Antisense oligonucleotides-Laden UiO-66@Au nanohybrid for enhanced radiotherapy against hypoxic tumor by dual-inhibition of carbonic anhydrase IX

Abstract Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.

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Theoretical investigation of the structural and electronic features of SLC-0111, a novel inhibitor of human carbonic anhydrase IX, and its anion

Structural Chemistry ◽

10.1007/s11224-021-01741-x ◽

2021 ◽

Author(s):

Varun Chahal ◽

Rita Kakkar

Keyword(s):

Carbonic Anhydrase ◽

Theoretical Investigation ◽

Carbonic Anhydrase Ix ◽

Human Carbonic Anhydrase

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Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22116098 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6098

Author(s):

Ebru Temiz ◽

Ismail Koyuncu ◽

Mustafa Durgun ◽

Murat Caglayan ◽

Ataman Gonel ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Intracellular Ph ◽

Hela Cells ◽

Protein Level ◽

Caspase 3 ◽

Solid Tumours ◽

Carbonic Anhydrase Ix ◽

Parp Activation ◽

Ca Ix ◽

Cervical Cancer Cells

Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO/EB, AnnexinV-PI, and γ-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib/II clinical trials as an antitumour/antimetastatic drug.

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Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints

Cancers ◽

10.3390/cancers13051022 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1022

Author(s):

Shawn C. Chafe ◽

Nazia Riaz ◽

Samantha Burugu ◽

Dongxia Gao ◽

Samuel C. Y. Leung ◽

...

Keyword(s):

Breast Cancer ◽

Carbonic Anhydrase ◽

Immune Checkpoint ◽

Positive Association ◽

Carcinoma Cells ◽

Carbonic Anhydrase Ix ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Significant Positive Association ◽

Stimulating Factor

Purpose: Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer specimens, their relation to breast cancer subtypes, and clinical outcome. Methods: Using validated protocols and prespecified scoring methodology, G-CSF expression on carcinoma cells and CD163 expression on tumour-associated macrophages were assayed by immunohistochemistry and applied to a tissue microarray series of 2960 primary excision specimens linked to clinicopathologic, biomarker, and outcome data. Results: G-CSFhigh expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSFhigh phenotype was associated with improved survival in non-luminal cases, although the CAIX+ subset had a significantly adverse prognosis. A significant positive association was observed between immune checkpoint biomarkers on tumour-infiltrating lymphocytes and both G-CSF- and CAIX-expressing carcinoma cells. Immune checkpoint biomarkers correlated significantly with favourable prognosis in G-CSFhigh/non-luminal cases independent of standard clinicopathological features. Conclusions: The prognostic associations linking G-CSF to immune biomarkers and CAIX strongly support their immunomodulatory roles in the tumour microenvironment.

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