Detachment of glycolytic enzymes from cytoskeleton of Lewis lung carcinoma and colon adenocarcinoma cells induced by clotrimazole and its correlation to cell viability and morphology

Penso, Julia; Beitner, Rivka

doi:10.1016/s1096-7192(02)00046-x

Cited by 45 publications

(36 citation statements)

References 44 publications

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“…As a third in vivo cancer model, we used LL/2 lung carcinoma because it was demonstrated that the viability of these cells was strongly hampered following a reduction of activity of the glycolytic enzymes caused by clotrimazole treatment (45,46). Thus, LL/2 (Lewis) carcinoma cells were implanted in C57BL/6 mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Schwartz¹

2010

Oncol Rep

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Abstract. The impact of metabolic dysregulation on tumor development has long been established. We have targeted two enzymes that are altered during carcinogenesis: pyruvate dehydrogenase (PDH), which is down-regulated, and ATP citrate lyase, which is overexpressed in cancer cells. Alpha lipoic acid is a cofactor of PDH, while hydroxycitrate is a known inhibitor of ATP citrate lyase. Our hypothesis is that a combination of these drugs may have antitumoral potential. The efficacy of these molecules was screened in vitro by treatment of different human cancer and murine cell lines. Lipoic acid reduced the cell number by 10-50% depending on concentrations (0.1-10 μM) and cell types. Calcium hydroxycitrate reduced the cell number by 5-60% at different concentrations (10-500 μM). When hydroxycitrate and lipoic acid were used together, there was a major cytotoxic effect: complete cell death was seen following 8 μM lipoic acid and 300 μM hydroxycitrate treatment for 72 h. The combination of alpha lipoic acid and hydroxycitrate was administered to healthy mice, at doses currently utilized for other indications than cancer; no demonstrable toxicity was observed. The combination was used to treat mouse syngenic cancer models: MBT-2 bladder transitional cell carcinoma, B16-F10 melanoma and LL/2 Lewis lung carcinoma. The efficacy of this combination appears similar to conventional chemotherapy (cisplatin or 5-fluorouracil) as it resulted in significant tumor growth retardation and enhanced survival. This preliminary study suggests that this combination of drugs is efficient against cancer cell proliferation both in vitro and in vivo. A clinical trial is warranted.

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Section: Resultsmentioning

confidence: 99%

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Schwartz¹

2010

Oncol Rep

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“…It has been stated that in conditions that glycolysis occurs at elevated rates, such as cancer, the particulate fraction of glycolytic enzyme, that is the fractions of these enzymes that are associated to intracellular ultrastructures, increases (17,41). Additionally, the detachment of these enzymes from intracellular ultrastructures has been proved to the lethal to tumor cells and is proposed as a target for anticancer drugs development (41,50,51,(54)(55)(56)(57). Similarly, promoting the association of glycolytic enzymes, these intracellular ultrastructures might be a possible mechanism for the prevention of complications associated to DM owing to the diminished glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Silva¹,

Ausina²,

Alencar³

et al. 2012

IUBMB Life

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SummaryDiabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects.

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“…Clotrimazole (Fig. 3) induced HK detachment from mitochondria in B16 melanoma cells, but also detached PFK-1 and ALD from the cytoskeleton in mouse LL/2 Lewis lung cancer cells, leading to diminished G6P, F1,6BP, and ATP levels, and glycolytic flux [78]. Clotrimazole reduces cellular proliferation and viability of human CT-26 colon, Lewis lung and breast MCF-7 carcinomas (IC 50 = 50-80 M) [78,79]; and the size and development of intracranial gliomas (C6 and 9L), prolonging survival in rodents [80].…”

Section: Hexokinase (Hk)mentioning

confidence: 97%

HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

Marín‐Hernández¹,

Gallardo‐Pérez²,

Ralph³

et al. 2009

MRMC

389

287

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To develop new and more efficient anti-cancer strategies it will be important to characterize the products of transcription factor activity essential for tumorigenesis. One such factor is hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by low oxygen conditions and found in high levels in malignant solid tumors, but not in normal tissues or slow-growing tumors. In fast-growing tumors, HIF-1alpha is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps, vascular remodeling and angiogenesis as well as metastasis. In cancer cells, HIF-1alpha induces over-expression and increased activity of several glycolytic protein isoforms that differ from those found in non-malignant cells, including transporters (GLUT1, GLUT3) and enzymes (HKI, HKII, PFK-L, ALD-A, ALD-C, PGK1, ENO-alpha, PYK-M2, LDH-A, PFKFB-3). The enhanced tumor glycolytic flux triggered by HIF-1alpha also involves changes in the kinetic patterns of expressed isoforms of key glycolytic enzymes. The HIF-1alpha induced isoforms provide cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmax(f)) in forward reactions because of marked over-expression compared to those isoforms expressed in normal tissues. Some of the HIF1alpha-induced glycolytic isoforms also participate in survival pathways, including transcriptional activation of H2B histone (by LDH-A), inhibition of apoptosis (by HKII) and promotion of cell migration (by ENO-alpha). HIF-1alpha action may also modulate mitochondrial function and oxygen consumption by inactivating the pyruvate dehydrogenase complex in some tumor types, or by modulating cytochrome c oxidase subunit 4 expression to increase oxidative phosphorylation in other cancer cell lines. In this review, the roles of HIF-1alpha and HIF1alpha-induced glycolytic enzymes are examined and it is concluded that targeting the HIF1alpha-induced glucose transporter and hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting tumor growth and progression than targeting HIF1alpha itself.

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Detachment of glycolytic enzymes from cytoskeleton of Lewis lung carcinoma and colon adenocarcinoma cells induced by clotrimazole and its correlation to cell viability and morphology

Cited by 45 publications

References 44 publications

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

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Detachment of glycolytic enzymes from cytoskeleton of Lewis lung carcinoma and colon adenocarcinoma cells induced by clotrimazole and its correlation to cell viability and morphology

Cited by 45 publications

References 44 publications

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

HIF-1&#945; Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

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HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms