Targeting cancer metabolism: a therapeutic window opens

Heiden, Matthew G. Vander

doi:10.1038/nrd3504

Cited by 1,280 publications

(1,116 citation statements)

References 161 publications

Supporting

Mentioning

1,092

Contrasting

Unclassified

Order By: Relevance

“…In summary, the present results support the hypothesis that targeting cancer metabolism by simultaneously inhibiting 3 key metabolic pathways may actually have a wide therapeutic window (26), as no unacceptable effects in mice were observed when treated at translated doses slightly below to those used in patients for LND and DON administered separately. Notably, DON and LND are drugs that are currently being re-studied (27)(28)(29), while formulations of orlistat suitable for systemic administration have been investigated (19).…”

Section: Discussionsupporting

confidence: 74%

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

et al. 2017

View full text Add to dashboard Cite

Abstract. The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6-diazo-5-oxo-L-norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21-day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21.The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy. IntroductionCancer cells commonly exhibit a malignant metabolic phenotype, which is characterized by increased rates of glycolysis, glutaminolysis and de novo synthesis of fatty acids (FAs) compared with normal cells. These metabolic alterations result from diverse gain-of-function mutations in oncogenes and loss-of-function of tumor suppressor genes, which aid cancer cells to thrive under various environmental conditions (1).Glucose and glutamine supply the majority of the necessary carbon and nitrogen for the synthesis of macromolecules, energy and reducing equivalents to support cell growth through glycolysis and glutaminolysis (2). Lipogenesis is a third metabolic feature of cancer. In general, malignant cells synthetize de novo FAs instead of taking them up from the circulation, and malignant cells frequently overexpress FA synthase (FASN) (3). For de novo synthesis of FAs, glucose and glutamine supply citrate. Glucose is converted to acetyl-coenzyme A (CoA) in the mitochondrial matrix to synthesize citrate in the tricarboxylic acid (TCA) cycle, whereas glutamine supplies carbon in the form of mitochondrial oxaloacetate to maintain citrate production in the first step of the TCA cycle (4). Thus, the metabolism of glutamine and glucose is orchestrated to support the production of acetyl-CoA and NADPH required for fatty acid synthesis (4).Despite the strong ratio...

show abstract

Section: Discussionsupporting

confidence: 74%

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…33 In addition, clinical studies also have provided evidence of a close relationship between altered cellular metabolism and the cancer outcome. 34 Reactive oxygen species (ROS), which are generated by mitochondrial oxidative phosphorylation, was reported to limit the life span of HSCs. 35 However, mitochondrial ROS levels in HSCs were not increased before the development of disease by the overexpression of Fbxl10, as examined by flow cytometry using a fluorogenic molecular probe (supplemental Figure 8).…”

Section: Discussionmentioning

confidence: 99%

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Ueda¹,

Nagamachi

Takubo

et al. 2015

Blood

View full text Add to dashboard Cite

• Fbxl10 is a bona fide oncogene in vivo. • Fbxl10 overexpression inHSCs induces mitochondrial metabolic activation and enhanced expression of Nsg2.We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for 27/7q2 syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446) IntroductionAppropriate patterns of epigenetic alterations in histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases such as cancer. 1 We previously generated knockout mice for Samd9L (which was cloned as a candidate gene for the 27/7q2 syndrome frequently that is observed in myelodysplastic syndrome and acute leukemia patients) and demonstrated that mice deficient in Samd9L developed leukemia after a long latent period. 2 In addition, retroviral insertional mutagenesis revealed that the onset of the disease was highly accelerated with upregulation of F-box and leucine-rich repeat protein 10 (Fbxl10) or ectopic virus integration 1 (Evi1). 2 Clinically, an elevated expression of Fbxl10 is observed in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), seminoma, and pancreatic ductal adenocarcinoma. [3][4][5][6] These findings prompted us to further investigate the role of Fbxl10 in leukemia development in vivo.Fbxl10 belongs to the JmjC domain-containing histone demethylases, and contains an N-terminal JmjC domain, followed by a CXXC zinc finger domain, a plant homeodomain finger, an F-box, and 8 leucine-rich repeats. 7 Fbxl10 preferentially demethylates the dimethylation of histone H3 at lysine 36 (H3K36me2), but not H3K36me1 and H3K36me3. 6,8 Fbxl10 was also recently reported to mediate the monoubiquitination of t...

show abstract

“…the Warburg effect. Indeed, it has been suggested that specifically targeting cancer cell metabolism may reveal therapeutic opportunities (Vander Heiden 2011). Most tumour cells are predominantly glycolytic for ATP supply and provision in metabolic precursors for macromolecule biosynthesis, whereas in terminally differentiated fibroblasts, where biosynthetic demands are lower, ATP synthesis is predominantly mitochondrial in origin, as outlined by Warburg so many years ago.…”

Section: Introductionmentioning

confidence: 99%

Carnosine and cancer: a perspective

Gaunitz

Hipkiss

2012

Amino Acids

View full text Add to dashboard Cite

The application of carnosine in medicine has been discussed since several years, but many claims of therapeutic effects have not been substantiated by rigorous experimental examination. In the present perspective, a possible use of carnosine as an anti-neoplastic therapeutic, especially for the treatment of malignant brain tumours such as glioblastoma is discussed. Possible mechanisms by which carnosine may perform its anti-tumourigenic effects are outlined and its expected bioavailability and possible negative and positive side effects are considered. Finally, alternative strategies are examined such as treatment with other dipeptides or b-alanine.

show abstract

Targeting cancer metabolism: a therapeutic window opens

Cited by 1,280 publications

References 161 publications

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Carnosine and cancer: a perspective

Contact Info

Product

Resources

About