Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

Vali, Mustafa; Vossen, Josephina A.; Buijs, Manon; Engles, James; Liapi, Eleni; Ventura, Veronica Prieto; Khwaja, Afsheen; Acha-Ngwodo, Obele; Shanmugasundaram, Ganapathy; Syed, Labiq H.; Wahl, Richard L.; Geschwind, Jean François H.

doi:10.1124/jpet.108.141093

Cited by 34 publications

(24 citation statements)

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“…The effects on HK, GAPDH, SDH and vacuolar H + ATPase mentioned above were observed in rat liver mitochondria and in normal rat thymocytes (Dell'Antone 2009); it was indeed proposed that above 20-30 μM, 3-BP may lead to severe toxic side effects (Dell'Antone 2006). Direct effects on highly ATPdependent spermatozoa have been reported (Jones et al 1996;Kumar et al 2008), and on similarly ATP-dependent kidney proximal tubule cells (Jones et al 1996); these findings are in line with effects on mitochondria and with increased uptake of FDG in liver and kidney (Vali et al 2008;Buijs et al 2009). Clearly, more investigation of 3-BP effects on normal cells is warranted.…”

Section: Tumor Specificity In Vivo Studies and Toxicitysupporting

confidence: 71%

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3-bromopyruvate: Targets and outcomes

Shoshan

2012

J Bioenerg Biomembr

130

100

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The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.

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Section: Tumor Specificity In Vivo Studies and Toxicitysupporting

confidence: 71%

“…Error bars represent S.E.M. If absent, they were smaller than the symbol (Vali et al 2008). When intravenous and intraarterial administration were compared (3-BP at 1.75 mM; 25 mL), the latter route of delivery resulted in a better biodistribution profile (Vali et al 2008).…”

Section: Tumor Specificity In Vivo Studies and Toxicitymentioning

confidence: 98%

3-bromopyruvate: Targets and outcomes

Shoshan

2012

J Bioenerg Biomembr

130

100

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“…First, our sample size was relatively small, so further studies with a larger sample size are needed to confirm our conclusions. However, our results are in line with previous studies on intra-arterial therapy with 3-BrPA [14,26]. Second, the VX2 tumor used in our study is of non-hepatic origin.…”

Section: Discussionsupporting

confidence: 91%

Development of a new orthotopic animal model of metastatic liver cancer in the rabbit VX2 model: effect on metastases after partial hepatectomy, intra-arterial treatment with 3-bromopyruvate and chemoembolization

Vossen

Buijs

Syed

et al. 2008

Clin Exp Metastasis

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“…DOI 10.1002/em Targeting Mitochondria for Cancer Therapy3-Bromopyruvate 3-Bromopyruvate (3-BP) is an alkylating agent with multiple enzyme targets, including hexokinase, glyceraldehyde 3-phosphate dehydrogenase, and succinate dehydrogenase [Sanborn et al, 1971;Ko et al, 2001;Pereira da Silva et al, 2009]. Local administration of 3-BP by intraperitoneal or direct intratumoral injection [Ko et al, 2004] or as an intraarterial infusion [Vali et al, 2008] resulted in longterm control of transplantable epidermoid tumors. Increased expression and mitochondrial localization of hexokinase II in cancers has been proposed to selectively sensitize tumors to 3-BP [Mathupala et al, 2006].…”

Section: Dichloroacetatementioning

confidence: 99%

Targeting mitochondria for cancer therapy

Hockenbery

2010

Environ and Mol Mutagen

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Several recent insights into the roles of mitochondria in cancer have renewed efforts to develop nongenotoxic therapies targeting mitochondrial proteins and functions. Mitochondria are central hubs for intrinsic apoptotic pathways that are activated by cellular stress and injury, and as a consequence, cancers often have defects in these pathways. Bcl-2, the first identified regulator of apoptotic cell deaths, was discovered as an oncogene in human cancers. BCL-2 inhibits mitochondrial pathways of apoptosis through local effects at mitochondrial and endoplasmic reticulum membranes. Increased expression of BCL-2 and the related antiapoptotic proteins BCL-X(L), MCL-1, and BCL-W occurs in significant subsets of common cancer types (Table I) and is generally correlated with poor response. Although incomplete, the emerging understanding of BCL-2 functions through structural, biochemical, and organelle physiology studies has provided paths for targeting BCL-2 with small molecules. Cancer cells also exhibit metabolic differences with their normal cell counterparts, including aerobic glycolysis, known as the Warburg effect, mitochondrial membrane hyperpolarization, and unusual dependence on nutrient substrates such as glucose and glutamine. This knowledge has prompted reexamination of the potential cancer selectivity of previously identified mitochondriotoxic compounds, including approved drugs for other indications, and screening programs to identify new compounds with mitochondrial activities.

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Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

Cited by 34 publications

References 18 publications

3-bromopyruvate: Targets and outcomes

3-bromopyruvate: Targets and outcomes

Development of a new orthotopic animal model of metastatic liver cancer in the rabbit VX2 model: effect on metastases after partial hepatectomy, intra-arterial treatment with 3-bromopyruvate and chemoembolization

Targeting mitochondria for cancer therapy

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