Publications

Scholarly Journals--Published

  • Knecht, T., Liu, J., Davis, W.,dela Pena, I. “Adjunctive therapy approaches: innovations to expand time window for ischemic stroke treatment”. Int. J. Mol. Sci. 2017, 18(12), 2756 Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT-associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy. (12/2017)
  • dela Pena, I., Borlongan, C., Shen, G., Davis, W. “Strategies to extend thrombolytic time window for ischemic stroke treatment, an unmet clinical need”. Journal of Stroke. 2017 9(1):50-60. o date, reperfusion with tissue plasminogen activator (tPA) remains the gold standard treatment for ischemic stroke. However, when tPA is given beyond 4.5 hours of stroke onset, deleterious effects of the drug ensue, especially, hemorrhagic transformation (HT), which causes the most significant morbidity and mortality in stroke patients. An important clinical problem at hand is to develop strategies that will enhance the therapeutic time window for tPA therapy and reduce the adverse effects (especially HT) of delayed tPA treatment. We reviewed the pharmacological agents which reduced the risk of HT associated with delayed (beyond 4.5 hours post-stroke) tPA treatment in preclinical studies, which we classified into those that putatively preserve the blood-brain barrier (e.g., minocycline, cilostazol, fasudil, candesartan, and bryostatin) and/or enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte colony-stimulating factor). Recently, other new therapeutic modalities (e.g., oxygen transporters) have been reported which improved delayed tPA-associated outcomes by acting through other mechanisms. While the above-mentioned interventions unequivocally reduced delayed tPA-induced HT in stroke models, the long-term efficacy of these drugs are not yet established. Further optimization is required to expedite their future clinical application. The findings from this review indicate the need to explore the most ideal adjunctive interventions that will not only reduce delayed tPA-induced HT, but also preserve neurovascular functions. While waiting for the next breakthrough drug in acute stroke treatment, it is equally important to allocate considerable effort to find approaches to address the limitations of the only FDA-approved stroke therapy. (10/2017)
  • Badal, S.A.M,  Valenzuela, A.M.M., Zylstra, D., Huang, G., Vendantam, P., Francis, S., Quitugua, A., Amis, L.H., Davis, W., Tzeng, T-R.J., Jacobs, H., Gangemi, D.J., Raner, G., Rowland, L., Wooten, J., Campbell, P., Brantley, E., and Delgoda, R. “Glaucarubulone glucoside from Castela macrophylla suppresses MCF-7 breast cancer cell growth and attenuates benzo[a]pyrene-mediated CYP1A gene induction”. J Appl Toxicol. 2017 Jul;37(7):873-883. doi: 10.1002/jat.3436. Epub 2017 Jan 31. Quassinoids often exhibit antioxidant and antiproliferative activity. Emerging evidence suggests that these natural metabolites also display chemopreventive actions. In this study, we investigated the potential for the quassinoid glaucarubulone glucoside(Gg), isolated from the endemic Jamaican plant Castela macrophylla (Simaroubaceae), to display potent cytotoxicity and inhibit human cytochrome P450s (CYPs), particularly CYP1A enzymes, known to convert polyaromatic hydrocarbons into carcinogenic metabolites. Gg reduced the viability of MCF-7 breast adenocarcinoma cells (IC50 = 121 nm) to a greater extent than standard of care anticancer agents 5-fluorouracil, tamoxifen (IC50 >10 μm) and the tamoxifen metabolite 4-hydroxytamoxifen (IC50 = 2.6 μm), yet was not cytotoxic to non-tumorigenic MCF-10A breast epithelial cells. Additionally, Gg induced MCF-7 breast cancer cell death. Gg blocked increases in reactive oxygen species in MCF-10A cells mediated by the polyaromatic hydrocarbon benzo[a]pyrene (B[a]P) metabolite B[a]P 1,6-quinone, yet downregulated the expression of genesthat promote antioxidant activity in MCF-7 cells. This implies that Gg exhibits antioxidant and cytoprotective actions in non-tumorigenic breast epithelial cells and pro-oxidant, cytotoxic actions in breast cancer cells. Furthermore, Gg inhibited the activities of human CYP1A according to non-competitive kinetics and attenuated the ability of B[a]P to induce CYP1A geneexpression in MCF-7 cells. These data indicate that Gg selectively suppresses MCF-7 breast cancer cell growth without impacting non-tumorigenic breast epithelial cells and blocks B[a]P-mediated CYP1A induction. Taken together, our data provide a rationale for further investigations of Gg and similar plant isolates as potential agents to treat and prevent breast cancer. (07/2017)
  • Moldovan, C., Weldon, A., Daher, N.S., Schneider, L.E., Bellinger, D.L., Berk, L.S., Herme, A.C., Arechiga, A.L., Davis, W.L., Peters, W.R.  Effects of a meal replacement system alone or in combination with phentermine on weight loss and food cravings. Obesity (2016) Published online 24 September 2016. Objective To examine the effects of phentermine combined with a meal replacement program on weight loss and food cravings and to investigate the relationship between food cravings and weight loss. Methods In a 12-week randomized, double-blind, placebo-controlled clinical trial, 77 adults with obesity received either phentermine or placebo. All participants were provided Medifast® meal replacements, were instructed to follow the Take Shape for Life®Optimal Weight 5&1 Plan for weight loss, and received lifestyle coaching in the Habits of Health program. The Food Craving Inventory and the General Food Cravings State and Trait Questionnaires were used to measure food cravings. Results The phentermine group lost 12.1% of baseline body weight compared with 8.8% in the placebo group. Cravings for all food groups decreased in both groups; however, there was a greater reduction in cravings for fats and sweets in the phentermine group compared with the placebo group. Percent weight loss correlated significantly with reduced total food cravings (r = 0.332, P = 0.009), cravings for sweets (r = 0.412, P <0.000), and state food cravings (r = 0.320, P = 0.007). Conclusions Both phentermine combined with a meal replacement program and meal replacements alone significantly reduced body weight and food cravings; however, the addition of phentermine enhanced these effects. (09/2016) (link)
  • McLean, L., Watkins C.N., Zylstra D., Campbell P., Amis, L.H., Scott L., Babb CE., Livingston W.J., Rowland L., Darwanto A., Davis, W.L., Senthil M., Sowers, L. and Brantley, E. “Aryl hydrocarbon receptor ligand 5F 203 induces oxidative stress triggering DNA damage in human breast cancer cells.” Chem Res Toxicol. 2015 May 18;28(5):855-71. Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action. (05/2015) (link)
  • Lancelot S McLean, Cheri N Watkins, Petreena Campbell, Dain Zylstra, Leah Rowland, . . . Eileen Brantley. (2015). Aryl Hydrocarbon ReceptorLigand 5F 203 Induces OxidativeStress That TriggersDNA Damage in Human Breast Cancer Cells. Chemical Research in Toxicology, 28(5), 855-871. Breast tumors often show profoundsensitivity to exogenous oxidativestress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole(5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damagein certain breast cancer cells. Since AhR agonists often elevate intracellularoxidative stress, we hypothesize that 5F 203 increases reactive oxygenspecies (ROS) to induce DNA damage, which thwarts breast cancer cellgrowth. We found that 5F 203 induced single-strand break formation.5F 203 enhanced oxidative DNA damage that was specific to breast cancercells sensitive to its cytotoxic actions, as it did not increase oxidativeDNA damage or ROS formation in nontumorigenic MCF-10A breast epithelialcells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone,induced oxidative DNA damage and ROS formation, respectively, in MCF-10Acells. In sensitive breast cancer cells, 5F 203 activated ROS-responsivekinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated proteinkinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) orantioxidants (N-acetyl-l-cysteine, EUK-134)attenuated 5F 203-mediated JNK and p38 activation, depending on thecell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated5F 203-mediated increases in intracellular ROS, apoptosis, and single-strandbreak formation. 5F 203 induced the expression of cytoglobin, an oxidativestress-responsive gene and a putative tumor suppressor, which wasdiminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediatedincreases in ROS production and cytoglobin were suppressed in AHR100cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our datademonstrate 5F 203 induces ROS-mediated DNA damage at least in partvia AhR, JNK, or p38 activation and modulates the expression of oxidativestress-responsive genes such as cytoglobin to confer its anticanceraction. [ABSTRACT FROM AUTHOR] Copyright of Chemical Research in Toxicology is the property of American Chemical Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) (2015) (link)
  • Weldon David J, Saulsbury Marilyn D, Goh Joshua, Rowland Leah, Campbell Petreena, . . . Brantley Eileen. (2014). One-pot synthesis of cinnamylideneacetophenones and their in vitro cytotoxicity in breast cancer cells. Bioorg Med Chem Lett, 24(15), 3381-3384. A series of cinnamylideneacetophenones were synthesized via a modified Claisen-Schmidt condensation reaction and evaluated for cytotoxicity against breast cancer cells using the Alamar Blue (TM) assay. Derivatives 17 and 18 bearing a 2-nitro group on the B ring, exhibited sub-micromolar cytotoxicity in MCF-7 cells (IC50 = 71 and 1.9 nM), respectively. Derivative 17 also displayed sub-micromolar (IC50 = 780 nM) cytotoxicity in MDA-MB-468 cells. Additionally, 17 and 18 displayed significantly less cytotoxicity than the chemotherapeutic doxorubicin in non-tumorigenic MCF-10A cells. This study provides evidence supporting the continued development of nitro-substituted cinnamylideneacetophenones as small molecules to treat breast cancer. (08/2014) (link)
  • Richardson A E, Hamilton N, Davis W, Brito C, & De Leon D. (2011). Insulin-like growth factor-2 (IGF-2) activates estrogen receptor-alpha and -beta via the IGF-1 and the insulin receptors in breast cancer cells. Growth Factors, 29(2-3), 82-93. The estrogen receptor (ER) is a primary target for breast cancer (BC) treatment. As BC progresses to estrogen-independent growth, the insulin-like growth factor-1 receptor (IGF-1R) and the ER interact in synergistic cross-talk mechanisms, which result in enhanced activation of both receptors' signaling cascades. Insulin-like growth factor-2 (IGF-2) is critical in BC progression and its actions are mediated by the IGF-1R. Our previous studies showed that IGF-2 regulates survival genes that protect the mitochondria and promote chemoresistance. In this study, we analyzed BC cells by subcellular fractionation, Western-Blot, qRT-PCR, and siRNA analysis. Our results demonstrate that IGF-2 activates ER-alpha alpha and ER-beta beta, and modulates their translocation to the nucleus, membrane organelles, and the mitochondria. IGF-2 actions are mediated by the IGF-1R and the insulin receptor. This novel mechanism of IGF-2 synergistic cross-talk signaling with ER-alpha alpha and ER-beta beta can promote estrogen-independent BC progression and provide new therapeutic targets for the treatment of BC patients.</. (04/2011) (link)

Abstract

  • 2015 - Uppala, P.P.T., Kolli, K., Garberoglio, C., Lum, S., Davis, W.L., Leung, H-C. E., Liebman, M., Oda, K., Besen, L., and Morgan, J.W. “Identification and validation of the potential biomarkers insulin-like growth factor-binding protein acid labile subunit and vitamin D for breast cancer using Shot gun LC/MS and Western blot analysis” 9th Indo Global Summit on Cancer Therapy, Hyderabad, India. (10/2017)
  • 2016 - Uppala, P.P.T.,  Garberoglio, C., Lum, S., Davis, W., Leung, H-C.E., Liebman, M. Oda, K. and Patel, U.P.. “Identification and validation of the potential biomarker insulin-like growth factor binding protein acid-labile subunit for breast cancer in African American women”. AACR 107th Annual Meeting, New Orleans, LA. (10/2017)
  • 2016 - Khawar, T., Cooke, J., Daoud, N., Sandhu, V., Davis, W., Peters, W., Torralba, K.M.D., Ngo, M.T., Lezcano, S., Payne, K.J., Weldon, A.J. " Suppressor of cytokines function one (SOCS1) is elevated in non-classical monocytes and correlates with disease activity in systematic lupus erythematosus patients." 2016 American College of Rheumatology Annual Meeting, Washington, DC. (10/2017)
  • Badal Simone, Huang George, Francis Sheena, Davis Willie, Brantley Eileen, . . . Delgoda Rupika. (2014). GLAUCARUBULONE GLUCOPYRANOSIDE, A NATURAL QUASSINOID INHIBITS PRO-CARCINOGEN BIOACTIVATING CYP ENZYMES IN VITRO AND DISPLAYS POTENT IMPACT ON BREAST CANCER CELL PROLIFERATION. Drug Metabolism Reviews, 45, 153-154. (01/2014)