Oncology Commons^™

Effect Of Sirna Pre-Exposure On Subsequent Response To Sirna Therapy, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Nicole Chan, Hasan Uludag

Pharmacy Faculty Articles and Research

PURPOSE. An alternative cancer therapy based on RNA interference (RNAi) has shown considerable promise but the possibility of resistance development is not known. This study explored the possibility of therapeutic resistance against siRNA nanoparticles in human cancer cells. METHODS. Two approaches to siRNA treatment were undertaken using lipid-modified polyethylenimines, a single high concentration (shock) and repeated increasing concentrations (gradual). The targets were Mcl-1, RPS6KA5 and KSP in MDA-MB-435 cells. RESULTS. There was no evidence of resistance development in shock-treated cells, while the decrease in mRNA levels of targeted proteins was not as robust in naïve cells in gradual treatment. However, …

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 …

Targeting Cell Cycle Proteins In Breast Cancer Cells With Sirna By Using Lipid-Substituted Polyethylenimines, Manoj Parmar, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Robert Maranchuk, Judith C. Hugh, Hasan Uludag

Pharmacy Faculty Articles and Research

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle …

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.

Engineered Plga Nanoparticles For Delivery Of Sirna In Mcf-7 Breast Cancer Cells, Sydney Pong, Samit Shah, Vivek Gupta

Student Scholar Symposium Abstracts and Posters

Small interfering RNAs have been an emerging medical treatment for molecular based diseases as they are capable of gene-specific knockdown. Appropriate and efficient delivery remains one of the biggest challenges in the development of siRNA as an anti-cancer treatment. Nanoparticles containing siRNA were characterized and the efficacy of various peptides in the transfection of the nanoparticles were tested. A gene silencing assay was developed in order to determine the effect of siRNA therapeutics on gene functionality in breast cancer cells.

Molecular Insights Into Prostate Field Cancerization: Telomere Length, Egr-­‐1 Expression, And Regulation Of Mic-­‐1, Pdgf-­‐A, And Fas, Emily Frisch, Kristin Gabriel, Marco Bisoffi

Student Scholar Symposium Abstracts and Posters

The diagnosis of prostate cancer (adenocarcinoma) relies on screening for elevated prostate-specific antigen (PSA) in blood samples and on digital rectal examination (DRE). With high PSA levels and/or abnormal DRE, physicians recommend a biopsy, which often misses the location of the adenocarcinoma and results in false negatives. Previous studies have shown expression of the key transcription factor early growth response 1 (EGR-1), the pro-survival factor macrophage inhibitor cytokine 1 (MIC-1), and the growth stimulatory platelet derived growth factor A (PDGF-A) to be up-regulated in histologically normal tissues 1 centimeter adjacent to prostate adenocarcinomas. We hypothesize that tumors emerge from “field …

Toxicity And Cosmesis Outcomes For Single Fraction Intra-Operative Electron Radiotherapy (Ioert) For Breast Cancer, Monica Hanna, Robert Ash, Wesley Babaran, Michele M. Carpenter, Afshin Forouzannia, Jay K. Harness, Brian Kaltenecker, Snehith Maddula, Venita Williams, Lawrence Wagman

Student Scholar Symposium Abstracts and Posters

Background: Adjuvant radiation therapy is proven to reduce local recurrence in patients with early stage breast cancer. To reduce toxicity, improve geographic accuracy, and reduce treatment time, IOERT can be utilized as an alternative to external beam radiation therapy. The study’s objective was to determine the short term toxicity and cosmesis profile of single fraction IOERT given as definitive treatment in a community setting. Materials and Methods: From Mar 2012 to Jul 2014, 84 patients (3 bilateral), ages 45-91 y.o. with stage 0-II were treated with IOERT (Mobetron, IntraOp Medical, Sunnyvale, CA). A single 21 Gy fraction was administered to …

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 …

Beta-Alanine Suppresses Malignant Breast Epithelial Cell Aggressiveness Through Alterations In Metabolism And Cellular Acidity In Vitro, Roger A. Vaughan, Nicholas P. Gannon, Randi Garcia-Smith, Yamhilette Licon-Munoz, Miguel A. Barberena, Marco Bisoffi, Kristina A. Trujillo

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Background: Deregulated energetics is a property of most cancer cells. This phenomenon, known as the Warburg Effect or aerobic glycolysis, is characterized by increased glucose uptake, lactate export and extracellular acidification, even in the presence of oxygen. beta-alanine is a non-essential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. Because of this buffering capacity, we investigated the effects of beta-alanine on the metabolic cancerous phenotype.

Methods: Non-malignant MCF-10a and malignant MCF-7 breast epithelial cells were treated with beta-alanine at 100 mM for 24 hours. Aerobic glycolysis was quantified …

Structure-Functional Prediction And Analysis Of Cancer Mutation Effects In Protein Kinases, Anshuman Dixit, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational …

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 …

Synthesis And Antiproliferative Activities Of Quebecol And Its Analogs, Kasiviswanadharaju Pericherla, Amir Nasrolahi Shirazi, V. Kameshwara Rao, Rakesh Tiwari, Nicholas Dasilva, Kellen Mccaffrey, Yousef A. Beni, Antonio González- Sarrías, Navindra P. Seeram, Keykavous Parang, Anil Kumar

Pharmacy Faculty Articles and Research

Simple and efficient synthesis of quebecol and a number of its analogs was accomplished in five steps. The synthesized compounds were evaluated for antiproliferative activities against human cervix adenocarcinoma (HeLa), human ovarian carcinoma (SK-OV-3), human colon carcinoma (HT-29), and human breast adenocarcinoma (MCF-7) cancer cell lines. Among all the compounds, 7c, 7d, 7f, and 8f exhibited antiproliferative activities against four tested cell lines with inhibition over 80% at 75 mu M after 72 h, whereas, compound 7b and 7g were more selective towards MCF-7 cell line. The IC50 values for compounds 7c, 7d, and 7f were 85.1 mu M, 78.7 …

Associations Among Family History Of Cancer, Cancer Screening And Lifestyle Behaviors: A Population-Based Study, Georgiana Bostean, Catherine M. Crespi, William J. Mccarthy

Sociology Faculty Articles and Research

Purpose Some cancers are largely preventable through modification of certain behavioral risk factors and preventive screening, even among those with a family history of cancer. This study examined the associations between (1) family cancer history and cancer screening, (2) family history and cancer preventive lifestyle behaviors, and (3) cancer screening and lifestyle behaviors.

Methods Data were from the 2009 California Health Interview Survey (n = 12,603). Outcomes included screening for breast cancer (BC) and colorectal cancer (CRC) and six cancer preventive lifestyle behaviors, based on World Cancer Research Fund recommendations. Multivariate logistic regression analyses, stratified by gender and race–ethnicity, examined …

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 …

4-Aryl-4h-Naphthopyrans Derivatives: One-Pot Synthesis, Evaluation Of Src Kinase Inhibitory And Anti-Proliferative Activities, Ali Rafinejad, Asal Fallah-Tafti, Rakesh Tiwari, Amir Nasrolahi Shirazi, Dindyal Mandal, Abbas Shafiee, Keykavous Parang, Alireza Foroumadi, Tahmineh Akbarzadeh

Pharmacy Faculty Articles and Research

Background: A series of 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives were synthesized and evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines.

Methods: The one-pot, three-component reaction of a or beta-naphthol, malonitrile and an aromatic aldehyde in the presence of diammonium hydrogen phosphate was afforded the corresponding 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives, All target compounds were evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines.

Results: Among all tested compounds, unsubstituted 4-phenyl analog 4a showed Src kinas inhibitory effect with IC50 value of 28.1 mu M and was …

Effective Non-Viral Delivery Of Sirna To Acute Myeloid Leukemia Cells With Lipid-Substituted Polyethylenimines, Breanne Landry

Pharmacy Faculty Articles and Research

Use of small interfering RNA (siRNA) is a promising approach for AML treatment as the siRNA molecule can be designed to specifically target proteins that contribute to aberrant cell proliferation in this disease. However, a clinical-relevant means of delivering siRNA molecules must be developed, as the cellular delivery of siRNA is problematic. Here, we report amphiphilic carriers combining a cationic polymer (2 kDa polyethyleneimine, PEI2) with lipophilic moieties to facilitate intracellular delivery of siRNA to AML cell lines. Complete binding of siRNA by the designed carriers was achieved at a polymer:siRNA ratio of ~0.5 and led to siRNA/polymer complexes of …

Fatty Acyl Amide Dderivatives Of Doxorubicin: Synthesis And In Vitro Anticancer Activities, Bhupender S. Chhikara, Nicole St. Jean, Deendayal Mandal, Anil Kumar, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin is an anticancer drug extensively used in anticancer therapy. Doxorubicin is highly hydrophilic, has short half-life, and its use is associated with severe side effects at high doses. Fatty acyl amide derivatives of doxorubicin were synthesized with the expectation to improve the lipophilicity and anticancer activity of the drug. The lipophilicity was enhanced with the increase in chain length of fatty acyl moiety. Conjugation of 4-amino group with fatty acids through an amide bond reduced the anticancer activity in leukemia, breast, ovarian, and colon cancer cell lines, suggesting that the presence of free amino group is required for anticancer …

3-Substitued Indoles: One Pot Synthesis And Evaluation Of Anticancer And Src Kinase Inhibitory Activities, V. Kameshwara Rao, Bhupender S. Chhikara, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, Anil Kumar

Pharmacy Faculty Articles and Research

An efficient and economical method was developed for the synthesis of 3-substituted indoles by one pot three-component coupling reaction of a substituted or unsubstituted benzaldehyde, N-methylaniline, and indole or N-methylindole using Yb(OTf)3-SiO2 as a catalyst. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. The 4-methylphenyl (4o and 4p) and 4-methoxyphenyl (4q) indole derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 7077% at a concentration of 50 μM. The unsubstituted phenyl (4d) and 3-nitrophenyl (4l) derivatives showed the inhibition of c-Src kinase …

Synthesis Of 3-Phenylpyrazolopyrimidine-1,2,3-Triazole Conjugates And Evaluation Of Their Src Kinase Inhibitory And Anticancer Activities, Anil Kumar, Israr Ahmad, Bhupender S. Chhikara, Rakesh Tiwari, Deendayal Mandal, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyl triazolyl-substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with an IC50 value of 5.6 µM. 4-Methoxyphenyl triazolyl-substituted 3-phenylpyrazolopyrimidine inhibited the cell proliferation of HT-29 and SK-Ov-3 by 73% and 58%, respectively, at a concentration of 50 µM.

Thiazolyl N-Benzyl-Substituted Acetamide Derivatives: Synthesis, Src Kinase Inhibitory And Anticancer Activities, Asal Fallah-Tafti, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G. Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee

Pharmacy Faculty Articles and Research

KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI50 values of 1.34 μM and 2.30 M in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. …

Chemosensitization Of Cancer Cells By Sirna Using Targeted Nanogel Delivery, Erin B. Dickerson, William H. Blackburn, Michael H. Smith, Laura B. Kapa, L. Andrew Lyon, John F. Mcdonald

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Background: Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy. However, delivery represents the main hurdle for the broad development of RNAi therapeutics.

Methods: We report here …