Publications by authors named "Robert A Newman"

116 Publications

Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2.

Biomed Pharmacother 2021 Jun 3;138:111457. Epub 2021 Mar 3.

Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Phoenix Biotechnology, Inc., San Antonio, TX 78217, USA. Electronic address:

With continued expansion of the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), both antiviral drugs as well as effective vaccines are desperately needed to treat patients at high risk of life-threatening disease. Here, we present in vitro evidence for significant inhibition of SARS-CoV-2 by oleandrin and a defined extract of N. oleander (designated as PBI-06150). Using Vero cells, we found that prophylactic (pre-infection) oleandrin (as either the pure compound or as the active principal ingredient in PBI-06150) administration at concentrations as low as 0.05 µg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 µg/ml concentration resulted in a greater than 3000-fold reduction in infectious virus production. The half maximal effective concentration (EC) values were 11.98 ng/ml when virus output was measured at 24 h post-infection, and 7.07 ng/ml measured at 48 h post-infection. Therapeutic (post-infection) treatment up to 24 h after SARS-CoV-2 infection of Vero cells also reduced viral titers, with 0.1 µg/ml and 0.05 µg/ml concentrations causing greater than 100-fold reduction as measured at 48 h, and the 0.05 µg/ml concentration resulting in a 78-fold reduction. Concentrations of oleandrin up to 10 µg/ml were well tolerated in Vero cells. We also present in vivo evidence of the safety and efficacy of defined N. oleander extract (PBI-06150), which was administered to golden Syrian hamsters in a preparation containing as high as 130 µg/ml of oleandrin. In comparison to administration of control vehicle, PBI-06150 provided a statistically significant reduction of the viral titer in the nasal turbinates (nasal conchae). The potent prophylactic and therapeutic antiviral activities demonstrated here, together with initial evidence of its safety and efficacy in a relevant hamster model of COVID-19, support the further development of oleandrin and/or defined extracts containing this molecule for the treatment of SARS-CoV-2 and associated COVID-19 disease and potentially also for reduction of virus spread by persons diagnosed early after infection.
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http://dx.doi.org/10.1016/j.biopha.2021.111457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927596PMC
June 2021

Antiviral Effects of Oleandrin.

J Exp Pharmacol 2020 16;12:503-515. Epub 2020 Nov 16.

Department of Biological Sciences, the Dedman College Center for Drug Discovery, Design & Delivery, Southern Methodist University, Dallas, TX 75275, USA.

Over the past 15 years, investigators have reported on the utility and safety of cardiac glycosides for numerous health benefits including those as treatments for malignant disease, stroke-mediated ischemic injury and certain neurodegenerative diseases. In addition to those, there is a growing body of evidence for novel antiviral effects of selected cardiac glycoside molecules. One unique cardiac glycoside, oleandrin derived from , has been reported to have antiviral activity specifically against 'enveloped' viruses including HIV and HTLV-1. Importantly, a recent publication has presented in vitro evidence for oleandrin's ability to inhibit production of infectious virus particles when used for treatment prior to, as well as after infection by SARS-CoV-2/COVID-19. This review will highlight the known in vitro antiviral effects of oleandrin as well as present previously unpublished effects of this novel cardiac glycoside against Ebola virus, , and Herpes simplex viruses.
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http://dx.doi.org/10.2147/JEP.S273120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686471PMC
November 2020

The Botanical Drug PBI-05204, a Supercritical CO Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties.

Front Pharmacol 2020 11;11:552428. Epub 2020 Sep 11.

Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.

Glioblastoma multiform (GBM) is the most common primary glial tumor resulting in very low patient survival despite current extensive therapeutic efforts. Emerging evidence suggests that more effective treatments are required to overcome tumor heterogeneity, drug resistance and a complex tumor-supporting microenvironment. PBI-05204 is a specifically formulated botanical drug consisting of a modified supercritical C0 extract of that has undergone both phase I and phase II clinical trials in the United States for treatment of patients with a variety of advanced cancers. The present study was designed to investigate the antitumor efficacy of this botanical drug against glioblastoma using both and cancer models as well as exploring efficacy against glioblastoma stem cells. All three human GBM cell lines, U87MG, U251, and T98G, were inhibited by PBI-05204 in a concentration dependent manner that was characterized by induction of apoptosis as evidenced by increased ANNEXIN V staining and caspase activities. The expression of proteins associated with both Akt and mTOR pathway was suppressed by PBI-05240 in all treated human GBM cell lines. PBI-05204 significantly suppressed U87 spheroid formation and the expression of important stem cell markers such as SOX2, CD44, and CXCR4. Oral administration of PBI-05204 resulted in a dose-dependent inhibition of U87MG, U251, and T98G xenograft growth. Additionally, PBI-05204-treated mice carrying U87-Luc cells as an orthotropic model exhibited significantly delayed onset of tumor proliferation and significantly increased overall survival. Immunohistochemical staining of xenograft derived tumor sections revealed dose-dependent declines in expression of Ki67 and CD31 positive stained cells but increased TUNEL staining. PBI-05204 represents a novel therapeutic botanical drug approach for treatment of glioblastoma as demonstrated by significant responses with tumor models. Both cell culture and immunohistochemical studies of tumor tissue suggest drug induction of tumor cell apoptosis and inhibition of PI3k/mTOR pathways as well as cancer stemness. Given the fact that PBI-05204 has already been examined in phase I and II clinical trials for cancer patients, its efficacy when combined with standard of care chemotherapy and radiotherapy should be explored in future clinical trials of this difficult to treat brain cancer.
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http://dx.doi.org/10.3389/fphar.2020.552428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516200PMC
September 2020

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin.

bioRxiv 2020 Jul 15. Epub 2020 Jul 15.

With continued expansion of the COVID-19 pandemic, antiviral drugs are desperately needed to treat patients at high risk of life-threatening disease and even to limit spread if administered early during infection. Typically, the fastest route to identifying and licensing a safe and effective antiviral drug is to test those already shown safe in early clinical trials for other infections or diseases. Here, we tested oleandrin, derived from the plant and shown previously to have inhibitory activity against several viruses. Using Vero cells, we found that prophylactic oleandrin administration at concentrations down to 0.05 μg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 μg/ml dose resulted in a greater than 3,000-fold reduction in infectious virus production. The EC values were 11.98ng/ml when virus output was measured at 24 hours post-infection, and 7.07ng/ml measured at 48 hours post-infection. Therapeutic (post-infection) treatment up to 24 hours after infection of Vero cells also reduced viral titers, with the 0.1 μg/ml dose causing greater than 100-fold reductions as measured at 48 hours, and the 0.05 μg/ml dose resulting in a 78-fold reduction. The potent prophylactic and therapeutic antiviral activities demonstrated here strongly support the further development of oleandrin to reduce the severity of COVID-19 and potentially also to reduce spread by persons diagnosed early after infection.

Importance: COVID-19, a pandemic disease caused by infection with SARS-CoV-2, has swept around the world to cause millions of infections and hundreds-of-thousands of deaths due to the lack of vaccines and effective therapeutics. We tested oleandrin, derived from the plant and shown previously to reduce the replication of several viruses, against SARS-CoV-2 infection of Vero cells. When administered both before and after virus infection, nanogram doses of oleandrin significantly inhibited replication by up to 3,000-fold, indicating the potential to prevent disease and virus spread in persons recently exposed to SARS-CoV-2, as well as to prevent severe disease in persons at high risk. These results indicate that oleandrin should be tested in animal models and in humans exposed to infection to determine its medical usefulness in controlling the pandemic.
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http://dx.doi.org/10.1101/2020.07.15.203489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373128PMC
July 2020

A Phase II, Single-Arm, Open-Label, Bayesian Adaptive Efficacy and Safety Study of PBI-05204 in Patients with Stage IV Metastatic Pancreatic Adenocarcinoma.

Oncologist 2020 10 2;25(10):e1446-e1450. Epub 2020 Jul 2.

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.

Lessons Learned: This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment.

Background: Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR.

Methods: A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles.

Results: Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea.

Conclusion: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.
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http://dx.doi.org/10.1634/theoncologist.2020-0440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543353PMC
October 2020

The Botanical Glycoside Oleandrin Inhibits Human T-cell Leukemia Virus Type-1 Infectivity and Env-Dependent Virological Synapse Formation.

J Antivir Antiretrovir 2019 21;11(3). Epub 2019 Aug 21.

Laboratory of Molecular Virology, Department of Biological Sciences, The Dedman College Center for Drug Discovery, Design & Delivery, Southern Methodist University, Dallas, Texas, 75275-0376, USA.

At present, there are no antiretroviral drugs that inhibit incorporation of the envelope glycoprotein into newly-synthesized virus particles. The botanical glycoside, oleandrin, derived from extracts of Nerium oleander, has previously been shown to reduce the levels of the gp120 envelope glycoprotein on human immunodeficiency virus type-1 (HIV-1) particles and inhibit HIV-1 infectivity . We therefore tested whether oleandrin or an extract from could also inhibit the infectivity of the human T-cell leukemia virus type-1 (HTLV-1): A related enveloped retrovirus and emerging tropical infectious agent. The treatment of HTLV-1+ lymphoma T-cells with either oleandrin or a extract did not significantly inhibit viral replication or the release of p19-containing particles into the culture supernatants. However, the collected virus particles from treated cells exhibited reduced infectivity on primary human peripheral blood mononuclear cells (huPBMCs). Unlike HIV-1, extracellular HTLV-1 particles are poorly infectious and viral transmission typically occurs via direct intercellular interactions across a virological synapse. We therefore investigated whether oleandrin or a extract could inhibit virus transmission from a GFP-expressing HTLV-1+ lymphoma T-cell-line to huPBMCs in co- assays. These results demonstrated that both oleandrin and the crude phytoextract inhibited the formation of virological synapses and the transmission of HTLV-1 . Importantly, these findings suggest oleandrin may have broad antiviral activity against enveloped viruses by reducing the incorporation of the envelope glycoprotein into mature particles, a stage of the infection cycle not targeted by modern HAART.
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http://dx.doi.org/10.35248/1948-5964.19.11.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904119PMC
August 2019

Sharp-Tailed Grouse Nest Survival and Nest Predator Habitat Use in North Dakota's Bakken Oil Field.

PLoS One 2017 12;12(1):e0170177. Epub 2017 Jan 12.

Department of Biology, University of North Dakota, Grand Forks, ND, United States of America.

Recent advancements in extraction technologies have resulted in rapid increases of gas and oil development across the United States and specifically in western North Dakota. This expansion of energy development has unknown influences on local wildlife populations and the ecological interactions within and among species. Our objectives for this study were to evaluate nest success and nest predator dynamics of sharp-tailed grouse (Tympanuchus phasianellus) in two study sites that represented areas of high and low energy development intensities in North Dakota. During the summers of 2012 and 2013, we monitored 163 grouse nests using radio telemetry. Of these, 90 nests also were monitored using miniature cameras to accurately determine nest fates and identify nest predators. We simultaneously conducted predator surveys using camera scent stations and occupancy modeling to estimate nest predator occurrence at each site. American badgers (Taxidea taxus) and striped skunks (Mephitis mephitis) were the primary nest predators, accounting for 56.7% of all video recorded nest depredations. Nests in our high intensity gas and oil area were 1.95 times more likely to succeed compared to our minimal intensity area. Camera monitored nests were 2.03 times more likely to succeed than non-camera monitored nests. Occupancy of mammalian nest predators was 6.9 times more likely in our study area of minimal gas and oil intensity compared to the high intensity area. Although only a correlative study, our results suggest energy development may alter the predator community, thereby increasing nest success for sharp-tailed grouse in areas of intense development, while adjacent areas may have increased predator occurrence and reduced nest success. Our study illustrates the potential influences of energy development on the nest predator-prey dynamics of sharp-tailed grouse in western North Dakota and the complexity of evaluating such impacts on wildlife.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170177PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231376PMC
August 2017

Water-soluble egg membrane enhances the immunoactivating properties of an -based extract of leaves.

Clin Cosmet Investig Dermatol 2016 3;9:393-403. Epub 2016 Nov 3.

NIS Labs, Klamath Falls, OR.

Objective: To evaluate a blend of two natural ingredients on immune parameters relevant for their current topical use and potential support of microcirculation in skin tissue.

Materials And Methods: A blend (BL) of -based extract (NAE-8i, oleandrin-free) and hydrolyzed water-soluble egg membrane (WSEM) was applied to human whole-blood cultures for 24 hours, with each separate ingredient serving as a control. Immune-cell subsets were analyzed for expression levels of the activation markers CD69 and CD25. Culture supernatants were analyzed for cytokines, chemokines, and immunoregulating peptides.

Results: BL increased CD69 expression on lymphocytes, monocytes, and CD3CD56 natural killer cells, and CD25 expression on natural killer cells. The number of CD69CD25 lymphocytes increased in cultures treated with BL and the separate ingredients. BL triggered production of multiple cytokines and chemokines, where CC chemokines MIP1α and MIP3α, as well as cytokines involved in wound healing - Groα, Groβ, ENA78, and fractalkine - reached levels manyfold above treatment with either NAE-8i or WSEM alone.

Conclusion: Data on BL showed that WSEM strongly enhanced NAE-8i's effects on immunoactivation in vitro. This has potential relevance for support of immunity in skin tissue, including antibacterial and antiviral defense mechanisms, wrinkle reduction, and wound care.
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http://dx.doi.org/10.2147/CCID.S114471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098409PMC
November 2016

Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer.

Mar Drugs 2016 Jun 17;14(6). Epub 2016 Jun 17.

Department of Physiology, Faculty of Medicine, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE.

The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of ~1 µM. Frondoside B was less potent (EC50 ~2.5 µM). Frondoside C and the aglycone had no effect. At 100 µg/kg, frondoside A administered to CD₂F₁ mice as an i.v. bolus, the Cpmax was 129 nM, Cltb was 6.35 mL/min/m², and half-life was 510 min. With i.p. administration the Cpmax was 18.3 nM, Cltb was 127 mL/min/m² and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 µg/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.
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http://dx.doi.org/10.3390/md14060115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926074PMC
June 2016

Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

Sci Rep 2016 05 12;6:25626. Epub 2016 May 12.

Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.

We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD.
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http://dx.doi.org/10.1038/srep25626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865873PMC
May 2016

Antioxidant, anti-inflammatory, anti-apoptotic, and skin regenerative properties of an Aloe vera-based extract of Nerium oleander leaves (nae-8(®)).

Clin Cosmet Investig Dermatol 2015 6;8:239-48. Epub 2015 May 6.

NIS Labs, Klamath Falls, Oregon, USA.

Objective: The goal for this study was to evaluate the effects of an Aloe vera-based Nerium oleander extract (NAE-8(®)), compared to an extract of A. vera gel alone (ALOE), and to an aqueous extract of N. oleander (AQ-NOE) in bioassays pertaining to dermatologic potential with respect to antioxidant protection, anti-inflammatory effects, and cytokine profiles in vitro.

Methods: Cellular antioxidant protection was evaluated in three separate bioassays: The cellular antioxidant protection of erythrocytes (CAP-e) assay, protection of cellular viability and prevention of apoptosis, and protection of intracellular reduced glutathione levels, where the last two assays were performed using human primary dermal fibroblasts. Reduction of intracellular formation of reactive oxygen species (ROS) was tested using polymorphonuclear cells in the absence and presence of oxidative stress. Changes to cytokine and chemokine profiles when whole blood cells and human primary dermal fibroblasts were exposed to test products were determined using a 40-plex Luminex array as a method for exploring the potential cross-talk between circulating and skin-resident cells.

Results: The NAE-8(®) provided significantly better antioxidant protection in the CAP-e bioassay than AQ-NOE. NAE-8(®) and AQ-NOE both protected cellular viability and intracellular reduced glutathione, and reduced the ROS formation significantly when compared to control cells, both under inflamed and neutral culture conditions. ALOE showed minimal effect in these bioassays. In contrast to the NAE-8(®), the AQ-NOE showed induction of inflammation in the whole blood cultures, as evidenced by the high induction of CD69 expression and secretion of a number of inflammatory cytokines. The treatment of dermal fibroblasts with NAE-8(®) resulted in selective secretion of cytokines involved in collagen and hyaluronan production as well as re-epithelialization during wound healing.

Conclusion: NAE-8(®), a novel component of a commercial cosmetic product, showed beneficial antioxidant protection in several cellular models, without the induction of leukocyte activation and secretion of inflammatory cytokines. The biological efficacy of NAE-8(®) was unique from both ALOE and AQ-NOE.
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http://dx.doi.org/10.2147/CCID.S79871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427598PMC
May 2015

Response to: Does the Nerium oleander extract PBI-05204 have potential for pancreatic cancer?

Invest New Drugs 2015 Jun 20;33(3):788-9. Epub 2015 Jan 20.

Department of Experimental Therapeutics, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA,

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http://dx.doi.org/10.1007/s10637-015-0208-8DOI Listing
June 2015

PBI-05204, a supercritical CO₂ extract of Nerium oleander, inhibits growth of human pancreatic cancer via targeting the PI3K/mTOR pathway.

Invest New Drugs 2015 Apr 6;33(2):271-9. Epub 2014 Dec 6.

Department of General Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0462, Houston, TX, 77030, USA.

Introduction Oleandrin, a cardiac glycoside, exerts strong anti-proliferative activity against various human malignancies in in vitro cells. Here, we report the antitumor efficacy of PBI-05204, a supercritical C0₂ extract of Nerium oleander containing oleandrin, in a human pancreatic cancer Panc-1 orthotopic model. Results While all the control mice exhibited tumors by the end of treatment, only 2 of 8 mice (25%) treated for 6 weeks with PBI-05204 (40 mg/kg) showed dissectible tumor at the end of the treatment period. The average tumor weight (222.9 ± 116.9 mg) in mice treated with PBI-05204 (20 mg/kg) was significantly reduced from that in controls (920.0 ± 430.0 mg) (p < 0.05). Histopathologic examination of serial sections from each pancreas with no dissectible tumor in the PBI-05204 (40 mg/kg) treated group showed that the pancreatic tissues of 5/6 mice were normal while the remaining mouse had a tumor the largest diameter of which was less than 2.3 mm. In contrast, while gemcitabine alone did not significantly reduce tumor growth, PBI-05204 markedly enhanced the antitumor efficacy of gemcitabine in this particular model. Ki-67 staining was reduced in pancreatic tumors from mice treated with PBI-05204 (20 mg/kg) compared to that of control, suggesting that PBI-05204 inhibited the proliferation of the Panc-1 tumor cells. PBI-05204 suppressed expression of pAkt, pS6, and p4EPB1 in a concentration-dependent manner in both Panc-1 tumor tissues and human pancreatic cancer cell lines, implying that this novel botanical drug exerts its potent antitumor activity, at least in part, through down-regulation of PI3k/Akt and mTOR pathways.
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http://dx.doi.org/10.1007/s10637-014-0190-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387257PMC
April 2015

BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin.

J Neurosci 2014 Jan;34(3):963-8

Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27704, and Department of Experimental Therapeutics, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030.

We have previously shown that the botanical drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, provides neuroprotection in both in vitro and in vivo brain slice-based models for focal ischemia (Dunn et al., 2011). Intriguingly, plasma levels of the neurotrophin BDNF were increased in patients treated with PBI-05204 in a phase I clinical trial (Bidyasar et al., 2009). We thus tested the hypothesis that neuroprotection provided by PBI-05204 to rat brain slices damaged by oxygen-glucose deprivation (OGD) is mediated by BDNF. We found, in fact, that exogenous BDNF protein itself is sufficient to protect brain slices against OGD, whereas downstream activation of TrkB receptors for BDNF is necessary for neuroprotection provided by PBI-05204, using three independent methods. Finally, we provide evidence that oleandrin, the principal cardiac glycoside component of PBI-05204, can quantitatively account for regulation of BDNF at both the protein and transcriptional levels. Together, these findings support further investigation of cardiac glycosides in providing neuroprotection in the context of ischemic stroke.
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http://dx.doi.org/10.1523/JNEUROSCI.2700-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891971PMC
January 2014

Simultaneous reduction of particulate matter and NO(x) emissions using 4-way catalyzed filtration systems.

Environ Sci Technol 2013 May 15;47(9):4521-7. Epub 2013 Apr 15.

University of Minnesota, Department of Mechanical Engineering, 111 Church Street SE, Minneapolis, Minnesota 55455, USA.

The next generation of diesel emission control devices includes 4-way catalyzed filtration systems (4WCFS) consisting of both NOx and diesel particulate matter (DPM) control. A methodology was developed to simultaneously evaluate the NOx and DPM control performance of miniature 4WCFS made from acicular mullite, an advanced ceramic material (ACM), that were challenged with diesel exhaust. The impact of catalyst loading and substrate porosity on catalytic performance of the NOx trap was evaluated. Simultaneously with NOx measurements, the real-time solid particle filtration performance of catalyst-coated standard and high porosity filters was determined for steady-state and regenerative conditions. The use of high porosity ACM 4-way catalyzed filtration systems reduced NOx by 99% and solid and total particulate matter by 95% when averaged over 10 regeneration cycles. A "regeneration cycle" refers to an oxidizing ("lean") exhaust condition followed by a reducing ("rich") exhaust condition resulting in NOx storage and NOx reduction (i.e., trap "regeneration"), respectively. Standard porosity ACM 4-way catalyzed filtration systems reduced NOx by 60-75% and exhibited 99.9% filtration efficiency. The rich/lean cycling used to regenerate the filter had almost no impact on solid particle filtration efficiency but impacted NOx control. Cycling resulted in the formation of very low concentrations of semivolatile nucleation mode particles for some 4WCFS formulations. Overall, 4WCFS show promise for significantly reducing diesel emissions into the atmosphere in a single control device.
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http://dx.doi.org/10.1021/es304971hDOI Listing
May 2013

Effects of host species and life stage on the helminth communities of sympatric northern leopard frogs (Lithobates pipiens) and wood frogs (Lithobates sylvaticus) in the Sheyenne National Grasslands, North Dakota.

J Parasitol 2013 Aug 14;99(4):587-94. Epub 2013 Feb 14.

Department of Zoology, Oklahoma State University, Life Sciences West, Stillwater, Oklahoma 74078, USA.

We studied helminth communities in sympatric populations of leopard frogs (Lithobates pipiens) and wood frogs (Lithobates sylvaticus) and assessed the effects of host species and life stage on helminth community composition and helminth species richness. We examined 328 amphibians including 218 northern leopard frogs and 110 wood frogs collected between April and August of 2009 and 2010 in the Sheyenne National Grasslands of southeastern North Dakota. Echinostomatid metacercariae were the most common helminths found, with the highest prevalence in metamorphic wood frogs. Host species significantly influenced helminth community composition, and host life stage significantly influenced the component community composition of leopard frogs. In these sympatric populations, leopard frogs were common hosts for adult trematodes whereas wood frogs exhibited a higher prevalence of nematodes with direct life cycles. Metamorphic frogs were commonly infected with echinostomatid metacercariae and other larval trematodes whereas juvenile and adult frogs were most-frequently infected with directly transmitted nematodes and trophically transmitted trematodes. Accordingly, helminth species richness increased with the developmental life stage of the host.
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http://dx.doi.org/10.1645/GE-3246.1DOI Listing
August 2013

Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation.

Mol Carcinog 2014 Jul 31;53(7):566-77. Epub 2013 Jan 31.

Department of General Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas.

The beneficial effects of omega-3 fatty acids are believed to be due in part to selective alteration of arachidonate metabolism that involves cyclooxygenase (COX) enzymes. Here we investigated the effect of eicosapentaenoic acid (EPA) on the proliferation of human non-small cell lung cancer A549 (COX-2 over-expressing) and H1299 (COX-2 null) cells as well as their xenograft models. While EPA inhibited 50% of proliferation of A549 cells at 6.05 µM, almost 80 µM of EPA was needed to reach similar levels of inhibition of H1299 cells. The formation of prostaglandin (PG)E3 in A549 cells was almost threefold higher than that of H1299 cells when these cells were treated with EPA (25 µM). Intriguingly, when COX-2 expression was reduced by siRNA or shRNA in A549 cells, the antiproliferative activity of EPA was reduced substantially compared to that of control siRNA or shRNA transfected A549 cells. In line with this, dietary menhaden oil significantly inhibited the growth of A549 tumors by reducing tumor weight by 58.8 ± 7.4%. In contrast, a similar diet did not suppress the development of H1299 xenograft. Interestingly, the ratio of PGE3 to PGE2 in A549 was about 0.16 versus only 0.06 in H1299 xenograft tissues. Furthermore, PGE2 up-regulated expression of pAkt, whereas PGE3 downregulated expression of pAkt in A549 cells. Taken together, the results of our study suggest that the ability of EPA to generate PGE3 through the COX-2 enzyme might be critical for EPA-mediated tumor growth inhibition which is at least partly due to down-regulation of Akt phosphorylation by PGE3.
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http://dx.doi.org/10.1002/mc.22008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395033PMC
July 2014

Nerium oleander derived cardiac glycoside oleandrin is a novel inhibitor of HIV infectivity.

Fitoterapia 2013 Jan 2;84:32-9. Epub 2012 Nov 2.

Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

We evaluated the effectiveness of Anvirzel™, an aqueous extract of Nerium oleander on HIV infection of human peripheral blood mononuclear cells. Oleandrin, the principle cardiac glycoside (CG) in Anvirzel™ has been shown to exhibit anti-cancer properties but its efficacy against HIV is unknown. Treatment with Anvirzel™ significantly reduced the infectivity of virus produced from infected cells without any change in the total amount of virus produced. This is in contrast to treatment with AZT, a potent inhibitor of HIV replication that has been shown to significantly reduce virus production. Relative to untreated cultures, virus in cultures treated with oleandrin had significantly reduced expression of the envelope protein gp120, the sole determinant of virus infectivity, suggesting a novel mechanism underlying the impaired infectivity. These results support the potential utility of the Nerium oleander aqueous extract, containing the CG oleandrin as a novel candidate anti-HIV therapeutic.
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http://dx.doi.org/10.1016/j.fitote.2012.10.017DOI Listing
January 2013

Cellular location and expression of Na+, K+ -ATPase α subunits affect the anti-proliferative activity of oleandrin.

Mol Carcinog 2014 Apr 16;53(4):253-63. Epub 2012 Oct 16.

Department of General Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas; Department of Cancer Biology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas.

The purpose of this study was to investigate whether intracellular distribution of Na(+), K(+) -ATPase α3 subunit, a receptor for cardiac glycosides including oleandrin, is differentially altered in cancer versus normal cells and whether this altered distribution can be therapeutically targeted to inhibit cancer cell survival. The cellular distribution of Na(+), K(+) -ATPase α3 isoform was investigated in paired normal and cancerous mucosa biopsy samples from patients with lung and colorectal cancers by immunohistochemical staining. The effects of oleandrin on α3 subunit intracellular distribution, cell death, proliferation, and EKR phosphorylation were examined in differentiated and undifferentiated human colon cancer CaCO-2 cells. While Na(+), K(+) -ATPase α3 isoform was predominantly located near the cytoplasmic membrane in normal human colon and lung epithelia, the expression of this subunit in their paired cancer epithelia was shifted to a peri-nuclear position in both a qualitative and quantitative manner. Similarly, distribution of α3 isoform was also shifted from a cytoplasmic membrane location in differentiated human colon cancer CaCO-2 cells to a peri-nuclear position in undifferentiated CaCO-2 cells. Intriguingly, oleandrin exerted threefold stronger anti-proliferative activity in undifferentiated CaCO-2 cells (IC50, 8.25 nM) than in differentiated CaCO-2 cells (IC50, >25 nM). Oleandrin (10 to 20 nM) caused an autophagic cell death and altered ERK phosphorylation in undifferentiated but not in differentiated CaCO-2 cells. These data demonstrate that the intracellular location of Na(+), K(+) -ATPase α3 isoform is altered in human cancer versus normal cells. These changes in α3 cellular location and abundance may indicate a potential target of opportunity for cancer therapy.
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http://dx.doi.org/10.1002/mc.21968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442617PMC
April 2014

Arachidonic acid metabolism in human prostate cancer.

Int J Oncol 2012 Oct 10;41(4):1495-503. Epub 2012 Aug 10.

Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The arachidonic acid pathway is important in the development and progression of numerous malignant diseases, including prostate cancer. To more fully evaluate the role of individual cyclooxygenases (COXs), lipoxygenases (LOXs) and their metabolites in prostate cancer, we measured mRNA and protein levels of COXs and LOXs and their arachidonate metabolites in androgen-dependent (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cell lines, bone metastasis-derived MDA PCa 2a and MDA PCa 2b cell lines and their corresponding xenograft models, as well as core biopsy specimens of primary prostate cancer and nonneoplastic prostate tissue taken ex vivo after prostatectomy. Relatively high levels of COX-2 mRNA and its product PGE2 were observed only in PC-3 cells and their xenografts. By contrast, levels of the exogenous 12-LOX product 12-HETE were consistently higher in MDA PCa 2b and PC-3 cells and their corresponding xenograft tissues than were those in LNCaP cells. More strikingly, the mean endogenous level of 12-HETE was significantly higher in the primary prostate cancers than in the nonneoplastic prostate tissue (0.094 vs. 0.010 ng/mg protein, respectively; p=0.019). Our results suggest that LOX metabolites such as 12-HETE are critical in prostate cancer progression and that the LOX pathway may be a target for treating and preventing prostate cancer.
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http://dx.doi.org/10.3892/ijo.2012.1588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982713PMC
October 2012

Perioperative polyphenon E, a green tea extract, does not affect the wound complication rate in mice after sham laparotomy yet has an inhibitory effect on wound healing.

Surg Innov 2012 Dec 18;19(4):399-406. Epub 2012 Mar 18.

Columbia University, New York, NY, USA.

Introduction: Major surgery is associated with physiologic alterations that may promote tumor growth, and catechins in green tea may inhibit tumor growth. This study's aim was to assess the impact of a green tea extract on laparotomy wound healing in mice.

Methods: Mice were randomized to daily oral catechins solution (n = 25) or placebo (n = 20), underwent sham laparotomy after 10 days, and were sacrificed on postoperative day 7 or 21. The peak force and total energy required to rupture the abdominal wall wound, wound collagen content, and histology were assessed.

Results: There were no wound complications in either group, and mean peak wound rupture forces and collagen concentration were similar. Mean energy was lower and more fibroblast proliferation was found in the treatment group on postoperative day 21.

Conclusions: These results suggest that catechins has only mild clinically significant adverse effect on wound healing, and its perioperative use warrants further study.
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http://dx.doi.org/10.1177/1553350612436565DOI Listing
December 2012

Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites.

PLoS One 2011 22;6(12):e28813. Epub 2011 Dec 22.

Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245236PMC
May 2012

In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models.

J Neurochem 2011 Nov 26;119(4):805-14. Epub 2011 Sep 26.

Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27514, USA.

The principal active constituent of the botanical drug candidate PBI-05204, a supercritical CO(2) extract of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clinical trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 extract can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that additional, non-cardiac glycoside components of PBI-05204 may also contribute to the observed neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clinical potential for PBI-05204 in the treatment of ischemic stroke and prevention of associated neuronal death.
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http://dx.doi.org/10.1111/j.1471-4159.2011.07439.xDOI Listing
November 2011

Zyflamend mediates therapeutic induction of autophagy to apoptosis in melanoma cells.

Nutr Cancer 2011 11;63(6):940-9. Epub 2011 Jul 11.

Department of Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.

Melanoma is the most aggressive form of skin cancer. The rising incidence of melanoma and its poor prognosis in advanced stages are compelling reasons to identify novel therapeutic agents. Though isolated dietary components such as lycopene, resveratrol, and isothiocyanate compounds have been shown to provide limited protection against cancer development, the use of whole herbs and herbal extracts for the treatment of cancer remains of great interest. As suggested by earlier studies, the antiinflammatory activity of many plants available as intact products or as extracts has long been considered for supplemental therapeutics for cancer. Zyflamend, a unique multiherbal extract preparation, is a promising antiinflammatory agent that has also been suggested to regulate multiple pathways in cancer progression. As Zyflamend contains ingredients that can suppress tumor cell proliferation, invasion, angiogenesis, and metastasis through regulation of inflammatory pathway products, we hypothesized that this preparation might inhibit melanoma proliferation. To test this hypothesis, we studied the effect of Zyflamend on melanoma proliferation. Here, we present that Zyflamend inhibits melanoma growth by regulating the autophagy-apoptosis switch. Based on the responsible molecular mechanisms of Zyflamend, our study highlights the importance of the use of herbal preparations for the prevention and treatment of cancer.
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http://dx.doi.org/10.1080/01635581.2011.586488DOI Listing
December 2011

Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach.

Bone 2011 Sep 15;49(3):356-67. Epub 2011 May 15.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 5545, USA.

The heterogeneous and chaotic nature of osteosarcoma has confounded accurate molecular classification, prognosis, and prediction for this tumor. The occurrence of spontaneous osteosarcoma is largely confined to humans and dogs. While the clinical features are remarkably similar in both species, the organization of dogs into defined breeds provides a more homogeneous genetic background that may increase the likelihood to uncover molecular subtypes for this complex disease. We thus hypothesized that molecular profiles derived from canine osteosarcoma would aid in molecular subclassification of this disease when applied to humans. To test the hypothesis, we performed genome wide gene expression profiling in a cohort of dogs with osteosarcoma, primarily from high-risk breeds. To further reduce inter-sample heterogeneity, we assessed tumor-intrinsic properties through use of an extensive panel of osteosarcoma-derived cell lines. We observed strong differential gene expression that segregated samples into two groups with differential survival probabilities. Groupings were characterized by the inversely correlated expression of genes associated with 'G2/M transition and DNA damage checkpoint' and 'microenvironment-interaction' categories. This signature was preserved in data from whole tumor samples of three independent dog osteosarcoma cohorts, with stratification into the two expected groups. Significantly, this restricted signature partially overlapped a previously defined, predictive signature for soft tissue sarcomas, and it unmasked orthologous molecular subtypes and their corresponding natural histories in five independent data sets from human patients with osteosarcoma. Our results indicate that the narrower genetic diversity of dogs can be utilized to group complex human osteosarcoma into biologically and clinically relevant molecular subtypes. This in turn may enhance prognosis and prediction, and identify relevant therapeutic targets.
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http://dx.doi.org/10.1016/j.bone.2011.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143255PMC
September 2011

γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer.

Free Radic Biol Med 2011 May 16;50(10):1344-54. Epub 2011 Feb 16.

Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.

Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.
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http://dx.doi.org/10.1016/j.freeradbiomed.2011.02.007DOI Listing
May 2011

Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+ -ATPase subunitst.

J Exp Ther Oncol 2010 ;8(4):271-86

Department of Experimental Therapeutics, The Univ. of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

The membrane enzyme Na+, K+ -ATPase is known to help maintain ion homeostasis in mammalian cells. Newly identified functions of this enzyme suggest that inhibition of Na+, K+ -ATPase by cardiac glycosides may be useful to patients with cancer. Twelve human tumor cell lines were chosen to examine determinants of human tumor cell sensitivity to cardiac glycosides. In vitro cell culture models of human glioma HF U251 and U251 cells as well as human parental and modified melanoma BRO cells were also included in these studies. Data derived from both models and twelve tumor cell lines indicated that high expression of Na+, K+ -ATPase alpha 1 isoform in the presence of low alpha 3 expression correlated with increased resistance to inhibition of cell proliferation by cardiac glycosides such as oleandrin, ouabain and bufalin. Interestingly, increased expression of Na+, K+ -ATPase alpha 1 and therefore total Na+, K+ -ATPase activity is associated with increased cellular levels of glutathione. The altered enzyme activity and glutathione content were associated with a delayed and diminished release of cytochrome c and caspase activation. Additionally, an increased colony-forming ability was noted in cells with high levels of Na+, K+ -ATPase alpha 1 expression, suggesting that Na+, K+ -ATPase alpha 1 isoform may be actively involved in tumor growth and cell survival. Its inhibition by cardiac glycosides may provide a strategy for effective cancer therapy.
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February 2011

Profiling lipoxygenase metabolism in specific steps of colorectal tumorigenesis.

Cancer Prev Res (Phila) 2010 Jul 22;3(7):829-38. Epub 2010 Jun 22.

Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, 77030-4009, USA.

Lipoxygenases (LOX) are key enzymes for the oxidative metabolism of polyunsaturated fatty acids into biologically active products. Clinical data on comparative levels of various LOX products in tumorigenesis are lacking. Therefore, we examined the profiles of several LOX products (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2) by liquid chromatography/tandem mass spectrometry in the major steps of colorectal tumorigenesis (normal, polyp, and cancer) in a clinical study of 125 subjects (49 with normal colon, 36 with colorectal polyps, and 40 with colorectal cancer) who underwent prospective colorectal biopsies to control for various potential confounding factors (e.g., diet, medications). Mean 13-hydroxyoctadecadienoic acid (13-HODE) levels were significantly higher in normal colon [mean, 36.11 ng/mg protein; 95% confidence interval (95% CI), 31.56-40.67] than in paired colorectal cancer mucosa (mean, 27.01 ng/mg protein; 95% CI, 22.00-32.02; P = 0.0002), and in normal colon (mean, 37.15 ng/mg protein; 95% CI, 31.95-42.34) than in paired colorectal polyp mucosa (mean, 28.07 ng/mg protein; 95% CI, 23.66-32.48; P < 0.001). Mean 13-HODE levels, however, were similar between the left (mean, 37.15 ng/mg protein; 95% CI, 31.95-42.35) and the right normal colon (mean, 32.46 ng/mg protein; 95% CI, 27.95-36.98; P = 0.09). No significant differences with regard to 12- or 15-hydroxyeicosatetraenoic acid or leukotriene B(4) levels were detected between normal, polyp, and cancer mucosae. 15-LOX-1 inhibited interleukin-1beta expression. This study establishes that reduced 13-HODE levels are a specific alteration in the LOX product profile associated with human colorectal tumorigenesis.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900425PMC
July 2010

Pomegranate (Punica granatum) seed linolenic acid isomers: concentration-dependent modulation of estrogen receptor activity.

Endocr Res 2010 Jan;35(1):1-16

Department of Experimental Therapeutics, Kyungpook National University, Taegu, Republic of Korea.

Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 microM, ERbeta at 8.8 microM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 microM. PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 microM, antagonizing at 101/80 microM. AEA antagonized ERalpha/ERbeta at 150/140 microM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.
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http://dx.doi.org/10.3109/07435800903524161DOI Listing
January 2010

Biological activity of celecoxib in the bronchial epithelium of current and former smokers.

Cancer Prev Res (Phila) 2010 Feb 26;3(2):148-59. Epub 2010 Jan 26.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Non-small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers-a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non-small cell lung cancer chemoprevention may be warranted.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028718PMC
February 2010