Ronald A Lubet

National Cancer Institute (USA), 베서스다, Maryland, United States

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Publications (441)2148.81 Total impact

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    ABSTRACT: Peroxisome-proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates cell proliferation, differentiation, and apoptosis. In vivo studies were performed to evaluate the activities of two thiazolidinedione PPARγ agonists, rosiglitazone and pioglitazone, as inhibitors of oral carcinogenesis in rats. Oral squamous cell carcinomas (OSCC) were induced in male F344 rats by 4-nitroquinoline-1-oxide (NQO; 20 ppm in the drinking water for 10 weeks). In each study, groups of 30 NQO-treated rats were exposed to a PPARγ agonist beginning at week 10 (one day after completion of NQO administration) or at week 17 (7 weeks post-NQO); chemopreventive agent exposure was continued until study termination at week 22 (rosiglitazone study) or week 24 (pioglitazone study). Administration of rosiglitazone (800 mg/kg diet) beginning at week 10 increased survival, reduced oral cancer incidence, and reduced oral cancer invasion score in comparison to dietary controls; however, chemopreventive activity was largely lost when rosiglitazone administration was delayed until week 17. Administration of pioglitazone (500 mg/kg diet beginning at week 10 or 1000 mg/kg diet beginning at week 17) induced significant reductions in oral cancer incidence without significant effects on OSCC invasion scores. Transcript levels of PPARγ and its three transcriptional variants (PPARγv1, PPARγv2, and PPARγv3) were not significantly different in OSCC versus age- and site-matched phenotypically normal oral tissues from rats treated with NQO. These data suggest that PPARγ provides a useful molecular target for oral cancer chemoprevention, and that overexpression of PPARγ at the transcriptional level in neoplastic lesions is not essential for chemopreventive efficacy.
    Full-text · Article · Oct 2015 · PLoS ONE
  • Vernon E. Steele · Clinton J. Grubbs · Ronald A. Lubet

    No preview · Article · Oct 2015 · Cancer Prevention Research
  • Johnathan D. Ebben · Ronald A. Lubet · Ekram Gad · Mary L. Disis · Ming You
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    ABSTRACT: The ability to prevent disease is the holy grail of medicine. For decades, efforts have been made to extend the successes seen with vaccination against infectious diseases to cancer. In some instances, preventive vaccination against viruses (prototypically HPV) has successfully prevented tumorigenesis and will make a major impact on public health in the decades to come. However, the majority of cancers that arise are a result of genetic mutation within the host, or non-viral environmental exposures. We present compelling evidence that vaccination against an overexpressed self-tumor oncoprotein has the potential to prevent tumor development. Vaccination against the Epidermal Growth Factor Receptor (EGFR) using a multipeptide vaccine in a preventive setting decreased EGFR-driven lung carcinogenesis by 76.4% in a mouse model of EGFR-driven lung cancer. We also demonstrate that anti-EGFR vaccination primes the development of a robust immune response in vivo. This study provides proof of concept for the first time that targeting tumor drivers in a preventive setting in lung cancer using peptide vaccination can inhibit tumorigenesis and may provide useful clinical insights into the development of strategies to vaccinate against EGFR in populations where EGFR-mutant disease is highly prevalent. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Sep 2015 · Molecular Carcinogenesis

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · May 2015 · Cancer Research

  • No preview · Conference Paper · Apr 2015
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    ABSTRACT: The COX inhibitors (NSAID/Coxibs) are a major focus for the chemoprevention of cancer. The COX-2-specific inhibitors have progressed to clinical trials and have shown preventive efficacy in colon and skin cancers. However, they have significant adverse cardiovascular effects. Certain NSAIDs (e.g., naproxen) have a good cardiac profile, but can cause gastric toxicity. The present study examined protocols to reduce this toxicity of naproxen. Female Fischer-344 rats were treated weekly with the urinary bladder-specific carcinogen hydroxybutyl(butyl)nitrosamine (OH-BBN) for 8 weeks. Rats were dosed daily with NPX (40 mg/kg body weight/day, gavage) or with the proton pump inhibitor omeprazole (4.0 mg/kg body weight/day) either singly or in combination beginning 2 weeks after the final OH-BBN. OH-BBN-treated rats, 96% developed urinary bladder cancers. While omeprazole alone was ineffective (97% cancers), naproxen alone or combined with omeprazole-prevented cancers, yielding 27 and 35% cancers, respectively. In a separate study, OH-BBN -: treated rats were administered naproxen: (A) daily, (B) 1 week daily naproxen/1week vehicle, (C) 3 weeks daily naproxen/3 week vehicle, or (D) daily vehicle beginning 2 weeks after last OH-BBN treatment. In the intermittent dosing study, protocol A, B, C, and D resulted in palpable cancers in 27%, 22%, 19%, and 96% of rats (P < 0.01). Short-term naproxen treatment increased apoptosis, but did not alter proliferation in the urinary bladder cancers. Two different protocols that should decrease the gastric toxicity of NSAIDs in humans did not alter chemopreventive efficacy. This should encourage the use of NSAIDs (e.g., naproxen) in clinical prevention trials. Cancer Prev Res; 1-7. ©2015 AACR. ©2015 American Association for Cancer Research.
    No preview · Article · Mar 2015 · Cancer Prevention Research
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    ABSTRACT: Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared with sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK (AMP-activated protein kinase) and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in nondiabetic women, the efficacy of metformin in nondiabetic rat and mouse mammary cancer models was evaluated. Metformin was administered by gavage or in the diet, at a human equivalent dose, in standard mammary cancer models: (i) methylnitrosourea (MNU)-induced estrogen receptor-positive (ER(+)) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER(-) (estrogen receptor-negative) mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/kg BW/d, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/d, by gavage) yielded plasma levels (Cmax and AUC) higher than humans taking 1.5 g/d. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/d) treatment increased levels of phospho-AMPK and phospho-p53 (Ser20), but failed to reduce Ki67 labeling or expression of proliferation-related genes. In the mouse model, dietary metformin (1,500 mg/kg diet) did not alter final cancer incidence, multiplicity, or weight. Metformin did not prevent mammary carcinogenesis in two mammary cancer models, raising questions about metformin efficacy in breast cancer in nondiabetic populations. Cancer Prev Res; 1-9. ©2014 AACR. ©2014 American Association for Cancer Research.
    No preview · Article · Feb 2015 · Cancer Prevention Research
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    ABSTRACT: 3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the Serine/Threonine protein kinase "mammalian target of rapamycin (mTOR). Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-Bromopyruvate and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3- bromopyruvate did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-bromopyruvate, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Feb 2015 · Cancer Prevention Research
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    ABSTRACT: The ability of the retinoid X receptors (RXRs) specific agonists (targretin [TRG] and UAB30) to alter rat liver gene and protein expression was determined using Affymetrix Exon arrays and high-performance liquid chromatography – tandem mass spectrometry (LC-MS/MS). TRG profoundly increases triglycerides levels while UAB30 does not. The expression patterns of transcripts or proteins from rat liver treated with TRG or UAB-30 were different from controls and each other. There were six times more gene transcripts identified than proteins. Differentially expressed RNAs or proteins were mapped into known gene ontology (GO) categories and GeneGo Metacore (KEGG) pathway maps. The GO categories which were highly overrepresented with differentially expressed RNAs (P < 10−16) were also overrepresented at the protein level. This high concordance of GO Terms was achieved despite the fact that typically ≤1/3 of the elements identified by gene expression were identified by proteomics. Within these GO categories, the magnitude of alterations induced by RXR agonists at the transcript and protein levels were correlated. When GO categories with moderate overrepresentation (10−5 < P < 10−9) were examined, there was greater discordance between the transcript and protein data. Examination of KEGG pathway maps with highly significant changes at both the protein and the RNA levels showed that the individual proteins/genes altered were often the same and changes were of similar magnitude; while KEGG pathways showed limited statistical significance and exhibited minimal overlap. Finally, metabolomics analysis of liver and serum identified altered expression of metabolites related to fatty acid oxidation and bile acid metabolism that were consistent with transcript/protein changes. We observed significant concordance between genomics and proteomics implying either can identify pathways modulated and can indirectly predict resulting physiologic effects.
    Full-text · Article · Dec 2014
  • V. E. Steele · C. Grubbs · C. V. Rao · R.A. Lubet

    No preview · Article · Nov 2014 · European Journal of Cancer

  • No preview · Article · Nov 2014 · European Journal of Cancer

  • No preview · Article · Nov 2014 · European Journal of Cancer
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    ABSTRACT: 9-cis-UAB30 (UAB30) and Targretin are well-known retinoid X receptor (RXR) agonists. They were highly effective in decreasing the incidence of methylnitrosourea (MNU)-induced mammary cancers. However, whether the anti-mammary cancer effects of UAB30 or Targretin originate from the activation of RXR is unclear. In the present study, we hypothesized that UAB30 and Targretin not only affect RXR, but likely influence one or more off-target proteins. Virtual screening results suggest that Src is a potential target for UAB30 and Targretin that regulates extracellular matrix (ECM) molecules and cell motility and invasiveness. In vitro kinase assay data revealed that UAB30 or Targretin interacted with Src and attenuated its kinase activity. We found that UAB30 or Targretin substantially inhibited invasiveness and migration of MCF-7 and SK-BR-3 human breast cancer cells. We examined the effects of UAB30 and Targretin on the expression of matrix metalloproteinases (MMP)-9, which are known to play an essential role in tumor invasion. We show that activity and expression of MMP-9 were decreased by UAB30 or Targretin. Western blot data showed that UAB30 or Targretin decreased AKT and its substrate molecule p70s6k, which are downstream of Src in MCF-7 and SK-BR-3 cells. Moreover, knocking down the expression of Src effectively reduced the sensitivity of SK-BR-3 cells to the inhibitory effects of UAB30 and Targretin on invasiveness. Taken together, our results demonstrate that UAB30 and Targretin each inhibit invasion and migration by targeting Src in human breast cancer cells. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Oct 2014 · Molecular Carcinogenesis
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    ABSTRACT: Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a non-adipogenic PPARγ agonist, and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of squamous cell lung cancer (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU) which is applied topically, reliably triggering the development of SCC within 24-26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol treated group (p= 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol treated group (p= 0.004)). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1/S cell cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol increased generation of reactive oxygen species (ROS) in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent.
    Preview · Article · Sep 2014 · Cancer Prevention Research
  • Qi Zhang · Jing Pan · Ronald A. Lubet · Yian Wang · Ming You
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    ABSTRACT: Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane heterotetramer that is activated by Insulin-like growth factor 1 and is crucial for tumor transformation and survival of malignant cells. Importantly, IGF-1R overexpression has been reported in many different cancers, implicating this receptor as a potential target for anticancer therapy. Picropodophyllin (PPP) is a potent inhibitor of IGF-1R and has antitumor efficacy in several cancer types. However, the chemopreventive effect of PPP in lung tumorigenesis has not been investigated. In this study, we investigated the chemopreventive activity of PPP in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and PPP was given by nasal inhalation to female A/J mice. Lung tumorigenesis was assessed by tumor multiplicity and tumor load. PPP significantly decreased tumor multiplicity and tumor load. Tumor multiplicity and load were decreased by 52% and 78% respectively by 4 mg/ml aerosolized PPP. Pharmacokinetics analysis showed good bioavailability of PPP in lung and plasma. Treatment with PPP increased staining for cleaved caspase-3 and decreased Ki-67 in lung tumors, suggesting that the lung tumor inhibitory effects of PPP were partially through inhibition of proliferation and induction of apoptosis. In human lung cancer cell lines, PPP inhibited cell proliferation, and also inhibited phosphorylation of IGF-1R downstream targets, AKT and MAPK, ultimately resulting in increased apoptosis. PPP also reduced cell invasion in lung cancer cell lines. In view of our data, PPP merits further investigation as a promising chemopreventive agent for human lung cancer. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Aug 2014 · Molecular Carcinogenesis

  • No preview · Article · Jan 2014 · Cancer Prevention Research
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    ABSTRACT: Green tea is a promising chemopreventive agent for lung cancer. Multiple signaling events have been reported, however, the relative importance of these mechanisms in mediating the chemopreventive function of green tea is unclear. In the present study, to examine the involvement of AP-1 in green tea polyphenols induced tumor inhibition, human NSCLC cell line H1299 and mouse SPON 10 cells were identified as AP-1 dependent, as these two lines exhibit high constitutive AP-1 activity, and when TAM67 expression was induced with doxycycline, cell growth was inhibited and correlated with suppressed AP-1 activity. RNA-seq was used to determine the global transcriptional effects of AP-1 inhibition and also uncover the possible involvement of AP-1 in tea polyphenols induced chemoprevention. TAM67 mediated changes in gene expression were identified, and within down-regulated genes, AP-1 was identified as a key transcription regulator. RNA-seq analysis revealed that Polyphenon E-treated cells shared 293 commonly down-regulated genes within TAM67 expressing H1299 cells, and by analysis of limited Chip-seq data, over 10% of the down-regulated genes contain a direct AP-1 binding site, indicating that Polyphenon E elicits chemopreventive activity by regulating AP-1 target genes. Conditional TAM67 expressing transgenic mice and NSCLC cell lines were used to further confirm that the chemopreventive activity of green tea is AP-1 dependent. Polyphenon E lost its chempreventive function both in vitro and in vivo when AP-1 was inhibited, indicating that AP-1 inhibition is a major pathway through which green tea exhibits chemopreventive effects. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2014 · Molecular Carcinogenesis
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    ABSTRACT: Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen (standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO) derivatives. Additionally, the effects of the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent doses (HEDs), as well as at lower doses. In the hydroxybutyl(butyl)nitrosamine (OH-BBN) model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the incidence of large bladder cancers by 82, 68 and 44%, respectively, when the agents were initially given 3 months after the final dose of the carcinogen; microscopic cancers already existed. NO-naproxen was highly effective, while NO-sulindac was inactive. To further compare naproxen and NO-naproxen, we examined their effects on gene expression in rat livers following a 7 day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 1000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had minimal effects whereas the combination of DMFO and sulindac was more active than either agent alone. Thus, naproxen and NO-naproxen were highly effective, while sulindac was moderately effective in the OH-BBN model at their HEDs.
    Preview · Article · Dec 2013 · Cancer Prevention Research

Publication Stats

13k Citations
2,148.81 Total Impact Points


  • 1990-2015
    • National Cancer Institute (USA)
      • • Division of Cancer Prevention
      • • Cancer Etiology Branch (CEB)
      베서스다, Maryland, United States
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1992-2014
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1992-2013
    • National Institutes of Health
      • • Group of Chemopreventive Agent Development Research
      • • Division of Cancer Prevention
      • • Branch of Genetics
      베서스다, Maryland, United States
  • 2012
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      North Carolina, United States
  • 2001-2010
    • University of Alabama at Birmingham
      • • Department of Surgery
      • • Department of Pathology
      Birmingham, Alabama, United States
    • University of Louisville
      • Department of Pharmacology and Toxicology
      Louisville, Kentucky, United States
    • University of Alabama
      Tuscaloosa, Alabama, United States
  • 1995-2007
    • Medical University of Ohio at Toledo
      • • Department of Biochemistry and Cancer Biology
      • • Department of Surgery
      Toledo, Ohio, United States
  • 2003-2006
    • Washington University in St. Louis
      • Department of Surgery
      San Luis, Missouri, United States
  • 2004
    • Università degli Studi di Genova
      • Dipartimento di Scienze della salute (DISSAL)
      Genova, Liguria, Italy
  • 2002
    • The Ohio State University
      Columbus, Ohio, United States
    • Columbus State University
      Columbus, Georgia, United States
  • 1996-2002
    • University of Illinois at Chicago
      • • Department of Surgical Oncology (Chicago)
      • • Center for Pharmaceutical Biotechnology
      Chicago, Illinois, United States
  • 2000-2001
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
  • 1998
    • National Eye Institute
      Maryland, United States
  • 1991
    • Leidos Biomedical Research
      Фредерик, Maryland, United States
  • 1979
    • University of Texas Health Science Center at Tyler
      Tyler, Texas, United States
  • 1971
    • The University of Tennessee Medical Center at Knoxville
      Knoxville, Tennessee, United States