The Warburg effect and mitochondrial stability in cancer cells

Gogvadze, Vladimir; Zhivotovsky, Boris; Orrenius, Sten

doi:10.1016/j.mam.2009.12.004

Cited by 181 publications

(141 citation statements)

References 137 publications

(124 reference statements)

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“…Although normal liver and cancer cell mitochondria present certain structural and functional differences, 44,45 we believe that sufficient similarities exist to justify using isolated liver mitochondria as models to gain insight into the interactions of xenobiotic compounds with mitochondria. Also, isolated mitochondrial fractions present the advantage of a much higher isolation yield so that more aspects of mitochondrial function and compound-induced toxicity can be studied with one single isolation procedure.…”

Section: ' Discussionmentioning

confidence: 99%

Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

Serafim

Carvalho

Marques

et al. 2011

Chem. Res. Toxicol.

121

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In the present work, lipophilic caffeic and ferulic acid derivatives were synthesized, and their cytotoxicity on cultured breast cancer cells was compared. A total of six compounds were initially evaluated: caffeic acid (CA), hexyl caffeate (HC), caffeoylhexylamide (HCA), ferulic acid (FA), hexyl ferulate (HF), and feruloylhexylamide (HFA). Cell proliferation, cell cycle progression, and apoptotic signaling were investigated in three human breast cancer cell lines, including estrogen-sensitive (MCF-7) and insensitive (MDA-MB-231 and HS578T). Furthermore, direct mitochondrial effects of parent and modified compounds were investigated by using isolated liver mitochondria. The results indicated that although the parent compounds presented no cytotoxicity, the new compounds inhibited cell proliferation and induced cell cycle alterations and cell death, with a predominant effect on MCF-7 cells. Interestingly, cell cyle data indicates that effects on nontumor BJ fibroblasts were predominantly cytostatic and not cytotoxic. The parent compounds and derivatives also promoted direct alterations on hepatic mitochondrial bioenergetics, although the most unexpected and never before reported one was that FA induces the mitochondrial permeability transition. The results show that the new caffeic and ferulic acid lipophilic derivatives show increased cytotoxicity toward human breast cancer cell lines, although the magnitude and type of effects appear to be dependent on the cell type. Mitochondrial data had no direct correspondence with effects on intact cells suggesting that this organelle may not be a critical component of the cellular effects observed. The data provide a rational approach to the design of effective cytotoxic lipophilic hydroxycinnamic derivatives that in the future could be profitably applied for chemopreventive and/or chemotherapeutic purposes.

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Section: ' Discussionmentioning

confidence: 99%

Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

Serafim

Carvalho

Marques

et al. 2011

Chem. Res. Toxicol.

121

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“…These alterations lead to specific defects of the respiratory chain, which are described in detail below and depicted in Figure 2. Equally important for RC inhibition is the global metabolic shift from OxPhos to glycolysis (Gatenby and Gillies, 2004;Pelicano et al, 2006), notably in hypoxia during the early stages of tumourigenesis (Papandreou et al, 2006;Gogvadze et al, 2010).…”

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confidence: 99%

“…MtDNA-derived subunits of RCC I (7/45 subunits: NADH dehydrogenase subunits ND1 to ND6 and ND4L), III (1/11 subunits: cytochrome b) and IV (3/13 subunits, cytochrome c oxidase subunits COXI to III) have been found altered in various types of cancers (Brandon et al, 2006;Lu et al, 2009), although they, like their nuclear-encoded counterparts, can also lead to neurodevelopmental impairment, neurodegenerative diseases or cardiomyopathies when mutated Distelmaier et al, 2009;Diaz, 2010;Schapira, 2010). Consequently, the actual contribution of these mutations to tumourigenesis is an important question-do these mutations act as a significant cause or do they merely constitute a side effect of tumour development, caused by, for example, the combined effect of the intrinsic oxidative stress in cancer cells (Pelicano et al, 2004;Gogvadze et al, 2010) and the low DNA repair capacity for mtDNA (Penta et al, 2001)? A confounding factor is the multiplicity of the mtDNA, which is present in these organelles in hundreds of copies.…”

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confidence: 99%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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“…Another potential factor to elevate the apoptotic threshold is the Warburg effect, by which the cancer cells produce energy mainly by glycolysis 37. However, excessive glycolysis in cancer cells renders the outer mitochondrial membrane (OMM) less susceptible to permeabilization, which leads to elevated apoptotic threshold38, 39 because the apoptotic pathway requires regular permeabilization of OMM to release the mitochondrial proapoptotic proteins. Thus, the extent of extra or intracellular insults, which are able to induce apoptosis in normal cancer cells, is ineffective to MDR cancer cells.…”

Section: Mechanisms Of Cancer Multidrug Resistancementioning

confidence: 99%

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

et al. 2016

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Cancer multidrug resistance (MDR) could lead to therapeutic failure of chemotherapy and radiotherapy, and has become one of the main obstacles to successful cancer treatment. Some advanced drug delivery platforms, such as inorganic nanocarriers, demonstrate a high potential for cancer theranostic to overcome the cancer‐specific limitation of conventional low‐molecular‐weight anticancer agents and imaging probes. Specifically, it could achieve synergetic therapeutic effects, demonstrating stronger killing effects to MDR cancer cells by combining the inorganic nanocarriers with other treatment manners, such as RNA interference and thermal therapy. Moreover, the inorganic nanocarriers could provide imaging functions to help monitor treatment responses, e.g., drug resistance and therapeutic effects, as well as analyze the mechanism of MDR by molecular imaging modalities. In this review, the mechanisms involved in cancer MDR and recent advances of applying inorganic nanocarriers for MDR cancer imaging and therapy are summarized. The inorganic nanocarriers may circumvent cancer MDR for effective therapy and provide a way to track the therapeutic processes for real‐time molecular imaging, demonstrating high performance in studying the interaction of nanocarriers and MDR cancer cells/tissues in laboratory study and further shedding light on elaborate design of nanocarriers that could overcome MDR for clinical translation.

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The Warburg effect and mitochondrial stability in cancer cells

Cited by 181 publications

References 137 publications

Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

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