Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma

Vaeteewoottacharn, Kulthida; Kariya, Ryusho; Pop, Dana; Fujikawa, Sawako; Matsuda, Kouki; Ohkuma, Koichi; Kudo, Eriko; Kraiklang, Ratthaphol; Wongkham, Chaisiri; Wongkham, Sopit; Okada, Seiji

doi:10.1007/s13277-016-4785-8

Cited by 38 publications

(29 citation statements)

References 34 publications

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“…For example, targeting HIF1α increases the efficacy of bevacizumab in neuroblastoma xenografts [38]. A similar effect has also been reported when bevacizumab is combined with acetazolamide [14] [39]. More importantly, such strategies are also tested in clinical trials [37].…”

Section: Discussionmentioning

confidence: 83%

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

et al. 2016

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The inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) by chemical inhibitors, such as rapamycin, has demonstrated anti-cancer activity in preclinical and clinical trials. Their efficacy is, however, limited and tumors eventually relapse through resistance formation. In this study, using two different cancer mouse models, we identify tumor hypoxia as a novel mechanism of resistance of cancer cells against mTORC1 inhibitors. Indeed, we show that the activity of mTORC1 is mainly restricted to the non-hypoxic tumor compartment, as evidenced by a mutually exclusive staining pattern of the mTORC1 activity marker pS6 and the hypoxia marker pimonidazole. Consequently, whereas rapamycin reduces cancer cell proliferation in non-hypoxic regions, it has no effect in hypoxic areas, suggesting that cancer cells proliferate independently of mTORC1 under hypoxia. Targeting the hypoxic tumor compartment by knockdown of carbonic anhydrase IX (CAIX) using short hairpin RNA or by chemical inhibition of CAIX with acetazolamide potentiates the anti-cancer activity of rapamycin. Taken together, these data emphasize that hypoxia impairs the anti-cancer efficacy of rapalogs. Therapeutic strategies targeting the hypoxic tumor compartment, such as the inhibition of CAIX, potentiate the efficacy of rapamycin and warrant further clinical evaluation.

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Section: Discussionmentioning

confidence: 83%

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

et al. 2016

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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]. It was also shown that treating cells with CAIX and CAXII inhibitors promote the susceptibility to radiotherapy-induced apoptosis [97].…”

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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“…Therefore, in addition to canonical TGF-β target genes, VEGF represents the first proangiogenic factor regulated by TGF-β1 through Sp1. Molecules such as Bevacizumab show promising results because of their ability to neutralize VEGF-induced angiogenic effect which leads to a decrease of tumor progression [93]. Vandetanib, an inhibitor of both VEGFR and EGFR factors, reveals anti-tumor and anti-metastatic properties [87], while Apatinib, which selectively suppresses VEGFR2 signaling and results in anti-apoptosis action, is proven as one of the candidates in the treatment of CCA [94].…”

Section: Vascular Endothelial Growth Factors (Vegfs) and Placental Grmentioning

confidence: 99%

Role of the Angiogenic Factors in Cholangiocarcinoma

et al. 2019

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Angiogenesis plays a fundamental role in tumor growth and progression. It is regulated by several growth factors, including vascular endothelial growth factor protein family (VEGF) and its receptors, which are probably the most important factors responsible for the development of new vessels. The VEGF family includes several members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placental growth factor (PlGF), and their receptors VEGFR-1, VEGFR-2 and VEGFR-3. Other relevant factors are represented by angiopoietins, thrombospondin-1, and endothelins. However, since the therapeutic benefit associated with VEGF-targeted therapy is really complex, a better understanding of these pathways will lead to future advances in the use of these agents for clinic management of tumors. Here we present a review regarding the role of angiogenic factors in cholangiocarcinoma, which arise from cholangiocytes, the epithelial cells of bile ducts. They are rare and aggressive neoplasms with a poor prognosis and limited treatment options, classified as intrahepatic, perihilar, and distal cholangiocarcinoma based on their anatomical location. Therefore, the identification of specific signaling pathways or new tumor biomarkers is crucial in order to develop more effective anti-angiogenic therapies.

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Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma

Cited by 38 publications

References 34 publications

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

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

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Role of the Angiogenic Factors in Cholangiocarcinoma

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