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Metabolic approaches to breast cancer treatment and prevention

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Standard systemic therapy for breast cancer treatment and prevention are generally directed at reduction in cell growth and increase in apoptosis by direct inhibition of DNA synthesis or signalling pathways that control cell proliferation and cell death... Data are accumulating that calorie restriction (CR) and/or exercise, or agents that target metabolic pathways may have antitumour effects either alone or in combination with standard therapies for cancer prevention and treatment, and merit further investigation... Here, we outline evidence concerning the effectiveness of this approach... Caspase activity assays showed that caspase 9 and 3 are elevated in the mammary tumours of CR rats, as compared with carcinomas from fed animals given free access to food, which implies the mitochondrial pathway of apoptosis is activated by CR... Mechanistic studies on cell proliferation reduction and apoptosis activation are highly important but they do not indicate how a reduction in calories is translated into these effects on mammary tumour cells... Thus, there may be more than one metabolic pathway that mediates CR... In general, breast tumour metabolic pathways appear to be different compared with the normal cells from which they arise... An important advance in our understanding of how cells sense their own energy status was the discovery of adenosine monophosphate-related kinase (AMPK), which is activated when cellular energy levels are reduced (low AMP/ATP ratio)... Activation of AMPK results in reduction in cell synthetic (anabolic) pathways and increase in catabolic pathways and oxidative phosphorylation (to generate ATP), with associated reduction in cell proliferation... For example, inhibition of glycolysis in MCF7 cells with 2-deoxyglucose or of fatty acid synthesis with the fatty acid and synthase inhibitor C93, or stimulation of AMPK synthesis with the antidiabetic drug metformin all inhibit proliferation of human MCF7 cells in vitro... Also, enhancement of TCA cycle activity is associated with inhibition of cell growth... In tumours entry of pyruvate into the TCA cycle may be reduced either by metabolism to lactate or inhibition of pyruvate dehydrogenase by pyruvate dehydrogenase kinase (PDK)... Inhibition of lactate dehydrogenase activity by small interfering RNA or of PDK by 2-chloroacetate stimulates mitochondrial activity and is associated with inhibition of tumour cell growth or direct stimulation of TCA cycle activity using cell-permeating α-ketoglutarate.

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Simplified view of metabolic pathways in tumours. Enhanced pathways are shown as thick lines. Potential inhibitors of glycolysis and lipid synthesis and stimulators of the tricarboxylic acid (TCA) cycle are shown. Calorie restriction would be expected to enhance adenosine monophosphate-related kinase (AMPK) activity, which inhibits lipid synthesis and generally stimulates TCA cycle activity.
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Figure 1: Simplified view of metabolic pathways in tumours. Enhanced pathways are shown as thick lines. Potential inhibitors of glycolysis and lipid synthesis and stimulators of the tricarboxylic acid (TCA) cycle are shown. Calorie restriction would be expected to enhance adenosine monophosphate-related kinase (AMPK) activity, which inhibits lipid synthesis and generally stimulates TCA cycle activity.

Mentions: An important advance in our understanding of how cells sense their own energy status was the discovery of adenosine monophosphate-related kinase (AMPK), which is activated when cellular energy levels are reduced (low AMP/ATP ratio) [13]. Activation of AMPK results in reduction in cell synthetic (anabolic) pathways and increase in catabolic pathways and oxidative phosphorylation (to generate ATP), with associated reduction in cell proliferation. Some metabolic pathways in tumours are shown in Figure 1. Increased glycolysis and lipid synthesis may be thought of as oncogenic and enzymes in the AMPK/tricarboxylic acid (TCA) cycle pathway as tumour suppressors. Indeed, transfection of glycolytic enzymes into normal cells results in immortalization [14], and mutations in components of the LKB1/AMPK pathway result in tumour formation consistent with their tumour suppression function (Figure 1).


Metabolic approaches to breast cancer treatment and prevention
Simplified view of metabolic pathways in tumours. Enhanced pathways are shown as thick lines. Potential inhibitors of glycolysis and lipid synthesis and stimulators of the tricarboxylic acid (TCA) cycle are shown. Calorie restriction would be expected to enhance adenosine monophosphate-related kinase (AMPK) activity, which inhibits lipid synthesis and generally stimulates TCA cycle activity.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2230535&req=5

Figure 1: Simplified view of metabolic pathways in tumours. Enhanced pathways are shown as thick lines. Potential inhibitors of glycolysis and lipid synthesis and stimulators of the tricarboxylic acid (TCA) cycle are shown. Calorie restriction would be expected to enhance adenosine monophosphate-related kinase (AMPK) activity, which inhibits lipid synthesis and generally stimulates TCA cycle activity.
Mentions: An important advance in our understanding of how cells sense their own energy status was the discovery of adenosine monophosphate-related kinase (AMPK), which is activated when cellular energy levels are reduced (low AMP/ATP ratio) [13]. Activation of AMPK results in reduction in cell synthetic (anabolic) pathways and increase in catabolic pathways and oxidative phosphorylation (to generate ATP), with associated reduction in cell proliferation. Some metabolic pathways in tumours are shown in Figure 1. Increased glycolysis and lipid synthesis may be thought of as oncogenic and enzymes in the AMPK/tricarboxylic acid (TCA) cycle pathway as tumour suppressors. Indeed, transfection of glycolytic enzymes into normal cells results in immortalization [14], and mutations in components of the LKB1/AMPK pathway result in tumour formation consistent with their tumour suppression function (Figure 1).

View Article: PubMed Central - HTML

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Standard systemic therapy for breast cancer treatment and prevention are generally directed at reduction in cell growth and increase in apoptosis by direct inhibition of DNA synthesis or signalling pathways that control cell proliferation and cell death... Data are accumulating that calorie restriction (CR) and/or exercise, or agents that target metabolic pathways may have antitumour effects either alone or in combination with standard therapies for cancer prevention and treatment, and merit further investigation... Here, we outline evidence concerning the effectiveness of this approach... Caspase activity assays showed that caspase 9 and 3 are elevated in the mammary tumours of CR rats, as compared with carcinomas from fed animals given free access to food, which implies the mitochondrial pathway of apoptosis is activated by CR... Mechanistic studies on cell proliferation reduction and apoptosis activation are highly important but they do not indicate how a reduction in calories is translated into these effects on mammary tumour cells... Thus, there may be more than one metabolic pathway that mediates CR... In general, breast tumour metabolic pathways appear to be different compared with the normal cells from which they arise... An important advance in our understanding of how cells sense their own energy status was the discovery of adenosine monophosphate-related kinase (AMPK), which is activated when cellular energy levels are reduced (low AMP/ATP ratio)... Activation of AMPK results in reduction in cell synthetic (anabolic) pathways and increase in catabolic pathways and oxidative phosphorylation (to generate ATP), with associated reduction in cell proliferation... For example, inhibition of glycolysis in MCF7 cells with 2-deoxyglucose or of fatty acid synthesis with the fatty acid and synthase inhibitor C93, or stimulation of AMPK synthesis with the antidiabetic drug metformin all inhibit proliferation of human MCF7 cells in vitro... Also, enhancement of TCA cycle activity is associated with inhibition of cell growth... In tumours entry of pyruvate into the TCA cycle may be reduced either by metabolism to lactate or inhibition of pyruvate dehydrogenase by pyruvate dehydrogenase kinase (PDK)... Inhibition of lactate dehydrogenase activity by small interfering RNA or of PDK by 2-chloroacetate stimulates mitochondrial activity and is associated with inhibition of tumour cell growth or direct stimulation of TCA cycle activity using cell-permeating α-ketoglutarate.

No MeSH data available.


Related in: MedlinePlus