Sarah J Welsh

University of Houston, Houston, Texas, United States

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Publications (10)39.24 Total impact

  • Sarah J. Welsh, BM Bch
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    ABSTRACT: Personalized medicine is a model for the way medicine will evolve through the use of specific treatments and therapies best suited to an individual’s genotype. It is driven by patient demand for safer and more effective medicines and therapies. This chapter focuses on the role of personalized medicine in cancer and explores its use in current clinical practice, its likely application in the future, and the challenges to be overcome to achieve this goal. Economic, social, and ethical considerations relating to personalized medicine are also discussed.
    07/2008: pages 411-425;
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    ABSTRACT: We have reported previously that PX-478 (S-2-amino-3-[4'-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1alpha (HIF-1alpha) within the tumor. We now report that PX-478 inhibits HIF-1alpha protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1alpha inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1alpha mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5' untranslated region of HIF-1alpha. Moreover, to a lesser extent, PX-478 also inhibits HIF-1alpha deubiquitination resulting in increased levels of polyubiquitinated HIF-1alpha. The inhibitory effect of PX-478 on HIF-1alpha levels is primarily due to its inhibition of translation because HIF-1alpha translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1alpha at multiple levels that together or individually may contribute to its antitumor activity against HIF-1alpha-expressing tumors.
    Molecular Cancer Therapeutics 02/2008; 7(1):90-100. · 5.60 Impact Factor
  • Sarah J. Welsh, Garth Powis
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    ABSTRACT: Personalized medicine is a model of the way medicine will evolve through the use of specific treatments and therapies best suited to an individual's genotype and is driven by patient demand for safer and more effective medicines and therapies. This chapter focuses on the role of personalized medicine in cancer and explores its use in current clinical practice, its likely application in the future and the challenges which need to be overcome in order to achieve this goal. Economic, social, and ethical considerations relating to personalized medicine are also discussed.
    12/2007: pages 93-107;
  • Sarah J Welsh, Mei Yee Koh, Garth Powis
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    ABSTRACT: All solid tumors experience some degree of hypoxia. The response to the stress of hypoxia is mediated in large part by the hypoxia inducible factor-1 (HIF-1) transcription factor that increases the expression of a variety of genes that allow the tumor to survive and grow in the hostile hypoxic environment. Increased tumor HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis. This has lead to the current interest in HIF-1 as a cancer drug target. HIF-1 activity in tumors depends on the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions or through the activation of oncogenes and/or inactivation of tumor-suppressor genes. HIF-1alpha level and HIF-1 activity are regulated by multiple pathways involving transcription, translation, post-translational modification, and the interaction with other transcription factors. A number of agents have been reported to block HIF-1 activity, acting on all of these mechanisms. Not all of the agents have been shown to block tumor HIF-1 activity in vivo. Some have shown marked HIF-1 inhibition and anti-tumor activity. There are agents already, or soon to be, tested in the clinic as anti-tumor inhibitors of HIF-1. The challenges will be to determine whether the effects of these agents that are seen is due to HIF-1 inhibition and to identify which patients are most likely to benefit from treatment with HIF-1 inhibitors.
    Seminars in Oncology 09/2006; 33(4):486-97. · 4.33 Impact Factor
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    ABSTRACT: Metastatic tumors generally exhibit aerobic glycolysis (the Warburg effect). The advent of [18F]fluorodeoxyglucose positron emission tomography imaging, coupled with recent findings linking hypoxia-inducible factor (HIF-1alpha) overexpression to aggressive cancers, has rekindled an interest in this aspect of tumor metabolism. These studies explore the role of HIF-1alpha in human breast cancer lines and its relationship to glycolytic regulation. Here we demonstrate that, under normal oxygen conditions, nonmetastatic cells consume less glucose and express low HIF-1alpha, whereas metastatic cells constitutively express high glycolysis and HIF-1alpha, suggesting that dysregulation of HIF-1alpha may induce the Warburg effect. This hypothesis was tested by renormalizing HIF-1alpha levels in renal carcinoma cells, leading to inhibition of aerobic glycolysis.
    Neoplasia 05/2005; 7(4):324-30. · 5.47 Impact Factor
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    ABSTRACT: Metastatic tumors generally exhibit aerobic glycolysis (the Warburg effect). The advent of (18F)fluorodeoxy- glucose positron emission tomography imaging, coupled with recent findings linking hypoxia-inducible factor (HIF-1A) overexpression to aggressive cancers, has rekindled an interest in this aspect of tumor metabolism. These studies explore the role of HIF-1A in human breast cancer lines and its relationship to glycolytic regulation. Here we demonstrate that, under normal oxygen conditions, nonmetastatic cells con- sume less glucose and express low HIF-1A, whereas metastatic cells constitutively express high glycolysis and HIF-1A, suggesting that dysregulation of HIF-1A may induce the Warburg effect. This hypothesis was tested by renormalizing HIF-1A levels in renal carci- noma cells, leading to inhibition of aerobic glycolysis. Neoplasia (2005) 7, 324 -330
    Neoplasia. 01/2005; 7(4).
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    ABSTRACT: The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia that include increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated by the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and hypoxia-induced HIF-1alpha levels and thus HIF-1 activity. We report that PX-478 given to mice suppresses HIF-1alpha levels in HT-29 human colon cancer xenografts and inhibits the expression of HIF-1 target genes including vascular endothelial growth factor and the glucose transporter-1. PX-478 shows antitumor activity against established (0.15-0.40 cm(3)) human tumor xenografts with cures of SHP-77 small cell lung cancer and log cell kills up to 3.0 for other tumors including HT-29 colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and Panc-1 pancreatic cancers. Large (0.83 cm(3)) PC-3 prostate tumors showed 64% regression, which was greater than for smaller tumors. The antitumor response to PX-478 was positively correlated with tumor HIF-1alpha levels (P < 0.02) and was accompanied by massive apoptosis. The results show that PX-478 is an inhibitor of HIF-1alpha and HIF-1 transcription factor activity in human tumor xenografts and has marked antitumor activity against even large tumor xenografts, which correlates positively with HIF-1alpha levels.
    Molecular Cancer Therapeutics 03/2004; 3(3):233-44. · 5.60 Impact Factor
  • Sarah J Welsh, Garth Powis
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    ABSTRACT: Solid tumors with areas of hypoxia are the most aggressive and difficult tumors to treat and are a major reason for treatment failure. Previous attempts to treat hypoxic tumors have been largely unsuccessful and new agents are needed. The cellular response to hypoxia is controlled by the hypoxia inducible factor-1 (HIF-1) transcription factor. HIF-1 consists of an oxygen regulated alpha subunit and a constitutively expressed beta subunit, which bind and translocate to the nucleus to activate transcription of a range of genes involved in increasing glycolysis, inhibition of apoptosis and promotion of angiogenesis and metastasis. The activity of the HIF-1 complex is primarily controlled by levels of the alpha subunit and a series of mechanisms exist to control activation of the HIF-1 pathway. HIF-1alpha is over-expressed in a large number of human tumors and its over-expression correlates with poor prognosis and treatment failure. HIF-1 is therefore an important target for cancer chemotherapy. This review summarizes the literature surrounding the control of HIF-1, its role in cancer and potential drugs to target the pathway for cancer therapy.
    Current Cancer Drug Targets 01/2004; 3(6):391-405. · 4.00 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in tumor growth by increasing resistance to apoptosis and the production of angiogenic factors such as vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer comprised of oxygen-regulated HIF-1alpha and constitutively expressed HIF-1beta subunits. The redox protein thioredoxin-1 (Trx-1), which is found at high levels in many human cancers, increases both aerobic and hypoxia-induced HIF-1alpha protein in cells leading to increased expression of HIF-regulated genes. We have investigated whether two cancer drugs that inhibit Trx-1 signaling, PX-12 (1-methylpropyl 2-imidazolyl disulfide) and pleurotin, decrease HIF-1alpha protein levels and the expression of downstream target genes. Treatment of MCF-7 human breast cancer and HT-29 human colon carcinoma cells with PX-12 and pleurotin prevented the hypoxia (1% oxygen)-induced increase in HIF-1alpha protein. HIF-1-trans-activating activity, VEGF formation, and inducible nitric oxide synthase were also decreased by treatment with PX-12 and pleurotin under hypoxic conditions. PX-12 and pleurotin also decreased HIF-1alpha protein levels and HIF-1 trans-activation in RCC4 renal cell carcinoma cells that constitutively overexpress HIF-1alpha protein because of loss of the pVHL gene, indicating that HIF-1alpha is inhibited independently of the pVHL pathway. HIF-1alpha and VEGF protein levels in MCF-7 tumor xenografts in vivo were decreased by PX-12 treatment of mice. The results suggest that inhibition of HIF-1alpha by Trx-1 inhibitors may contribute to the growth inhibitory and antitumor activity of these agents.
    Molecular Cancer Therapeutics 04/2003; 2(3):235-43. · 5.60 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and HIF-1beta subunits, is a transcriptional activator central to the cellular response to low oxygen that includes metabolic adaptation, angiogenesis, metastasis, and inhibited apoptosis. Thioredoxin-1 (Trx-1) is a small redox protein overexpressed in a number of human primary tumors. We have examined the effects of Trx-1 on HIF activity and the activation of downstream genes. Stable transfection of human breast carcinoma MCF-7 cells with human Trx-1 caused a significant increase in HIF-1alpha protein levels under both normoxic (20% oxygen) and hypoxic (1% oxygen) conditions. Trx-1 increased hypoxia-induced HIF-1 transactivation activity measured using a luciferase reporter under the control of the hypoxia response element. Changes in HIF-1alpha mRNA levels did not account for the changes observed at the protein level, and HIF-1beta protein levels did not change. Trx-1 transfection also caused a significant increase in the protein products of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF) and nitric oxide synthase 2 in a number of different cell lines (MCF-7 human breast and HT29 human colon carcinomas and WEHI7.2 mouse lymphoma cells) under both normoxic and hypoxic conditions. The pattern of expression of the different isoforms of VEGF was not changed by Trx-1. Transfection of a redox-inactive Trx-1 (C32S/C35S) markedly decreased levels of HIF-1alpha protein, HIF-1 transactivating activity, and VEGF protein in MCF-7 cells compared with empty vector controls. In vivo studies using WEHI7.2 cells transfected with Trx-1 showed significantly increased tumor VEGF and angiogenesis. The results suggest that Trx-1 increases HIF-1alpha protein levels in cancer cells and increases VEGF production and tumor angiogenesis.
    Cancer Research 10/2002; 62(17):5089-95. · 8.65 Impact Factor

Publication Stats

574 Citations
39.24 Total Impact Points

Institutions

  • 2008
    • University of Houston
      Houston, Texas, United States
  • 2006
    • University of Oxford
      Oxford, England, United Kingdom
  • 2002–2004
    • The University of Arizona
      • Cancer Center
      Tucson, AZ, United States
  • 2003
    • Arizona Research Center
      Phoenix, Arizona, United States