The inactivation of succinate dehydrogenase by bromopyruvate

Sanborn, Barbara M.; Felberg, Norman T.; Hollocher, Thomas C.

doi:10.1016/0005-2744(71)90055-6

Cited by 36 publications

(23 citation statements)

References 28 publications

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“…3-BrPA has been reported to inhibit mitochondrial complex II (13,19,20). In line with these data, we found that 3-BrPA elicited a greater inhibition of complex II activity in glutaminestarved cells with respect to glutamine-fed counterparts (Fig.…”

Section: Glutamine Deprivation Potentiates Antitumor Activity Of 3-brpasupporting

confidence: 89%

Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

et al. 2012

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Anticancer drug efficacy might be leveraged by strategies to target certain biochemical adaptations of tumors. Here we show how depriving cancer cells of glutamine can enhance the anticancer properties of 3-bromopyruvate, a halogenated analog of pyruvic acid. Glutamine deprival potentiated 3-bromopyruvate chemotherapy by increasing the stability of the monocarboxylate transporter-1, an effect that sensitized cells to metabolic oxidative stress and autophagic cell death. We further elucidated mechanisms through which resistance to chemopotentiation by glutamine deprival could be circumvented. Overall, our findings offer a preclinical proof-of-concept for how to employ 3-bromopyruvate or other monocarboxylic-based drugs to sensitize tumors to chemotherapy. Cancer Res; 72(17); 4526-36. Ó2012 AACR.

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Section: Glutamine Deprivation Potentiates Antitumor Activity Of 3-brpasupporting

confidence: 89%

Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

et al. 2012

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“…Using high levels of succinate (20 mM) that is capable of entering cells (Spencer, 1977;Maehara et al, 1988) to promote both SDH activity (Maehara et al, 1988;Berridge and Tan, 1993) and mitochondrial respiration proceeding via CII, NeuTL cells were assayed for SDH activity in the presence or absence of a-TOS. The inhibitors of SDH activity, 3BP (Sanborn et al, 1971) and 3-nitropropionic acid (3NPA) (Scallet et al, 2003), were employed as positive controls. To establish the relationship between inhibition of SDH and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, initial experiments with 3BP and 3NPA were performed in the absence of succinate that might otherwise compete for binding to the enzyme, and the results confirmed that 3BP and 3NPA inhibited CII-mediated MTT reduction and that SDH activity and MTT reduction were closely related ( Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

et al. 2008

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a-Tocopheryl succinate (a-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of a-TOS has not been identified. Here, we show that a-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of a-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of a-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to a-TOS. We propose that a-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

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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.…”

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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The inactivation of succinate dehydrogenase by bromopyruvate

Cited by 36 publications

References 28 publications

Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

Targeting mitochondria for cancer therapy

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