022

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“…It must be emphasized that confirmed CAIX tissue expression was not used as an inclusion criterion for that study. There is also a Phase Ib clinical trial on the efficacy of SLC-0111 in combination with gemcitabine in CAIXpositive pancreatic cancer patients (79). These and future trials will hopefully identify patients who may benefit from SLC-0111 Impact of SLC-0111 on gene expression in normoxic and hypoxic HUH6 cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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BackgroundIn 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.MethodsWe 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.ResultsCAIX 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.ConclusionHypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells.

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“…Overall, these in vitro activity data are encouraging for further future development of this scaffold. Recently, selective CAIs were shown to sensitize tumor cells to cytotoxic agents in different preclinical models [ 70 ]. This enhanced efficacy can be the result of targeting residual cancer cells that are pharmacologically resistant due to their presence in the hypoxic niche or of suppressing tumor cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies

Pontecorvi

Mori

Picarazzi

et al. 2022

IJMS

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Human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII are overexpressed in solid hypoxic tumors, and they are considered as prognostic tools and therapeutic targets for cancer. Based on a molecular simplification of the well-known coumarin scaffold, we developed a new series of derivatives of the pyran-2-one core. The new compounds are endowed with potent and selective inhibitory activity against the tumor-related hCA isoforms IX and XII, in the low nanomolar range, whereas they are inactive against the two cytosolic off-targets hCA I and II. The compounds exhibiting the best hCA inhibition were further investigated against the breast adenocarcinoma cell line (MCF7) in hypoxic conditions, evaluating their ability to eventually synergize with doxorubicin. The compounds’ biocompatibility on healthy cells was also tested and confirmed on Human Gingival Fibroblasts (HGFs). Furthermore, the possible binding mode of all compounds to the active site of the tumor-associated human CA IX was investigated by computational techniques which predicted the binding conformations and the persistency of binding poses within the active site of the enzyme, furnishing relevant data for the design of tight binding inhibitors.

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Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

Cited by 69 publications

References 53 publications

Tumor acidity: From hallmark of cancer to target of treatment

Tumor acidity: From hallmark of cancer to target of treatment

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

Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies

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