Systemic Delivery of Microencapsulated 3-Bromopyruvate for the Therapy of Pancreatic Cancer

Chapiro, Julius; Sur, Surojit; Savic, Lynn Jeanette; Ganapathy-Kanniappan, Shanmugasundaram; Reyes, Juvenal; Duran, Rafael de Llorens; Chettiar, Sivarajan T.; Moats, Cassandra Rae; Lin, Ming De; Luo, Weibo; Tran, Phuoc T.; Herman, Joseph M.; Semenza, Gregg L.; Ewald, Andrew J.; Vogelstein, Bert; Geschwind, Jean François H.

doi:10.1158/1078-0432.ccr-14-1271

Cited by 54 publications

(34 citation statements)

References 43 publications

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“…Our results thus provide proof of concept that 3-BrPA could be employed to selectively eradicate MYC-overexpressing tumors given that formulated 3-BrPA without a prominent systemic toxicity is being developed. 36 MCT1-4, which mediate lactate efflux and maintain these glycolytic rates, are frequently overexpressed in different cancer types. Although MCT4 is transcriptionally activated by hypoxiainducible factor-1α, 37 much less is known about the regulation of other MCTs.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters

et al. 2015

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Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5]36,[53][54][55] shRNA analysis Specific shRNAs against human N-Myc and a control shRNA were purchased from Sigma (St Louis, MO, USA). Lentiviral production and infection were performed using a standard protocol from Addgene (www.addgene.com).…”

Section: Discussionmentioning

confidence: 99%

Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters

et al. 2015

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“…The pyruvate analog, 3-bromopyruvate (3-BrPA) is an energy blocker that has been validated for the treatment of multiple types of malignancies (refer reviews [9,10]). Recently, we developed a microencapsulated formulation of 3-BrPA using β-cyclodextrin (β-CD) which is relevant for systemic delivery [11]. The aim of the current study is to determine the effects of sublethal dose of 3-BrPA on activated-HSCs in vitro and in vivo , and to validate that targeting energy metabolism is a rational and viable strategy to treat liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model

Karthikeyan

Potter

Geschwind

et al. 2016

Biochemical and Biophysical Research Communications

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Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.

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“…This finding suggests potential benefits of dual targeting of glycolysis enzymes and PI3K/Akt-mediated cellular metabolism. 3-BrPA has been FDA approved for phase I clinical trials as a selective glycolysis inhibitor [288–290] and was shown to induce ER stress, inhibit global protein synthesis and thereby induce tumor cell death [291]. Attempts have also been made to target phosphofructokinase, particularly PFKB3, the isoform commonly upregulated in cancers.…”

Section: Current Therapeutic Options In Targeting Tumor Metabolismmentioning

confidence: 99%

Adipose tissue dysfunction and its effects on tumor metabolism

Diedrich¹,

Gusky²,

Podgorski³

2015

Hormone Molecular Biology and Clinical Investigation

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Growing by an alarming rate in the Western world, obesity has become a condition associated with a multitude of diseases such as diabetes, metabolic syndrome and various cancers. Generally viewed as an abnormal accumulation of hypertrophied adipocytes, obesity is also a poor prognostic factor for recurrence and chemoresistance in cancer patients. With more than two-thirds of the adult population in the United States considered clinically overweight or obese, it is critical that the relationship between obesity and cancer is further emphasized and elucidated. Adipocytes are highly metabolically active cells, which, through release of adipokines and cytokines and activation of endocrine and paracrine pathways, affect processes in neighboring and distant cells, altering their normal homeostasis. This work will examine specifically how adipocyte-derived factors regulate the cellular metabolism of malignant cells within the tumor niche. Briefly, tumor cells undergo metabolic pressure towards a more glycolytic and hypoxic state through a variety of metabolic regulators and signaling pathways, i.e., phosphoinositol-3 kinase (PI3K), hypoxia-inducible factor-1 alpha (HIF-1α), and c-MYC signaling. Enhanced glycolysis and high lactate production are hallmarks of tumor progression largely because of a process known as the Warburg effect. Herein, we review the latest literature pertaining to the body of work on the interactions between adipose and tumor cells, and underlining the changes in cancer cell metabolism that have been targeted by the currently available treatments.

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Systemic Delivery of Microencapsulated 3-Bromopyruvate for the Therapy of Pancreatic Cancer

Cited by 54 publications

References 43 publications

Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters

Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters

Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model

Adipose tissue dysfunction and its effects on tumor metabolism

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