C75 [4-Methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic Acid] Activates Carnitine Palmitoyltransferase-1 in Isolated Mitochondria and Intact Cells without Displacement of Bound Malonyl CoA

Yang, Nengyu; Kays, Joanne; Skillman, Tiffanie R.; Burris, Lorri; Seng, Thomas; Hammond, Craig

doi:10.1124/jpet.104.074104

Cited by 29 publications

(26 citation statements)

References 35 publications

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“…It is not clear how C75 promotes CPT1 activity as it does not compete for the malonyl-CoA binding inhibitory site on CPT1. Instead, it has a distinct and unknown mechanism possibly by modifying the relationship of CPT1 with the mitochondrial membrane (Yang et al, 2005).…”

Section: Succmentioning

confidence: 97%

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Ralph

Rodrı́guez-Enrı́quez

Neužil

et al. 2010

Molecular Aspects of Medicine

145

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Mitochondria are emerging as idealized targets for anti-cancer drugs. One reason for this is that although these organelles are inherent to all cells, drugs are being developed that selectively target the mitochondria of malignant cells without adversely affecting those of normal cells. Such anti-cancer drugs destabilize cancer cell mitochondria and these compounds are referred to as mitocans, classified into several groups according to their mode of action and the location or nature of their specific drug targets. Many mitocans selectively interfere with the bioenergetic functions of cancer cell mitochondria, causing major disruptions often associated with ensuing overloads in ROS production leading to the induction of the intrinsic apoptotic pathway. This in-depth review describes the bases for the bioenergetic differences found between normal and cancer cell mitochondria, focussing on those essential changes occurring during malignancy that clinically may provide the most effective targets for mitocan development. A common theme emerging is that mitochondrially mediated ROS activation as a trigger for apoptosis offers a powerful basis for cancer therapy. Continued research in this area is likely to identify increasing numbers of novel agents that should prove highly effective against a variety of cancers with preferential toxicity towards malignant tissue, circumventing tumor resistance to the other more established therapeutic anti-cancer approaches.

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Section: Succmentioning

confidence: 97%

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Ralph

Rodrı́guez-Enrı́quez

Neužil

et al. 2010

Molecular Aspects of Medicine

145

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“…Other inhibitors of FAS have been identified and have been shown to limit cancer growth [66][67][68][69][70][71][72][73]. As few of these inhibitors are expected to be highly selective for FAS (C75, for instance, has also been shown to function as a modulator of carnitine palmitoyltransferases [74,75]), the potential of FAS as a target for antineoplastic intervention was eventually confirmed by RNAi-mediated knockdown of FAS [22].…”

Section: Recent Progress In the Use Of Fatty Acid Synthase Inhibitorsmentioning

confidence: 99%

Increased lipogenesis in cancer cells: new players, novel targets

Swinnen

Brusselmans

Verhoeven

2006

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

552

423

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The same disturbances in signaling pathways responsible for oncogenic transformation may also contribute to the increased lipogenesis observed in tumor cells. Increased lipogenesis involves modulation of multiple lipogenic enzymes at both transcriptional and posttranscriptional level and is linked to other cancer-associated metabolic changes. Not only fatty acid synthase, but in fact all key enzymes involved in fatty acid synthesis as well as key metabolic regulators are potential targets for antineoplastic intervention.

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“…Treatment, however, was limited by anorexia and weight loss (18,31). While investigating the mechanism of action of C75-induced weight loss, we discovered that, in addition to FAS inhibition, C75 also stimulated carnitine palmitoyltransferase-1 (CPT-1) activity, leading to substantially increased fatty acid oxidation (32)(33)(34)(35). CPT-1 is the rate-limiting transporter of long-chain acyl-CoAs into the mitochondria for oxidation.…”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

Zhou¹,

Han²,

et al. 2007

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Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation. [Cancer Res 2007;67(7):2964-71]

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C75 [4-Methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic Acid] Activates Carnitine Palmitoyltransferase-1 in Isolated Mitochondria and Intact Cells without Displacement of Bound Malonyl CoA

Cited by 29 publications

References 35 publications

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Increased lipogenesis in cancer cells: new players, novel targets

Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

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