Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells

Nakano, Ayako; Tsuji, Daisuke; Miki, Hirokazu; Cui, Qu; Sayed, Salah Mohamed El; Ikegame, Akishige; Oda, Asuka; Amou, Hiroe; Nakamura, Shingen; Harada, Takeshi; Fujii, Shiro; Kagawa, Keiichiro; Takeuchi, Kyoko; Sakai, Akira; Ozaki, Shuji; Okano, Kazuma; Nakamura, Takahiro; Itoh, Kohji; Matsumoto, Toshio; Abe, Masahiro

doi:10.1371/journal.pone.0027222

Cited by 94 publications

(84 citation statements)

References 33 publications

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“…31 Recent studies from our laboratory and other groups suggest that CSCs may have even more active glycolytic activity compared to the bulk of the general cancer cells. 17,18,32 Consistently, the current study showed that SP cells were more glycolytic compared to the non-SP cells. These observations underscore the importance of glucose as an essential nutrient for cancer cells, especially for CSCs, and suggest a possibility that the levels of glucose in the tumor microenvironment might significantly affect CSCs.…”

Section: Discussionsupporting

confidence: 83%

Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway

et al. 2013

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Side population (SP) cells within tumors are a small fraction of cancer cells with stem-like properties that can be identified by flow cytometry analysis based on their high ability to export certain compounds such as Hoechst 33342 and chemotherapeutic agents. The existence of stem-like SP cells in tumors is considered as a key factor contributing to drug resistance, and presents a major challenge in cancer treatment. Although it has been recognized for some time that tumor tissue niches may significantly affect cancer stem cells (CSCs), the role of key nutrients such as glucose in the microenvironment in affecting stem-like cancer cells and their metabolism largely remains elusive. Here we report that SP cells isolated from human cancer cells exhibit higher glycolytic activity compared to non-SP cells. Glucose in the culture environment exerts a profound effect on SP cells as evidenced by its ability to induce a significant increase in the percentage of SP cells in the overall cancer cell population, and glucose starvation causes a rapid depletion of SP cells. Mechanistically, glucose upregulates the SP fraction through ATP-mediated suppression of AMPK and activation of the Akt pathway, leading to elevated expression of the ATP-dependent efflux pump ABCG2. Importantly, inhibition of glycolysis by 3-BrOP significantly reduces SP cells in vitro and impairs their ability to form tumors in vivo. Our data suggest that glucose is an essential regulator of SP cells mediated by the Akt pathway, and targeting glycolysis may eliminate the drug-resistant SP cells with potentially significant benefits in cancer treatment. Accumulating evidence suggests that tumors of various tissue origins, including the brain, breast, and lung, contain a small subpopulation of special cells with stem-like properties, often referred to as cancer stem cells (CSCs) or tumor-initiating cells. [1][2][3][4][5][6][7] In addition to the ability of CSCs to self-renew and initiate tumor formation, one important biochemical feature of CSCs is their ability to export certain toxic compounds and resistance to many chemotherapeutic agents due in part to their high expression of ATP-dependent efflux pump ABCG2, their increased DNA repair capacity, and activation of survival pathways. [8][9][10] The increase in expression of ABCG2 also confers CSCs the ability to effectively export the DNA-binding dye Hoechst 33342 out of the cells, leading to a low retention of the fluorescent signal in these cells, which appear at the low-left corner in flow cytometry analysis and thus are known as 'side population' or SP cells. 2,11 As SP cells can be readily identified by flow cytometry in a quantitative manner, the measurement of SP cells has been widely used as a quantitative assay for the relative number (%) of stem-like cancer cells in the bulk of the overall cancer cell population. Importantly, as this assay is functionally based on the ability of SP cells to export Hoechst 33342 and certain toxic compounds, it is also a quantitative analysis of the subpopulatio...

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Section: Discussionsupporting

confidence: 83%

Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway

et al. 2013

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“…3BP can decrease the level of glycolysis end products e.g. lactate (Nakano et al 2011) and exert antagonistic effects to both pyruvate and lactate which may be critical for cancer cell survival and migration. As metastatic potential is an important feature of aggressive malignant tumors which represents an important cause of death due to cancer disease, we investigated the effects of exogenous pyruvate and lactate on the migratory power of C6 glioma cells.…”

Section: Resultsmentioning

confidence: 99%

3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects

Sayed

El-Magd

Shishido

et al. 2012

J Bioenerg Biomembr

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Oxidative stress-energy depletion therapy using oxidative stress induced by D-amino acid oxidase (DAO) and energy depletion induced by 3-bromopyruvate (3BP) was reported recently (El Sayed et al., Cancer Gene Ther., 19, 1-18, 2012). Even in the presence of oxygen, cancer cells oxidize glucose preferentially to produce lactate (Warburg effect) which seems vital for cancer microenvironment and progression. 3BP is a closely related structure to lactate and pyruvate and may antagonize their effects as a novel mechanism of its action. Pyruvate exerted a potent H(2)O(2) scavenging effect to exogenous H(2)O(2), while lactate had no scavenging effect. 3BP induced H(2)O(2) production. Pyruvate protected against H(2)O(2)-induced C6 glioma cell death, 3BP-induced C6 glioma cell death but not against DAO/D-serine-induced cell death, while lactate had no protecting effect. Lactate and pyruvate protected against 3BP-induced C6 glioma cell death and energy depletion which were overcome with higher doses of 3BP. Lactate and pyruvate enhanced migratory power of C6 glioma which was blocked by 3BP. Pyruvate and lactate did not protect against C6 glioma cell death induced by other glycolytic inhibitors e.g. citrate (inhibitor of phosphofructokinase) and sodium fluoride (inhibitor of enolase). Serial doses of 3BP were synergistic with citrate in decreasing viability of C6 glioma cells and spheroids. Glycolysis subjected to double inhibition using 3BP with citrate depleted ATP, clonogenic power and migratory power of C6 glioma cells. 3BP induced a caspase-dependent cell death in C6 glioma. 3BP was powerful in decreasing viability of human glioblastoma multiforme cells (U373MG) and C6 glioma in a dose- and time-dependent manner.

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“…3-Bromopyruvate (3-BrPA), a member of this new class of anticancer drugs, is a specific alkylating agent and a potent ATP inhibitor, which blocks glycolytic tumor metabolism (6). Malignant cells generate a large amount of ATP via glycolysis (7,8) and 3-BrPA has been shown to interrupt the glycolytic metabolic pathway, leading to the death of the tumor cells through apoptosis (9) with almost no damage to the surrounding normal tissues. It has been experimentally used to target hexokinase/glycolysis and possesses chemical and structural properties that are very similar to the acid, lactic acid and glucose metabolic products of glycolysis.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of 3-bromopyruvate in human nasopharyngeal carcinoma cells

et al. 2015

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Abstract. Tumor cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, which is therefore targeted by therapeutic agents. The compound 3-bromopyruvate (3-BrPA), a strong alkylating agent and hexokinase inhibitor, inhibits tumor cell glycolysis and the production of ATP, causing apoptosis. 3-BrPA induces apoptosis of nasopharyngeal carcinoma (NPC) cell lines HNE1 and CNE-2Z, which may be related to its molecular mechanisms. In the present study, we investigated the effects of 3-BrPA on the viability, reactive oxygen species (ROS), apoptosis and other types of programmed cell death in NPC cells in vitro and in vivo. PI staining showed significant apoptosis in NPC cells accompanied by the overproduction of ROS and downregulation of mitochondrial membrane potential (MMP, ΔΨm) by 3-BrPA. However, the ROS scavenger N-acetyl-L-cysteine (NAC) significantly reduced 3-BrPA-induced apoptosis by decreasing ROS and facilitating the recovery of MMP. We elucidated the molecular mechanisms underlying 3-BrPA activity and found that it caused mitochondrial dysfunction and ROS production, leading to necroptosis of NPC cells. We investigated the effects of the caspase inhibitor z-VAD-fmk, which inhibits apoptosis but promotes death domain receptor (DR)-induced NPC cell necrosis. Necrostatin-1 (Nec-1) inhibits necroptosis, apparently via a DR signaling pathway and thus abrogates the effects of z-VAD-fmk. In addition, we demonstrated the effective attenuation of 3-BrPA-induced necrotic cell death by Nec-1. Finally, animal studies proved that 3-BrPA exhibited significant antitumor activity in nude mice. The present study is the first demonstration of 3-BrPA-induced non-apoptotic necroptosis and ROS generation in NPC cells and provides potential strategies for developing agents against apoptosis-resistant cancers.

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Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells

Cited by 94 publications

References 33 publications

Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway

Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway

3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects

Inhibitory effects of 3-bromopyruvate in human nasopharyngeal carcinoma cells

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