Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition

Jü, Rui; Guo, Lei; Li, Juan; Zhu, Lei; Yu, Xiaoli; Chen, Chen; Chen, Wei; Ye, Caiying; Zhang, Dechang

doi:10.1016/j.canlet.2015.10.025

Cited by 38 publications

(21 citation statements)

References 37 publications

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“…9,10 This reprogrammed cancer metabolism is known as the Warburg effect. 11 There is extensive evidence to indicate that the dysregulated Warburg-like glucose metabolism correlates well with either inherent or acquired drug resistance in cancer cells, [12][13][14] and enhanced glycolysis contributes to sorafenib resistance in HCC cells. [15][16][17] Moreover, 6-phosphofructo-2kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is found to be overexpressed in aggressive tumors compared with normal tissues, and this feature is highly linked to poor treatment effect and prognosis.…”

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confidence: 99%

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

Dai

et al. 2017

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.

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confidence: 99%

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

Dai

et al. 2017

Intl Journal of Cancer

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“…Similarly, another triazole-based compound, carboxyamidotriazole, was shown to inhibit the mitochondrial respiration of cancer cells, causing disturbance in their energy metabolism and inducing glucose uptake and lactate production. When treated in combination with 2-DG, carboxyamidotriazole resulted in a G2/M phase arrest (Ju et al, 2016). Previous studies have also described the use of 1 to 10 mM 2-DG that caused inhibition of cell culture (Barban and Schulze, 1961; Halicka et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…The novelty of the current study is that we explore here recently understood mechanisms of NCL-240 and exploit the anti-cancer potential of its combination with 2-DG, which was not done previously. The drug combination used in our study is different from recently proposed work based on carboxyamidotriazole (Ju et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG

Pattni

Jhaveri

Dutta

et al. 2017

International Journal of Pharmaceutics

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Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80–90% of the total, indicating an inability to grow and divide. Cytotoxicity studies with in vitro cancer cell monolayer models confirmed the results of cell cycle analysis. Significant improvements in cytotoxicity with combination treatments over control and individual treatments were seen in multiple cell lines. NCI/ADR-RES cancer cell spheroids further demonstrated the effectiveness of a NCL-240/2-DG combination.

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“…[24] Thus,t he protection of commercially available benzylic alcohol 19 with TIPSCl produced the silyl ether 20 which was smoothly magnesiated at position 4w ith TMP 2 Mg·LiCl [25] followed by copper-mediated acylation [15] with 4-chlorobenzoyl chloride.A fter desilylation using TBAF (tetra-n-butylammonium fluoride), benzylic alcohol (21)w as isolated in 82 %y ield. [24] Thus,t he protection of commercially available benzylic alcohol 19 with TIPSCl produced the silyl ether 20 which was smoothly magnesiated at position 4w ith TMP 2 Mg·LiCl [25] followed by copper-mediated acylation [15] with 4-chlorobenzoyl chloride.A fter desilylation using TBAF (tetra-n-butylammonium fluoride), benzylic alcohol (21)w as isolated in 82 %y ield.…”

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confidence: 99%

“…ity (Scheme 3). [24] Thus,t he protection of commercially available benzylic alcohol 19 with TIPSCl produced the silyl ether 20 which was smoothly magnesiated at position 4w ith TMP 2 Mg·LiCl [25] followed by copper-mediated acylation [15] with 4-chlorobenzoyl chloride.A fter desilylation using TBAF (tetra-n-butylammonium fluoride), benzylic alcohol (21)w as isolated in 82 %y ield. Ther esulting alcohol was brominated with PBr 3 at 25 8 8Ctoafford benzylic bromide 22 in 94 %y ield.…”

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confidence: 99%

Preparation of Solid Polyfunctional Alkynylzinc Pivalates with Enhanced Air and Moisture Stability for Organic Synthesis

et al. 2017

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We report the preparation of solid and air-stable polyfunctionalized alkynylzinc pivalates from the corresponding alkynes using TMPZnOPiv (TMP=2,2,6,6-tetramethylpiperidyl) as base. These organozinc pivalates are obtained as powders under mild conditions in excellent yields and can be manipulated in air for several hours without significant decomposition. These zinc reagents show an excellent reactivity in various carbon-carbon bond- forming reactions and 1,3-dipolar cycloadditions. An alkynylzinc pivalate has been used to prepare a carboxyamidotriazole with potential antineoplastic activity in eight steps and 38 % overall yield.

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Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition

Cited by 38 publications

References 37 publications

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG

Preparation of Solid Polyfunctional Alkynylzinc Pivalates with Enhanced Air and Moisture Stability for Organic Synthesis

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