Drug Docetaxel Research Articles

Mathematical modeling in scheduling cancer treatment with combination of VEGF inhibitor and chemotherapy drugs

The present paper considers a treatment of cancer with a combination of anti-VEGF (bevacizumab) and a chemotherapy drug (docetaxel). Since anti-VEGF reduces the perfusion of chemotherapy drugs, the question arises whether it is more effective to administer the two drugs at the same time, or non-overlapping, in order to reduce tumor volume more effectively. To address this question we develop a mathematical model and use it to simulate different schedules. We find that the treatment of cancer would be far more effective if the two drugs are given non-overlappingly, with the chemotherapy drug at day 0 and anti-VEGF at day 7 in cycles of 21 days.

Nanotechnology-based combinational drug delivery systems for breast cancer treatment

Modern chemotherapeutic anticancer treatments have come a long way in the fight against breast cancer, thus bringing science closer to a cure. However, the nature of these drugs is to attack both cancerous and non-cancerous cells at the same time. In our studies, we synthesized Magnetic Cyclodextrin-polyurethane based nano-composite (Fe3O4-ECA-PU-CD) which is a drug delivery system using a biocompatible magnetic polymer that directs chemotherapeutic drugs to cancerous regions in the body with an external magnet. This nano-composite was able to facilitate the loading and simultaneous release of the hydrophilic antitumor drug Doxorubicin (DOX) along with the hydrophobic antitumor drug docetaxel. The composite was made using a simple co-precipitation method with magnetic nano-particles (MNPs) followed by a silica coating process and an in situ polymerization process. Verification of synthesis for the drug carrier was carried out using techniques such as scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), Thermogravimetric Analysis (TGA), and a vibrating sample magnetometer (VSM) to measure magnetic properties. Drug loading and release efficiencies were monitored using an HPLC-UV detector. Finally, an MTT assay was performed in order to evaluate the biocompatibility and toxicity of the synthetic nano-composite on MCF7 cell lines. Our findings present a new biocompatible drug delivery system with a high capacity for loading and directing two different chemotherapeutic drugs simultaneously to cancer sites with little to no toxicity to the surrounding non-cancerous cells. These studies present a viable tool for cancer treatment and research where the cancer is efficiently removed while the patient remains healthy.

N,N,N-trimethyl chitosan embedded in situ Pluronic F127 hydrogel for the treatment of brain tumor

The malignant gliomas are most destructive brain tumor having low drug response. The thermosensitive hydrogel from pluronic F127 (PF127) and N,N,N-trimethyl chitosan (TMC) is developed as a drug delivery system for anticancer drug docetaxel (DTX) to the glioblastoma multiforme. The influence of TMC on morphology, physico-chemical, mechanical, and release properties of PF127 based thermosensitive hydrogel is investigated here. The hydrogels shows porous network as shown by scanning electron microscopy and TMC addition hindered close packing of PF127 layers in the gel system leaving more pores on the surface. TEM images demonstrate micelle formation by PF127-TMC with diameters of about 50 nm. MTT assay result shows that DTX loaded PF127-TMC hydrogel is more capable of killing U87MG cell than free DTX and DTX loaded PF-127. Hydrogels retain sustained release of DTX under different pH conditions more than one month. Furthermore, in vivo experiments are carried out by creating xenograft tumor model on the head of BALB/c nude mice for checking tumor suppression by PF127-TMC/DTX hydrogel. Overall, the hydrogels shows sustained release of DTX on different pH with tumor suppression suggests that it can be used for treating tumor.

Optical study of chemotherapy efficiency in cancer treatment via intracellular structural disorder analysis using partial wave spectroscopy.

As cancer progresses, macromolecules, such as DNA, RNA or lipids, inside cells undergo spatial structural rearrangements and alterations. Mesoscopic light transport-based optical partial wave spectroscopy (PWS) was recently introduced to quantify changes in the nanoscale structural disorder in biological cells. The PWS measurement is performed using a parameter termed as "disorder strength" (L d ), which represents the degree of nanoscale structural disorder inside the cells. It was shown that cancerous cells have higher disorder strength than normal cells. In this work, we first used the PWS to analyze the hierarchy of different types of prostate cancer cells, namely, C4-2, DU-145 and PC-3, by quantifying their average disorder strengths. Results expectedly showed that L d values increases in accordance with the increasing aggressiveness/tumorigenicity levels of these cells. Using the L d parameter, we then analyzed the chemoresistance properties of these prostate cancer cells to docetaxel drug compared to their chemosensitivity. Results show that chemoresistant cancer cells have increased L d values, that is, higher disorder strength, relative to chemosensitive cancer cells. Thus, use of the L d metric can be effective in determining the efficacy of particular chemotherapy.

Sensitizing non-small cell lung cancer to BCL-xL-targeted apoptosis

Lung cancer is the leading cause of death in the United States, with non-small cell lung cancers (NSCLC) accounting for 85% of all cases. By analyzing the expression profile of the pro-apoptotic and anti-apoptotic proteins, we have assigned NSCLCs into two distinct groups. While single agent treatment with the BCL-2/BCL-xL/BCL-w inhibitor ABT-263 (navitoclax) did not trigger apoptosis in either group, cells with a moderate to high level of MCL-1 expression were sensitive to ABT-263 treatment when MCL-1 expression was suppressed with a gene-specific siRNA. In contrast, those with a low MCL-1 expression did not undergo apoptosis upon combination treatment with ABT-263 and MCL-1 siRNA. Further studies revealed that cells with a low MCL-1 expression had low mitochondrial priming, and treatment with the chemotherapy drug docetaxel raised the mitochondrial priming level and consequently sensitized cells to ABT-263. These results establish a rationale for molecular profiling and a therapeutic strategy to treat NSCLC patients with pro-apoptotic anti-cancer drugs based on their MCL-1 expression level.

Mutagenicity assessment of environmental contaminations in a hospital centralized reconstitution unit

IntroductionCytotoxic drug exposure of hospital staff preparing intravenous chemotherapy is a major issue and related mutagenic risks should be more explored. The aim of this study was to assess the mutagenicity of several cytotoxic mixtures prepared at fixed concentrations, and the mutagenicity of environmental samples collected in a hospital centralized reconstitution unit. In parallel cytotoxic exposure in environmental samples was quantified. MethodsEnvironmental samples were performed by wiping method using swabs in five critical production unit areas. Mutagenicity was assessed with a liquid microplate AMES test using two salmonella typhimurium strains (TA98 and TA100), in prepared cytotoxic mixtures containing 14 cytotoxic drugs (cyclophosphamide, cytarabine, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, methotrexate, paclitaxel and pemetrexed) according a dichotomous strategy and in environmental samples. Cytotoxic drugs were quantified in samples using liquid chromatography coupled to mass tandem spectrometry. ResultsMutagenesis was observed for the mix of 14 cytotoxic drugs with TA98 strain ± S9 fraction but not TA100 strain. After dichotomous approach, only doxorubicin and epirubicin exposure were associated to mutagenesis. The mutagenesis observed was expressed at lower concentrations with the mix of the 14 drugs than with anthracyclins alone, assuming a synergistic effect. Despite measurable level of cytotoxic contamination in environmental samples, no mutagenesis was highlighted in Ames tests performed on these environmental samples. ConclusionsThe analyses carried out show the conservation of the mutagenicity of cytotoxic drugs found in very low quantities in the environment. The traces of cytotoxic drugs found in our unit regularly exceed the limits given by some authors. This approach may be considered as a new tool to monitor environmental contamination by cytotoxic drugs.

Effects of 3-butenyl isothiocyanate on phenotypically different prostate cancer cells.

Isothiocyanates (ITCs) have gained increasing attention since they have been attributed the merits for the potential beneficial effects of cruciferous vegetable dietary consumption on cancer. The aim of the present study was to determine the cytotoxic effects of 3-butenyl ITC(3-BI) on prostate cancer(PC) cells under invitro conditions. Two androgen-insensitive human PC cell lines, PC-3 and DU145, were assayed. Cells were cultured in the presence of increasing concentrations of 3-BI (5, 10, 30 and 50µM) in the absence or presence of the chemotherapeutic drug docetaxel (DOCE) (1 and 2nM). The cytotoxic effects of these compounds were analyzed using the trypan blue exclusion assay at 24, 48 and 72h. Apoptosis and migration assays were also performed. The results showed that 3-BI induced a dose-dependent cytotoxic effect on PC-3 cells at 24, 48 and 72h. These effects were significantly higher than those found with DOCE at 72h of culture. Moreover, 3-BI also potentiated the effects of DOCE in a dose-dependent manner. Additionally, 3-BI showed inhibition of the migration of PC-3 cells. Nevertheless, 3-BI was not effective in the DU145 PC cell line. These results show a promising role for the 3-BI compound as a co-adjuvant agent in DOCE-based therapy in certain types of PC.

Boron nitride nanotubes as a nanotransporter for anti-cancer docetaxel drug in water/ethanol solution

Boron nitride nanotubes have gained significant attention as nano capsules for targeted drug delivery, and recently the behavior of drugs when encapsulated into BNNTs has been investigated. The goal of this article is to study the encapsulation of anticancer drug of DTX into BNNT (13, 13). All computations are surveyed by molecular dynamics simulation in water solution and EtOH co-solvent. The results indicate that encapsulation of DTX could be effected by the specific amounts of EtOH in mixtures. Some physical properties such as potential and Lennard-Jones energies, hydrogen bonding, number of contacts, also, the radial distribution function of DTX within BNNT and variation of the center of mass (COM) have been calculated during the simulation.

Role of zein incorporation on hydrophobic drug-loading capacity and colloidal stability of phospholipid nanoparticles.

Liposome, phosphatidylcholine nanoparticle (PC-NP), is an attractive colloidal carrier of hydrophobic drugs but its clinical development is often limited by low drug-loading capacity and the physical instability. Zein is a water-insoluble amphiphilic protein obtained from the corn. We herein investigated a possibility to develop zein-phosphatidylcholine hybrid nanoparticle (Z/PC-NP) as an advanced hydrophobic drug carrier. By employing the conventional liposome preparation method with the addition of zein, Z/PC-NP were produced. The extent of zein incorporation in PC-NP was affected by PC composition. DSC demonstrated the lowered phase transition temperature of PC by zein and FTIR showed the appearance of weakened but clear amide bonds of zein as well as increased levels of heterogeneous hydrogen bonding of Z/PC-NP compared to PC-NP. DLS, TEM and cryo-TEM studies suggested Z/PC-NP to be spherical nanoparticles composed of a zein core and a zein-PC hybrid shell. Z/PC-NP exhibited a higher loading capacity for hydrophobic model drugs (paclitaxel, docetaxel, celecoxib and curcumin), than did the zein nanoparticle and PC-NP, while exhibiting an intermediate drug release rate. The serum stability and the storage stability of Z/PC-NP were greater than those of PC-NP. Zein functioned as a cryoprotectant of PC-NP during freeze-drying. Z/PC-NP may provide a promising nanoparticle carrier of hydrophobic drugs.

Cyclic RGD-conjugated Pluronic® blending system for active, targeted drug delivery.

BackgroundBlending micellar systems of different types of polymers has been proposed as an efficient approach for tailor-made drug formulations. The lamellar structure of hydrophobic polymers may provide a high drug loading capacity, and hydrophilic polymers may provide good colloidal stability.MethodsIn this study, the anticancer model drug docetaxel was loaded onto a nanosized blending micellar system with two pluronics (L121/F127). To achieve increased antitumor activity, the cyclic arginine-glycine-aspartic acid tripeptide (cRGD) as an active tumor targeting ligand was conjugated to the blending system.ResultsThe docetaxel-loaded Pluronic blending system exhibited a higher drug loading capacity than that of F127 and showed high colloidal stability with a spherical structure. cRGD conjugates demonstrated enhanced drug cellular uptake and anticancer activity against αvβ3 integrin-overexpressing U87MG cancer cells. In vivo animal imaging also revealed that the prepared cRGD-conjugated nanoparticles effectively accumulated at the targeted tumor site through an active and passive targeting strategy.ConclusionAccordingly, the prepared nanosized system shows potential as a tailor-made, active targeting, nanomedicinal platform for anticancer therapy. We believe that this novel nanoplatform will provide insights for advancement of tumor therapy.

Dual drug delivery and sequential release by amphiphilic Janus nanoparticles for liver cancer theranostics

Co-delivery of two drugs with diverse physicochemical properties and specific administration order for cancer theranostics are vitally important for drug resistance conquering and side effects reducing. Consequently, we explored a unique amphiphilic PCL-AuNC/Fe(OH)3-PAA Janus nanoparticle (JNP) to simultaneously preserve the hydrophilic drug (doxorubicin) and hydrophobic drug (docetaxel) in their distinct domains. Owing to their extraordinary heterostructure and independent pH and NIR sensitive properties, the optional sequential drug release by a single inorganic JNP was realized for the first time, and the results presented the synchronous release of two drugs had 5% better therapeutic effect. In addition, the excellent computed X-ray tomography/magnetic resonance (CT/MR) imaging capabilities from AuNC and Fe(OH)3 suggested our JNPs could effectively guide the cancer therapy. Furthermore, the mice treated with dual drug loaded PCL-AuNC/Fe(OH)3-PAA JNPs under near infrared (NIR) laser irradiation showed better tumor inhibition than solo drug, cocktail and dual drug treated groups, indicating the effectivity and significance of combined cancer therapy.

Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport.

P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and VCR. However, the underlying mechanism is unclear. This study investigated the potential mechanism by which OPD improves P-gp-mediated drug transport. Molecular docking was performed to predict the binding force between OPD and P-gp and the contribution of OPD on P-gp activity. We observed the effect of OPD on the transport of VCR in MDCK-MDR1 cell monolayer and also measured the plasma pharmacokinetic parameters of DTX in the presence and absence of OPD by LC-MS/MS. Moreover, we further investigated the reversal mechanism of OPD on P-gp-mediated drug transport by determining the intracellular accumulation of Rhodamine-123 (Rh123) and P-gp ATPase activity as well as protein expression and mRNA level of P-gp. Our molecular docking results revealed that the binding force between OPD and P-gp was much lower than that between P-gp and verapamil (a P-gp substrate). The transport study in vitro indicated that OPD increased the flux of VCR across MDCK-MDR1 cell monolayer. The in vivo pharmacokinetic parameters data showed OPD increased the absorption of DTX. OPD activated P-gp ATPase activity and enhanced intracellular accumulation of Rh123 in MDCK-MDR1 cells. Western blotting and qRT-PCR outcomes indicated that OPD suppressed P-gp protein expression as well as downregulated P-gp mRNA level. Thus, OPD reverse P-gp-mediated drug transport via inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA level. Our results suggest that OPD could reverse P-gp-mediated drug resistance in tumor cells.

Design and testing of hydrophobic core/hydrophilic shell nano/micro particles for drug-eluting stent coating

In this study, we designed a novel drug-eluting coating for vascular implants consisting of a core coating of the anti-proliferative drug docetaxel (DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21. The core/shell structure was sprayed onto the surface of 316L stainless steel stents using a coaxial electrospray process with the aim of creating a coating that exhibited a differential release of the two drugs. The prepared stents displayed a uniform coating consisting of nano/micro particles. In vitro drug release experiments were performed, and we demonstrated that a biphasic mathematical model was capable of capturing the data, indicating that the release of the two drugs conformed to a diffusion-controlled release system. We demonstrated that our coating was capable of inhibiting the adhesion and activation of platelets, as well as the proliferation and migration of smooth muscle cells (SMCs), indicating its good biocompatibility and anti-proliferation qualities. In an in vivo porcine coronary artery model, the SZ-21/DTX drug-loaded hydrophobic core/hydrophilic shell particle coating stents were observed to promote re-endothelialization and inhibit neointimal hyperplasia. This core/shell particle-coated stent may serve as part of a new strategy for the differential release of different functional drugs to sequentially target thrombosis and in-stent restenosis during the vascular repair process and ensure rapid re-endothelialization in the field of cardiovascular disease.

Abstract 1158: Phenotypic screening using AMIDA identifies different drug responses in breast and prostate cancer cell lines in an organotypic cell culture model

Abstract Organotypic 3D cell culture models combined with screening modalities and automated high-content image analyses provide tools to gain a spectrum of biologically relevant information simultaneously from drug responses in tumor cells. This includes information about cell growth, death, differentiation and tumor cell invasion. In this study, we examined the phenotypic drug responses of prostate cancer cell lines PC-3 and LNCaP, and breast cancer cell lines MDA-MB-231 (SA) and MCF-7 cultured in a miniaturized, imaging-optimized, Matrigel-based organotypic screening platform. We demonstrate the use of the 3D cell culture technology combined with automated morphometric image data analysis software AMIDA, for phenotypic, high-content screening. The emerging tumor organoids were treated with the cytostatic drugs doxorubicin, docetaxel and paclitaxel, a selective inhibitor of matrix metalloproteinase-13 (WAY170523), and with ROCK-inhibitors RKI-1447 and Y-27632. Treatments were conducted at seven different drug concentrations for 4-10 days. At the end point, confocal live cell images were captured and analyzed using AMIDA. Among others, the numerical data representing cell growth (Area) and cell invasion (Appendages) were visualized and used for statistics. EC50 values were calculated based on the Area-parameter derived from AMIDA analysis. All cell lines initially formed multicellular, round organoids. PC-3 cells formed round and well-differentiated structures but spontaneously converted around day 9 of culture into structures showing massive, string-like collective invasion into the surrounding matrix. A different pattern of cell invasion was observed in MDA-MB-231 organoids, which developed strong and multicellular extensions by day 7-8. Interestingly, both ROCK-inhibitors promoted the invasion of PC-3 cells, as detected by phenotypic analysis with AMIDA. In contrast, Y-27632 reduced the invasion of MDA-MB-231 cells, whereas both ROCK-inhibitors induced cell invasion in MCF-7 cells at high concentration. WAY170523 inhibited the invasion of PC-3 cells but not of MDA-MB-231 cells, pointing to a different mechanism of invasiveness. All cell lines were highly sensitive to doxorubicin, docetaxel and paclitaxel at nanomolar range, as detected by the decrease of cell invasion, reduced organoid size, and increased cell death. The breast cancer cells were more sensitive to taxanes than PC-3 cells. Organotypic 3D cultures combined with high-content phenotypic analysis with AMIDA software provide a quantitative view of drug effects and enable assessment of differential drug responses on various cell lines. Citation Format: Mervi Toriseva, Katja Fagerlund, Jesse Mattsson, Tiina E. Kähkönen, Ilmari Ahonen, Malin Åkerfelt, Jenni Bernoulli, Jussi M. Halleen, Matthias Nees, Jenni H. Mäki-Jouppila. Phenotypic screening using AMIDA identifies different drug responses in breast and prostate cancer cell lines in an organotypic cell culture model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1158.

Abstract 5191: Targeting CX3CR1 Impairs the reseeding and colonization of circulating tumor cells and decelerates metastatic progression

Abstract This study aims to understand the mechanisms and dynamics by which cancer cells, departing from existing metastases as circulating cancer cells (CTCs), further seed and colonize skeleton and soft tissues, expanding metastatic spreading and precipitating the clinical progression to terminal disease. We have previously shown that the chemokine receptor CX3CR1 is implicated in the metastatic seeding of breast cancer cells and that FX-68, a novel small-molecule antagonist for this receptor, effectively contains both number of lesions and total tumor burden in animal models of metastatic disease. Here we established that FX-68 impairs the reseeding of skeleton and soft tissue and that the CTCs unable to reseed and forced to remain in the blood eventually succumb to apoptotic death. The metastatic potential of CTCs was confirmed by reinoculation experiments as well as by forcefully mobilizing cancer cells from metastases back in the blood and assessing the number of additional lesions generated, in the presence and absence of FX-68. Furthermore, we found that prolonging the permanence of CTCs in the blood by targeting CX3CR1 with FX-68 improved exposure of cancer cells to the chemotherapy drugs doxorubicin or docetaxel significantly decreased tumor progression and extended overall survival. Finally, we found evidence that cancer cells seeding the skeleton despite the inhibition of CX3CR1 failed to develop into tumors, suggesting a role of CX3CR1 expression in the metastasis-initiating properties of breast cancer cells. In summary, our results strongly support developing CX3CR1 antagonists and promoting their clinical use, as this approach will provide novel and effective tools to contain the progression of metastatic disease in patients. Citation Format: Chen Qian, Asurayya Worrede-Mahdi, Ramanpreet Kaur, Fei Shen, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. Targeting CX3CR1 Impairs the reseeding and colonization of circulating tumor cells and decelerates metastatic progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5191.

Abstract 4369: Functional role of RhoGEF FGD4 in promotion of aggressive prostate cancer

Abstract Hyperactivation of Rho family of GTPases including Rac, Cdc42 and Rho, as a result of deregulation of Rho guanine nucleotide exchange factors (GEF) is commonly noted in various cancers including prostate cancer. A number of GEFs are overexpressed in prostate and breast cancer cells and tissues, and show an association with poor prognosis. Earlier, we showed that a prolonged treatment with androgen receptor antagonist Casodex resulted in up regulation of a GEF FGD4, traditionally associated with hereditary motor and sensory neuropathies including Charcot-Marie-Tooth disease. FGD4 is a Cdc42 specific GEF and contains an actin binding domain FAB, in addition to the conserved FYVE domain, a DH domain for catalytic activity and two PH domains for targeting proteins to the membranes through phosphoinositide binding. Our study revealed that Casodex treatment of prostate cancer cells lead to down regulation of a microRNA cluster miR-17-92a that targets FGD4. Here we show that FGD4 is upregulated in cancerous prostate tissues compared to benign prostatic hyperplasia and PIN. FGD4 protein expression and altered localization gradually increase with increasing tumor grade and aggressiveness. Inhibition of FGD4 expression using siRNAs, reduced cell proliferation, resulted in a G2/M arrest, inhibited cell migration and reduced Cdc42 activity. Inhibition of FGD4 also improved sensitivity of androgen sensitive LNCaP cells to Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel. Our data demonstrate a tumor promoting function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells. Citation Format: Alexia Bossan, Richard Ottman, Domenico Coppola, Ratna Chakrabarti. Functional role of RhoGEF FGD4 in promotion of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4369.

Abstract 2452: Dysregulated expression of the human long noncoding RNA GHSROS may influence prostate cancer progression and resistance to docetaxel

Abstract Long noncoding RNAs (lncRNAs) play key regulatory roles in cancer progression and are novel therapeutic targets. We recently discovered the lncRNA gene, GHSROS (GHSR opposite strand), on the antisense DNA strand of the ghrelin receptor gene (GHSR). Here, we studied the expression and function of GHSROS in prostate cancer. Interrogation of microarray and RNA-seq data sets revealed that (similar to other lncRNA oncogenes) GHSROS is actively transcribed, although expressed at very low levels in cancer cell lines and tissues. By quantitative RT-PCR we demonstrate that GHSROS is highly expressed in a subset of high-grade prostate cancers (~11.4%). Moreover, the lncRNA is upregulated in high Gleason-score prostate tumors in two clinical data sets. Forced GHSROS overexpression significantly increased in vitro cell proliferation and migration of PC3, DU145, and LNCaP prostate cancer cell lines (P ≤ 0.05, Student's t-test). Increased cell proliferation observed in GHSROS-overexpressing prostate cancer cell lines was recapitulated in PC3, DU145, and LNCaP prostate cancer xenografts in NOD/SCID mice. Cell survival was significantly increased in GHSROS-overexpressing LNCaP cells treated with the cytotoxic drug docetaxel (P ≤ 0.05, Student's t-test). Docetaxel treatment also increased GHSROS expression in native LNCaP and PC3 cells in a dose-dependent manner (P ≤ 0.05, Student's t-test). These data suggest that GHSROS mediates tumor survival and resistance to docetaxel. To identify fundamental drivers of the observed tumorigenic phenotype of GHSROS-overexpressing cell lines, high-throughput RNA-seq data from in vitro cultured PC3 cells and LNCaP xenografts were examined. A quarter of the genes differentially expressed by GHSROS-overexpressing PC3 cells were also differentially expressed by GHSROS-overexpressing LNCaP xenografts. These 101 genes include several transcription factors with established roles in prostate cancer (including the androgen receptor) and genes associated with metastasis and poor prognosis. Finally, we developed two distinct antisense oligonucleotides (ASOs) targeting GHSROS, achieving >60% knockdown, and their function was assessed in vitro. ASO inhibition of GHSROS expression reciprocally regulated cell growth and migration and the expression of a range of genes. These ASOs are currently being assessed in preclinical animal models. Our findings suggest that the long noncoding RNA GHSROS reprograms prostate cancer cells toward a more aggressive phenotype and that the lncRNA represents a promising therapeutic target. Citation Format: Patrick B. Thomas, Penny L. Jeffery, Gahete D. Manuel, Eliza J. Whiteside, Michelle Maugham, Carina Walpole, Jennifer H. Gunter, Elizabeth D. Williams, Colleen C. Nelson, Adrian C. Herington, Raul M. Luque, Rakesh N. Veedu, Lisa K. Chopin, Inge Seim. Dysregulated expression of the human long noncoding RNA GHSROS may influence prostate cancer progression and resistance to docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2452.

Selection of Aptamers for Hydrophobic Drug Docetaxel To Improve Its Solubility

With the development of combinatorial chemistry and high-throughput screening, the number of hydrophobic drug candidates continues to increase. However, the low solubility of hydrophobic drugs could induce erratic absorption patterns and affect the drug efficacy. Aptamers are artificially selected highly water-soluble oligonucleotides that bind to ions, small molecules, proteins, living cells, and even tissues. Herein, to increase the solubility of hydrophobic drug, we screened the aptamer by exploiting DNA library immobilization selection strategy and microfluidic technology. The highly water-soluble aptamer might influence the dissolving capacity of its target. To demonstrate the concept, docetaxel (DOC), a second-generation taxoid cytotoxic with significant antitumor agent activity, was chosen as the model. It is generally known that the clinical application of docetaxel is limited greatly owing to its poor water solubility and serious side effects. After seven rounds of selection, two docetaxel-specif...

A Thermo-electromagnetically Actuated Microrobot for the Targeted Transport of Therapeutic Agents

This work proposes the targeted transport of therapeutic agents using a thermo-electromagnetically actuated microrobot. This microrobot is fabricated via UV polymerization using 2D lithography and is composed of an electromagnetically actuated layer (polyethyleneglycol diacrylate dispersed with iron(II,III) oxide and a thermo-responsive layer (N-isopropylacrylamide). The microrobot can self-fold, driven by temperature changes, and can be steered using an electromagnetic actuation (EMA) system that provides external magnetic fields. In particular, during the EMA, pulling and rolling motions are applied to the unfolded and folded shapes, respectively, of the microrobot. As fundamental tests, the microrobot was characterized in terms of its magnetization curve, swelling properties, travel velocity, and shape changing behavior. In addition, typical polystyrene bead manipulations such as trapping, delivery, and release were performed using the microrobot. Finally, we performed an in vitro test for tumor therapy, in which the robot demonstrated the ability to trap, deliver, and release an anti-cancer drug (docetaxel) encapsulated in microbeads of approximately 300 mm in diameter with an appropriate drug concentration against a mouse mammary tumor cell line (4T1). The outcomes of this research suggest that our thermo-electromagnetically actuated microrobot is suitable for use in biomedical applications.

Monitoring Cytotoxic Effects In Non‐Cancerous Cells via Docetaxel

Therapeutic chemotherapy drugs are known to induce cytotoxicity in both non‐cancerous cells and in malignant cells. However, it is still unknown if the chemotherapy drug Docetaxel induces cytotoxic events in non‐cancerous cells. Our approach to measuring cytotoxic events was H&E staining (hematoxylin and eosin) followed by immunohistochemistry (IHC) with Estrogen Receptor α (ERα), Androgen Receptor α (ARα) or Ki‐67 antibodies to determine if the cytotoxicity occurred in cancerous or non‐cancerous cells. In the MCF7 breast cancer cell line, chemotherapy drug Docetaxel induced cytotoxic effects in 44.20% of malignant breast cancer cells and 34.86% in non‐malignant cells as classified according to their response to the ERα antibody with a standard deviation of 26.89%. Patient derived prostate cancer cells grown in mice generated from the MDA‐MB‐231 cell line were also treated with Docetaxel. An average of 28.3% of prostate cancer cells exhibited ARα monoclonal antibody sensitivity, and 28.3% of prostate cancer cells displayed cytotoxic effects after administration of Docetaxel with a standard deviation of 34.3%. In conclusion, Docetaxel was shown to induce cytotoxic effects in both in prostate cancer cells and non‐malignant cells however it induced a greater toxic effect in nonmalignant breast cancer cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.