Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors

Faes, Seraina; Planche, Anne; Uldry, Émilie; Santoro, Tania; Pythoud, Catherine; Stehle, Jean-Christophe; Horlbeck, Janine; Letovanec, Igor; Riggi, Nicolò; Datta, Dipak; Demartines, Nicolas; Dormond, Olivier

doi:10.18632/oncotarget.9134

Cited by 27 publications

(30 citation statements)

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“…Accordingly, mTORC1 activity is mainly restricted to the non-hypoxic tumor compartment, and the hypoxic tumor response mediated by HIF-1 induces resistance to mTORC1 inhibitors [30]. As hypoxia promotes tumor acidosis, a complex relationship exists between mTORC1 activity, hypoxia and acidity in tumors [2].…”

Section: Discussionmentioning

confidence: 99%

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors

et al. 2016

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BackgroundBlocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study.MethodsCancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis.ResultsExposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment.ConclusionsTaken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.

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Section: Discussionmentioning

confidence: 99%

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors

et al. 2016

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“…For example, a knock-down of HIF-1α in combination with anti-angiogenic therapy reduced tumor growth in neuroblastoma xenografts [ 61 ]. Similarly, blocking carbonic anhydrase IX, an enzyme whose expression is increased by hypoxia and which regulates intratumoral pH, enhanced the anti-cancer efficacy of anti-angiogenic drugs [ 62 , 63 ]. Also, buffering intratumoral acidity with sodium bicarbonate in combination with anti-VEGF therapy provided stronger anti-cancer effects compared to anti-VEGF treatment alone [ 64 ].…”

Section: Disrupting the Formation Of New Blood Vesselsmentioning

confidence: 99%

Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer

Uldry

Faes

Demartines

et al. 2017

IJMS

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Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host’s anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential.

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“…The state of hypoxia and acidity of the tumor microenvironment represents a challenge for chemotherapeutic agents [95][96][97][98][99][100]. Carbonic anhydrase inhibitors were found to prohibit cancer metastasis; this was mainly linked to increasing the sensitivity of the cancer cells to the anti-angiogenic agents [98].…”

Section: Carbonic Anhydrase Enzymementioning

confidence: 99%

“…It was also shown that treating cells with CAIX and CAXII inhibitors promote the susceptibility to radiotherapy-induced apoptosis [97]. Intriguingly, mTOR inhibitor efficacy was stronger in non-hypoxic conditions; nevertheless, the combination of the mTOR inhibitors with CAIX inhibitors portrayed anti-cancer activity under hypoxic conditions [99]. Previous reports revealed that carbonic anhydrases, particularly the membrane-associated isoforms, are considered potential prognostic markers.…”

Section: Carbonic Anhydrase Enzymementioning

confidence: 99%

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Alfarouk¹,

Ahmed

et al. 2020

Cancers

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Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.

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Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors

Cited by 27 publications

References 50 publications

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors

Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

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