Transport of the new chemotherapeutic agent β-
            <scp>d</scp>
            -glucosylisophosphoramide mustard (D-19575) into tumor cells  is mediated by the Na
            <sup>+</sup>
            -
            <scp>d</scp>
            -glucose cotransporter SAAT1

Veyhl, Maike; Wagner, Katharina; Volk, Christopher; Gorboulev, Valentin; Baumgarten, Katharina; Weber, Wolf-Michael; Schaper, Marianne; Bertram, Barbara; Wießler, Manfred; Koepsell, Hermann

doi:10.1073/pnas.95.6.2914

Cited by 69 publications

(39 citation statements)

References 28 publications

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“…In vitro data suggested that a low-affinity Na + /glucose cotransporter transports glufosfamide into tumor cells, and that the drug accumulates in the cells. 30) In that study, the doselimiting toxicity of glufosfamide was nephrotoxicity, which may be due to the presence of Na + /glucose cotransporters in the proximal tubule of the kidney. Further, inhibition of glucose uptake and glucose deprivation have been shown to induce apoptosis, which was blocked by Bcl-2 expression in the cells but appeared to be independent of wild-type p53 activity.…”

Section: Discussionmentioning

confidence: 99%

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

Ishikawa

Oguri

Isobe

et al. 2001

Japanese Journal of Cancer Research

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Cancer cells show increased glucose uptake and utilization in comparison with their normal counterparts. Glucose transporters play an important role in glucose uptake. We previously reported the differential gene expression of the GLUT family in primary and metastatic lesions of lung cancer. To investigate the role of Na + /glucose cotransporter (SGLT) genes in cancers, we examined the levels of expression of SGLT1 and SGLT2 genes in primary lung cancers and their metastatic lesions. Ninety-six autopsy samples (35 primary lung cancers, 35 corresponding normal lung tissues, 10 metastatic liver lesions, and 16 metastatic lymph nodes) from 35 patients were analyzed for SGLT1 and SGLT2 expression by reverse transcription (RT)-polymerase chain reaction (PCR). There were no significant differences in the level of expression of either gene between the primary lung cancers and normal lung tissues. The level of SGLT1 expression in the metastatic lesions and primary lung cancers did not differ significantly. The level of SGLT2 expression was, however, significantly higher in the metastatic lesions of both the liver and lymph node than in the primary lung cancers. These results suggest that SGLT2 plays a role in glucose uptake in the metastatic lesions of lung cancer. Key words: SGLT1 -SGLT2 -Lung cancerGlucose is a basic source of energy in mammalian cells. Cancer cells show increased glucose uptake and utilization relative to their normal counterparts.1-3) Two classes of glucose transporters have been described in mammalian cells. 4,5) One class is the facilitative glucose transporter (GLUT) family, which mediates the energy-independent transport of glucose. There are five functional isoforms of GLUT (GLUT1-GLUT5). The five transporters have different functions and distribution in human tissues. The second class is the Na + /glucose cotransporter (SGLT) family, which utilizes the electrochemical sodium gradient to transport glucose against the cell's internal concentration gradient. 4,5) Two isoforms (SGLT1 and SGLT2) have been cloned in mammalian cells.6, 7) SGLT1 is strongly expressed in the small intestine, and is expressed at lower levels in the kidneys, liver, and lungs. 8) In contrast to SGLT1, the kidneys express a high level of SGLT2, and the small intestine does not. 9)Previous studies have demonstrated the overexpression of GLUT1 in various human cancers relative to normal tissues.10) In addition, increased GLUT3 expression has been found in several cancers.11) Overexpression of GLUT5 was found in breast cancers.12) On the other hand, the expression of SGLT genes in cancers has not been studied, and the role of SGLT genes is still unclear in cancers.Recently, we studied the expression of genes belonging to the GLUT family in lung cancers and their metastatic lesions.13) Our results showed the differential expression of GLUT genes in primary lung cancers and their metastatic lesions. To investigate the role of the SGLT family in cancers, we examined the expression levels of SGLT1 and SGLT2 in primary lung cancer...

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Section: Discussionmentioning

confidence: 99%

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

Ishikawa

Oguri

Isobe

et al. 2001

Japanese Journal of Cancer Research

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“…IPM is subject to transport by a sodium-dependent glucose transporter (SAAT1), which is a member of a family of sodiumdependent glucose co-transporters (SGLTs) 43 and thus is supposed to accumulate in tumor tissue, which frequently over-expresses glucose-transport systems. Glufosfamide proved to be as active as ifosfamide but caused fewer side effects.…”

Section: Discussionmentioning

confidence: 99%

Inactivation ofO6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors

Reinhard

Eichhorn²,

Wießler

et al. 2001

Int. J. Cancer

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Methylating and chloroethylating agents have been used in the therapy of various kinds of cancer for a decade. 1 Methylating drugs (e.g., procarbazine, dacarbazine, streptozotocin and temozolomide) and chloroethylating agents (e.g., carmustine, lomustine, semustine and fotemustine) alkylate DNA at various sites, among them the O 6 position of guanine. The resulting DNA lesions, i.e., O 6 -methylguanine and O 6 -chloroethylguanine, are highly pro-mutagenic 2 and pro-carcinogenic 3,4 and act as a trigger of cytotoxicity 5,6 and apoptosis. 7,8 Cytotoxicity and apoptosis caused by O 6 -methylguanine are mediated by mismatch repair, 9,10 whereas when caused by O 6 -chloroethylguanine the result is chemical re-arrangement of the chloroethyl group forming cross-links between N1 of guanine and N3 of cytosine. 11 These cross-links are supposed to block DNA replication and trigger the cytotoxic response.The primary cytotoxic lesions O 6 -methylguanine and O 6 -chloroethylguanine are subject to repair by the DNA-repair protein O 6 -methylguanine-DNA methyltransferase (MGMT; also designated alkyltransferase), which transfers the alkyl group from the O 6 position of guanine onto an internal cysteine residue in its active site, leading to an alkylthioether that cannot be re-activated. Thus, guanine in the DNA is restored and the MGMT molecule inactivated. Due to the suicide mechanism of action, the repair reaction is stoichiometric, depending on the initial number of MGMT molecules per cell and the rate of resynthesis upon alkylation. 12,13 The MGMT-repair protein plays a key role in the resistance of tumor cells to methylating and chloroethylating drugs. This has been demonstrated by comparison of naturally occurring tumor cell variants, 14 by transfection experiments in which MGMT was over-expressed, 6 by MGMT knockout strategies 15 and by MGMTdepletion experiments with anti-sense oligonucleotides 16 or specific inhibitors. 17,18 In isogenic cell lines transfected with MGMT cDNA, the level of resistance was a linear function of cellular MGMT activity up to a maximal saturation level, where nonspecific effects of the drugs come into play. A significant protective effect of MGMT can be achieved with quite low expression levels. 6

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“…In a phase I trial of the alkylating agent glufosfamide, one patient with pancreatic cancer had a full response while two colon cancer patients and one breast cancer patient had partial responses (Briasoulis et al, 2000). It was shown previously that glufosfamide enters cells via SAAT1, a low-affinity sodium/glucose cotransporter (Veyhl et al, 1998), though other glucose transporters may also facilitate uptake of this compound. Inhibitors of glucose uptake that act by reducing GLUT activity are also being investigated.…”

Section: Implications and Conclusionmentioning

confidence: 99%

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

Macheda

Rogers

Best

2004

Journal Cellular Physiology

1,055

893

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Malignant cells are known to have accelerated metabolism, high glucose requirements, and increased glucose uptake. Transport of glucose across the plasma membrane of mammalian cells is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose transport in malignant cells has been associated with increased and deregulated expression of glucose transporter proteins, with overexpression of GLUT1 and/or GLUT3 a characteristic feature. Oncogenic transformation of cultured mammalian cells causes a rapid increase of glucose transport and GLUT1 expression via interaction with GLUT1 promoter enhancer elements. In human studies, high levels of GLUT1 expression in tumors have been associated with poor survival. Studies indicate that glucose transport in breast cancer is not fully explained by GLUT1 or GLUT3 expression, suggesting involvement of another glucose transporter. Recently, a novel glucose transporter protein, GLUT12, has been found in breast and prostate cancers. In human breast and prostate tumors and cultured cells, GLUT12 is located intracellularly and at the cell surface. Trafficking of GLUT12 to the plasma membrane could therefore contribute to glucose uptake. Several factors have been implicated in the regulation of glucose transporter expression in breast cancer. Hypoxia can increase GLUT1 levels and glucose uptake. Estradiol and epidermal growth factor, both of which can play a role in breast cancer cell growth, increase glucose consumption. Estradiol and epidermal growth factor also increase GLUT12 protein levels in cultured breast cancer cells. Targeting GLUT12 could provide novel methods for detection and treatment of breast and prostate cancer.

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Transport of the new chemotherapeutic agent β- d -glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na ⁺ - d -glucose cotransporter SAAT1

Cited by 69 publications

References 28 publications

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

Inactivation ofO6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

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Transport of the new chemotherapeutic agent β- d -glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na + - d -glucose cotransporter SAAT1

Cited by 69 publications

References 28 publications

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

Inactivation ofO6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

Contact Info

Product

Resources

About

Transport of the new chemotherapeutic agent β- d -glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na ⁺ - d -glucose cotransporter SAAT1