Pharmacy and Pharmaceutical Sciences Commons^™

S100a4 Drives Non-Small Cell Lung Cancer Invasion, Associates With Poor Prognosis, And Is Effectively Targeted By The Fda-Approved Anti-Helminthic Agent Niclosamide, Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Lili Liu, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Eric B. Durbin, Susanne M. Arnold, Kathleen L. O'Connor, Min Chen

Markey Cancer Center Faculty Publications

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular …

Current Therapeutic Role And Medicinal Potential Of Scutellaria Barbata In Traditional Chinese Medicine And Western Research, Geyang Tao, Marcy J. Balunas

Honors Scholar Theses

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria barbata is a common herb in Traditional Chinese Medicine (TCM) most often used to treat cancer. S. barbata has been found to exhibit efficacy both in vitro and in vivo on a variety of cancer types. Similarly encouraging results have been shown in patients with metastatic breast cancer from Phase Ia and Ib clinical trials. This study aims to elucidate the current use of S. barbata by TCM practitioners and in current Western research.

MATERIALS AND METHODS: Semi-structured interviews were conducted with fifteen TCM practitioners in Beijing and Nanjing, China to understand their clinical use of …

Tumor Growth Suppressive Effect Of Il-4 Through P21-Mediated Activation Of Stat6 In Il-4rα Overexpressed Melanoma Models, Hye Lim Lee, Mi Hee Park, Ju Kyoung Song, Yu Yeon Jung, Youngsoo Kim, Kyung Bo Kim, Dae Yeon Hwang, Do Young Yoon, Min Jong Song, Sang Bae Han, Jin Tae Hong

Pharmaceutical Sciences Faculty Publications

To evaluate the significance of interleukin 4 (IL-4) in tumor development, we compared B16F10 melanoma growth in IL-4-overespressing transgenic mice (IL-4 mice) and non-transgenic mice. In IL-4 mice, reduced tumor volume and weight were observed when compared with those of non-transgenic mice. Significant activation of DNA binding activity of STAT6, phosphorylation of STAT6 as well as IL-4, IL-4Rα and p21 expression were found in the tumor tissues of IL-4 mice compared to non-transgenic mice. Higher expression of IL-4, STAT6 and p21 in human melanoma tissue compared to normal human skin tissue was also found. Higher expression of apoptotic protein such …

Incidence And Risk Factors Of Thromboembolism With Multiple Myeloma In The Presence Of Death As A Competing Risk: An Empirical Comparison Of Statistical Methodologies, Joshua D. Brown, Val R. Adams

Pharmacy Practice and Science Faculty Publications

Multiple myeloma (MM) has an inherent high risk of thromboembolic events associated with patient as well as disease- and treatment-related factors. Previous studies have assessed the association of MM-related thromboembolism using “traditional” Kaplan–Meier (KM) and/or Cox proportional hazard (PH) regression. In the presence of high incidence of death, as would be the case in cancer patients with advanced age, these statistical models will produce bias estimates. Instead, a competing risk framework should be used. This study assessed the baseline patient demographic and clinical characteristics associated with MM-related thromboembolism and compared the cumulative incidence and the measures of association obtained using …

Multiple Sirna Delivery Against Cell Cycle And Anti-Apoptosis Proteins Using Lipid-Substituted Polyethylenimine In Triplenegative Breast Cancer And Non-Malignant Cells, Manoj B. Parmar, Bárbara E. Arteaga Ballesteros, Timothy Fu, Remant Bahadur Kc, Hamidreza Montazeri Aliabadi, Judith C. Hugh, Raimar Löbenberg, Hasan Uludag

Pharmacy Faculty Articles and Research

Conventional breast cancer therapies have significant limitations that warrant a search for alternative therapies. Short-interfering RNA (siRNA), delivered by polymeric biomaterials and capable of silencing specific genes critical for growth of cancer cells, holds great promise as an effective and more specific therapy. Here, we employed amphiphilic polymers and silenced the expression of two cell cycle proteins, TTK and CDC20, and the anti-apoptosis protein survivin to determine the efficacy of polymer-mediated siRNA treatment in breast cancer cells as well as side effects in non-malignant cells in vitro. We first identified effective siRNA carriers by screening a library of lipid-substituted polyethylenimines …

Pamam Dendrimers As Promising Nanocarriers For Rnai Therapeutics, Prashant Kesharwani, Sanjeev Banerjee, Umesh Gupta, Mohd Cairul Iqbal Mohd Amin, Subhash Padhye, Fazlul H. Sarkar, Arun K. Iyer

Pharmaceutical Sciences Faculty Publications

Therapeutics based on RNA interference mechanisms are highly promising for the management of several diseases including multi-drug resistant cancers. However, effective delivery of siRNAs and oligonucleotides still remains challenging. In this regard, hyper-branched, PAMAM dendrimers having unique three-dimensional architecture and nanoscale size, with cationic surface charge can potentially serve as siRNA condensing agents as well as robust nano-vectors for targeted delivery. In addition, their surface functionality permits conjugation of drugs and genes or development of hybrid systems for combination therapy. Thus far, in vitro cellular testing of dendrimer-mediated siRNA delivery has revealed great potential, with reports on their in vivo …

Pharmacists On The Front Lines Of Polypharmacy: The Individualized Medication Assessment And Planning (Imap) Project To Improve Medication Use In Senior Adults With Cancer, Ginah Nightingale Pharmd, Bcop, Laura T. Pizzi Pharmd, Mph, Emily Hajjar Pharmd, Bcps, Bcacp, Cgp, Elizabeth Pigott, Margaret Wang, Shannon Doherty, Kristine Swartz Md, Andrew Chapman Do, Facp

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Patent No. Us 9,090,589 B2: Specific Nnos Inhibitors For The Therapy And Prevention Of Human Melanoma, Richard B. Silverman, Frank L. Meyskens Jr., Sun Yang, Haitao Ji, Fengtian Xue, Thomas L. Poulos

Pharmacy Faculty Articles and Research

Methods for melanoma treatment and prevention with selective nitric oxide synthase inhibitor compounds and related pharmaceutical compositions, alone or in conjunction with one or more other melanoma therapies.

New Approach To Develop Ultra-High Inhibitory Drug Using The Power Function Of The Stoichiometry Of The Targeted Nanomachine Or Biocomplex, Dan Shu, Fengmei Pi, Chi Wang, Peng Zhang, Peixuan Guo

Pharmaceutical Sciences Faculty Publications

AIMS: To find methods for potent drug development by targeting to biocomplex with high copy number.

METHODS: Phi29 DNA packaging motor components with different stoichiometries were used as model to assay virion assembly with Yang Hui's Triangle [Formula: see text], where Z = stoichiometry, M = drugged subunits per biocomplex, p and q are the fraction of drugged and undrugged subunits in the population.

RESULTS: Inhibition efficiency follows a power function. When number of drugged subunits to block the function of the complex K = 1, the uninhibited biocomplex equals q(z), demonstrating the multiplicative effect of stoichiometry on inhibition with …

Clinical Applications Of A Combination Chemotherapy Using 8-Chloro Camp And 8-Chloro Adenosine, Erik Munoz, Andrea Saich, Andrew Cox, Yu-An Peter Chang

Student Scholar Symposium Abstracts and Posters

Dr. Cho-Chung from the NIH first thought to use halogenated cAMP derivatives as competitive inhibitors of cAMP to slow down cancer cell mitosis. While the iodine and bromine substituted versions showed very little therapeutic actions, 8-Chloro cAMP has been shown to have strong anti-cancer effects. This has been shown in the phase II clinical trials this drug has undergone. However, these trials have had issues with solubility and toxicity. The drug is similar to vitamin C and is excreted quickly. Scientists tried to overcome this by using a peristaltic pump to give patients a continuous dosage, but this proved too …

Polymeric Nanoparticle-Based Delivery Of Microrna-199a-3p Inhibits Proliferation And Growth Of Osteosarcoma Cells, Linlin Zhang, Arun K. Iyer, Xiaoqian Yang, Eisuke Kobayashi, Yuqi Guo, Henry Mankin, Francis J. Hornicek, Mansoor M. Amiji, Zhenfeng Duan

Pharmaceutical Sciences Faculty Publications

Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain …

The Flavonoid Nobiletin Inhibits Tumor Growth And Angiogenesis Of Ovarian Cancers Via The Akt Pathway, Jianchu Chen, Allen Y. Chen, Haizhi Huang, Xingqian Ye, William D. Rollyson, Haley E. Perry, Kathleen C. Brown, Yon Rojanasakul, Gary O. Rankin, Piyali Dasgupta, Yi Charlie Chen

Pharmaceutical Science and Research

Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving …

Mdr1 Sirna Loaded Hyaluronic Acid-Based Cd44 Targeted Nanoparticle Systems Circumvent Paclitaxel Resistance In Ovarian Cancer, Xiaoqian Yang, Arun K. Iyer, Amit Singh, Edwin Choy, Francis J. Hornicek, Mansoor M. Amiji, Zhenfeng Duan

Pharmaceutical Sciences Faculty Publications

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of …

The Cost Of Treating Cancer Patients With Antineoplastic Medications During Inpatient Hospital Admission, Alexandra Foster, David J. Reeves

Scholarship and Professional Work – COPHS

Abstract from 2015 American College of Clinical Pharmacy Global Conference, San Francisco, CA

Tolerability Of Induction Chemotherapy Dosing Practices In Acute Myeloid Leukemia Patients, Kaylene M. Peric, David J. Reeves

Scholarship and Professional Work – COPHS

For patients with high body surface areas (BSA), differing chemotherapy dosing strategies have been utilized in attempts to reduce toxicity. In a retrospective evaluation, we compared the effects of chemotherapy dosing in acute myeloid leukemia patients with high BSA (>2 m²) who received capped doses (n = 12) to those who received uncapped doses (n = 24), and to patients with BSA ≤ 2 m² (n = 42). There were no statistically significant differences among groups (BSA ≤ 2 m², BSA > 2 m² capped, and BSA > 2 m² uncapped) …

Curcuminoid In Nanoemulsion Formulations Cause Enhanced Cell Death In The Hela Cancer Cell Culture Model, Nikita Kheradia, Nandita Das, Sudip Das

Scholarship and Professional Work – COPHS

Purpose: To formulate and characterize curcuminoid (insoluble chemoprevention agent) loaded nanoemulsions and evaluate their cytotoxicity in HeLa cells.

Drug-Induced Cardiotoxicity Of Oncological Agents: Monitoring Parameters, Prevention, And Future Chemotherapy, Sarah Nguyen, Mary Nguyen, Laura Tsu

Pharmacy Faculty Articles and Research

The goal of this article is to educate pharmacists of the impact of cardiotoxicity on chemotherapy regimens including key cancer agents, monitoring parameters, prevention, and the future of chemotherapy.

The Role Of Ape/Ref-1 In Hepatocellular Carcinoma Progression, Zhen Yang, Sun Yang, Bobbye J. Misner, Feng Liu-Smith, Frank L. Meyskens

Pharmacy Faculty Articles and Research

Hepatocellular carcinoma (HCC) is responsible for a third of the estimated cancer-caused deaths worldwide. To deeply understand the mechanisms controlling HCC progression is of primary importance to develop new approaches for treatment. Apurinic/apyrimidinic endonuclease-1/redox effector factor 1 (APE/Ref-1) has been uncovered elevated in various types of cancer, including HCC. Additionally, HCC progression is always correlated with elevated copper (Cu). Our previous data demonstrated that Cu treatment initiated APE/Ref-1 expression and its downstream targets. Therefore, we hypothesized that APE/Ref-1 may be involved in HCC progression through mediating the effect of Cu to its signaling cascades. Following different treatments, human HCC cell …

Influence Networks Based On Coexpression Improve Drug Target Discovery For The Development Of Novel Cancer Therapeutics, Nadia M. Penrod, Jason H. Moore

Dartmouth Scholarship

Background: Thedemandfornovelmolecularlytargeteddrugswillcontinuetoriseaswemoveforwardtowardthe goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. …

Gold(Iii)-Dithiocarbamato Peptidomimetics In The Forefront Of The Targeted Anticancer Therapy: Preclinical Studies Against Human Breast Neoplasia, Chiara Nardon, Sara M. Schmitt, Huanjie Yang, Jian Zuo, Delores Fregona, Q. Ping Dou

Oncology Faculty Publications

Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. …

Quantification Of Factors Governing Drug Release Kinetics From Nanoparticles: A Combined Experimental And Mechanistic Modeling Approach, Kyle Daniel Fugit

Theses and Dissertations--Pharmacy

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.

A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release …

Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin

Theses and Dissertations--Pharmacy

Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …

Characterization Of Prophylactic Antiemetic Regimens In Pediatric Patients Receiving Moderately And Highly Emetogenic Chemotherapy, Jessica Degiacomo Pharmd, Kristin M. Held Pharmd, Bcop

Department of Pharmacy

No abstract provided.

Synthesis Of Novel Ciprofloxacin Analogues And Evaluation Of Their Anti-Proliferative Effect On Human Cancer Cell Lines, Narva Suresh, Hunsur Nagendra Nagesh, Kondapalli Venkata Govri Chandra Sekhar, Anil Kumar, Amir Nasrolahi Shirazi, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of twenty two novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substitutedpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized (1H NMR, 13C NMR and LCMS) and evaluated for their inhibitory activity on the proliferation of human caucasian acute lymphoblastic leukemiacells (CCRF-CEM), breast adenocarcinoma cells (MDA-MB-468) and human colon carcinoma cells (HCT-116). Among all the synthesized ciprofloxacin analogues 3t at 50 µM showed comparable potency to doxorubicin (10mol) in all three cell lines and 3j inhibited proliferation of MDA-MB-468 up to 35% selectively over other two cell lines. Cancer is a leading cause of death worldwide. It is a group of diseases characterized by uncontrolled growth. Cancer …

Combination Of Sirna-Directed Gene Silencing With Cisplatin Reverses Drug Resistance In Human Non-Small Cell Lung Cancer, Shanthi Ganesh, Arun K. Iyer, Jan Weller, David V. Morrissey, Mansoor M. Amiji

Pharmaceutical Sciences Faculty Publications

One of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug-resistant (MDR) phenotype. One effective approach would be to identify and downregulate resistance-causing genes in tumors using small interfering RNAs (siRNAs) to increase the sensitivity of tumor cells to chemotherapeutic challenge. After identifying the overexpressed resistance-related antiapoptotic genes (survivin and bcl-2) in cisplatin-resistant cells, the siRNA sequences were designed and screened to select the most efficacious candidates. Modifications were introduced in them to minimize off-target effects. Subsequently, the combination of siRNA and cisplatin that gave the maximum synergy was identified in resistant cells. We then …

Flurbiprofen Benzyl Nitrate (Nbs-242) Inhibits The Growth Of A-431 Human Epidermoid Carcinoma Cells And Targets Β-Catenin, Niharika Nath, Xiaoping Liu, Lloydine Jacobs, Khosrow Kashfi

Publications and Research

Background: The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing moiety through a chemical spacer. Previously we showed that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer.

Methods: We synthesized an NO-releasing NSAID with an aromatic spacer (flurbiprofen benzyl nitrate, NBS-242), and using the human skin cancer cell line A-431, we evaluated its effects on cell kinetics, Wnt/β-catenin, cyclin D1, and caspase-3.

Results: NBS-242 inhibited the growth of …

Gambogic Acid Is A Tissue-Specific Proteasome Inhibitor In Vitro And In Vivo, Xiaofen Li, Shouting Liu, Hongbiao Huang, Ningning Liu, Chong Zhao, Siyan Liao, Changshan Yang, Yurong Liu, Canguo Zhao, Shujue Li, Xiaoyu Lu, Chunjiao Liu, Lixia Guan, Kai Zhao, Xiaoqing Shi, Wenbin Song, Ping Zhou, Xiaoxian Dong, Haiping Guo, Guanmei Wen, Change Zhang, Lili Jiang, Ningfang Ma, Bing Li, Shunqing Wang, Huo Tan, Xuejun Wang, Q. Ping Dou, Jinbao Lin

Oncology Faculty Publications

Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues …

An Update On Braf Inhibitors And Other New Molecular Targets For The Treatment Of Malignant Melanoma Of The Skin, M. O. Faruk Khan, Carroll L. Ramos

Pharmaceutical Science and Research

Malignant melanoma of the skin originates from mutations in melanocytes and can be lethal if unrecognized or untreated in its earlier stages. Deaths from melanoma are increasing in the United States and around the world every year. The available treatments produce low rates of response with modest survival impact. Among potential molecular targets under investigation, which are mostly in the tyrosine kinase pathway, the BRAF (V-raf murine sarcoma viral oncogene homolog B1) gene is the best studied and most frequently reported mutation in melanoma. The molecular targets for melanoma treatment, promising drugs for future melanoma treatment as well as the …

Activation Of Amp-Activated Protein Kinase By 3,39-Diindolylmethane (Dim) Is Associated With Human Prostate Cancer Cell Death In Vitro And In Vivo, Di Chen, Sanjeev Banerjee, Qiuzhi C. Cui, Dejuan Kong, Fazlul H. Sarkar, Q. Ping Dou

Oncology Faculty Publications

There is a large body of scientific evidence suggesting that 3,39-Diindolylmethane (DIM), a compound derived from the digestion of indole-3-carbinol, which is abundant in cruciferous vegetables, harbors anti-tumor activity in vitro and in vivo. Accumulating evidence suggests that AMP-activated protein kinase (AMPK) plays an essential role in cellular energy homeostasis and tumor development and that targeting AMPK may be a promising therapeutic option for cancer treatment in the clinic. We previously reported that a formulated DIM (BR-DIM; hereafter referred as B-DIM) with higher bioavailability was able to induce apoptosis and inhibit cell growth, angiogenesis, and invasion of prostate cancer cells. …

Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Development of tumor resistance to chemotherapeutics is related to inherent tumor variations regarding sensitivity to chemotherapeutics and to sub-optimal dosing regimens, including variation in patient pharmacokinetics that result in suboptimal exposure of tumor cells to anti-neoplastic drugs [1, 2]. The rate and extent of drug efficacy depends on the extent of drug exposure at the tumor site and the time above the effective concentration [3]. In vitro models that incorporate these pharmacokinetic and pharmacodynamic (PK/PD) principles to optimize therapeutic response may be considered the method of choice for optimizing dosing schedules before translating data from static assays to animals and …