Browsing by Subject "CANCER-THERAPY"

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  • Singh, Abhishek A.; Mandoli, Amit; Prange, Koen H. M.; Laakso, Marko; Martens, Joost H. A. (2017)
    Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.
  • Ora, Ari; Järvihaavisto, Erika; Zhang, Hongbo; Auvinen, Henni; Santos, Helder A.; Kostiainen, Mauri A.; Linko, Veikko (2016)
    In this communication, we show that active enzymes can be delivered into HEK293 cells in vitro when they are attached to tubular DNA origami nanostructures. We use bioluminescent enzymes as a cargo and monitor their activity from a cell lysate. The results show that the enzymes stay intact and retain their activity in the transfection process. The method is highly modular, which makes it a compelling candidate for a great variety of delivery applications.
  • Mauramo, Matti; Rohde, Luzius; Ramseier, Adrian M.; Rovo, Alicia; Waltimo, Tuomas (2017)
    The aetiology of hyposalivation in haematopoietic stem cell transplantation (HSCT) recipients is not fully understood. This study examined the effects of treatment-related aetiological factors, particularly medications, on stimulated salivary flow in HSCT recipients. Adult HSCT recipients (N = 118, 66 males, 27 autologous and 91 allogeneic transplants) were examined. Stimulated whole salivary flow rates (SWSFR) were measured before HSCT and at 6 and 12 months post-HSCT. Linear regression models were used to analyse the associations of medications and transplant-related factors with salivary flow rates, which were compared to salivary flow rates of generally healthy controls (N = 247). The SWSFR of recipients were lower pre-HSCT (mean +/- standard deviation, 0.88 +/- 0.56 ml/min; P <0.001), 6 months post-HSCT (0.84 +/- 0.61; P <0.001) and 12 months post-HSCT (1.08 +/- 0.67; P = 0.005) than the SWSFR of controls (1.31 +/- 0.65). In addition, hyposalivation (<0.7 ml/min) was more frequent among HSCT recipients pre-HSCT (P <0.001), 6 months post-HSCT (P <0.001) and 12 months post-HSCT (P = 0.01) than among controls. The SWSFR was observed to improve over time being significantly higher 12 months post-HSCT compared to pre-HSCT (P <0.001). The observed decrease of salivary flow could not be explained by the examined transplant-related factors and medications. Decreased stimulated salivary flow rates could not be explained by the examined factors alone; these findings indicate that hyposalivation in HSCT recipients exhibits a multifactorial aetiology. All HSCT recipients should be considered to be at high risk of hyposalivation and consequent oral diseases, and they should be treated accordingly.
  • Kolberg, Matthias; Bruun, Jarle; Murumagi, Astrid; Mpindi, John P.; Bergsland, Christian H.; Holand, Maren; Eilertsen, Ina A.; Danielsen, Stine A.; Kallioniemi, Olli; Lothe, Ragnhild A. (2017)
    Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis. DNA copy number, gene expression, and protein expression were determined for the cell lines to assess pharmacogenomic relationships. MPNST cells were more sensitive to BI2536 and gemcitabine compared to a reference set of 94 cancer cell lines. PLK1, RRM1, and RRM2 mRNA levels were increased in MPNST compared to benign neurofibroma tissue, and the protein level of PLK1 was increased in the MPNST cell lines compared to normal Schwann cells, indicating an increased dependence on these drug targets in malignant cells. Furthermore, we observed an association between increased mRNA expression of PLK1, RRM1, and RRM2 in patient samples and worse disease outcome, suggesting a selective benefit from inhibition of these genes in the most aggressive tumors.
  • Hirvinen, Mari; Capasso, Cristian; Guse, Kilian; Garofalo, Mariangela; Vitale, Andrea; Ahonen, Marko; Kuryk, Lukasz; Vähä-Koskela, Markus; Hemminki, Akseli; Fortino, Vittorio; Greco, Dario; Cerullo, Vincenzo (2016)
    In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate-and eventually the long-lasting adaptive immunity against cancer.
  • Liu, Zehua; Li, Yunzhan; Li, Wei; Xiao, Chen; Liu, Dongfei; Dong, Chao; Zhang, Ming; Mäkilä, Ermei; Kemell, Marianna; Salonen, Jarno; Hirvonen, Jouni T.; Zhang, Hongbo; Zhou, Dawang; Deng, Xianming; Santos, Helder A. (2018)
    Herein, a novel nanohybrid based on porous silicon, gold nanoparticles (Au NPs), and acetalated dextran (DPSi/DAu@AcDEX) is reported to encapsulate and deliver one drug and increase the computer tomography (CT) signal for acute-liver-failure (ALF) theranostics. A microfluidic-assisted method is used to co-encapsulate different NPs in a single step. By alternating the surface properties of different NPs and by modulating the composition of the organic phase, both PSi and Au NPs are effectively encapsulated into the polymer matrix simultaneously, thus further achieving a multifunctional application. This system can be used to identify pathologically changes in the tissues and selectively deliver drugs to these sites. The loading of a therapeutic compound (XMU-MP-1) improves the drug solubility, precise, in situ drug delivery, and the drug-functioning time. In vivo results confirm a superior treatment effect and better compliance of this newly developed nanoformulation than free compound. This nanosystem plays a crucial role in targeting the lesion area, thus increasing the local drug concentration important for ALF reverse-effect. Moreover, the residence of Au NPs within the matrix further endows our system for CT-imaging. Altogether, these results support that this nanohybrid is a potential theranostic platform for ALF.
  • Barattin, Michela; Mattarei, Andrea; Balasso, Anna; Paradisi, Cristina; Cantu, Laura; Del Favero, Elena; Viitala, Tapani; Mastrotto, Francesca; Caliceti, Paolo; Salmaso, Stefano (2018)
    An innovative pH-switchable colloidal system that can be exploited for site-selective anticancer drug delivery has been generated by liposome decoration with a new novel synthetic non-peptidic oligo-arginine cell-penetration enhancer (CPE) and a quenching PEGylated counterpart that detaches from the vesicle surface under the acidic conditions of tumors. The CPE module (Arg(4)-DAG) is formed by four arginine units conjugated to a first-generation (G1) 2,2-bis(hydroxymethyl)propionic acid (bis-MPA)/2,2-bis(aminomethyl)propionic acid (bis-AMPA) polyester dendron terminating with 1,2-distearoyl-3-azidopropane for liposome bilayer insertion. The zeta potential of the Arg(4)-DAG-decorated liposomes increased up to +32 mV as the Arg(4)-DAG/lipids molar ratio increased. The Arg(4)-DAG liposome shielding at pH 7.4 was provided by methoxy-PEGS(5 kDa)-polymethacryloyl sulfadimethoxine (mPEG(5) (kDa)-SDM8) with 7.1 apparent pK(a). Zeta potential, surface plasmon resonance and synchrotron small-angle X-ray scattering analyses showed that at pH 7.4 mPEG(5) (kDa)-SDM8 associates with polycationic Arg(4)-DAG-decorated liposomes yielding liposomes with neutral zeta potential. At pH 6.5, which mimics the tumor environment, mPEG(5) (kDa)-SDM8 detaches from the liposome surface yielding Arg(4)-DAG exposure. Flow cytometry and confocal microscopy showed a 30-fold higher HeLa cancer cell association of the Arg(4)-DAG-decorated liposomes compared to non-decorated liposomes. At pH 7.4, the mPEG(5) (kDa)-SDM8-coated liposomes undergo low cell association while remarkable cell association occurred at pH 6.5, which allowed for the controlled intracellular delivery of model macromolecules and small molecules loaded in the liposome under tumor conditions.
  • Figueiredo, Patricia Isabel; Sipponen, Mika H.; Lintinen, Kalle; Rebelo Correia, Alexandra Maria; Kiriazis, Alexandros; Yli-Kauhaluoma, Jari Tapani; Österberg, Monika; George, Anne; Hirvonen, Jouni Tapio; Kostiainen, Mauri A.; Almeida Santos, Helder (2019)
    The surface modification of nanoparticles (NPs) using different ligands is a common strategy to increase NP−cell interactions. Here, dentin phosphophoryn‐derived peptide (DSS) lignin nanoparticles (LNPs) are prepared and characterized, the cellular internalization of the DSS‐functionalized LNPs (LNPs‐DSS) into three different cancer cell lines is evaluated, and their efficacy with the widely used iRGD peptide is compared. It is shown that controlled extent of carboxylation of lignin improves the stability at physiological conditions of LNPs formed upon solvent exchange. Functionalization with DSS and iRGD peptides maintains the spherical morphology and moderate polydispersity of LNPs. The LNPs exhibit good cytocompatibility when cultured with PC3‐MM2, MDA‐MB‐231, and A549 in the conventional 2D model and in the 3D cell spheroid morphology. Importantly, the 3D cell models reveal augmented internalization of peptide‐functionalized LNPs and improve antiproliferative effects when the LNPs are loaded with a cytotoxic compound. Overall, LNPs‐DSS show equal or even superior cellular internalization than the LNPs‐iRGD, suggesting that DSS can also be used to enhance the cellular uptake of NPs into different types of cells, and release different cargos intracellularly.
  • Auvinen, Henni; Zhang, Hongbo; Nonappa,; Kopilow, Alisa; Niemelä, Elina H.; Nummelin, Sami; Correia, Alexandra; Santos, Helder A.; Linko, Veikko; Kostiainen, Mauri A. (2017)
    Fully addressable DNA nanostructures, especially DNA origami, possess huge potential to serve as inherently biocompatible and versatile molecular platforms. However, their use as delivery vehicles in therapeutics is compromised by their low stability and poor transfection rates. This study shows that DNA origami can be coated by precisely defined one-to-one protein-dendron conjugates to tackle the aforementioned issues. The dendron part of the conjugate serves as a cationic binding domain that attaches to the negatively charged DNA origami surface via electrostatic interactions. The protein is attached to dendron through cysteine-maleimide bond, making the modular approach highly versatile. This work demonstrates the coating using two different proteins: bovine serum albumin (BSA) and class II hydrophobin (HFBI). The results reveal that BSA-coating significantly improves the origami stability against endonucleases (DNase I) and enhances the transfection into human embryonic kidney (HEK293) cells. Importantly, it is observed that BSA-coating attenuates the activation of immune response in mouse primary splenocytes. Serum albumin is the most abundant protein in the blood with a long circulation half-life and has already found clinically approved applications in drug delivery. It is therefore envisioned that the proposed system can open up further opportunities to tune the properties of DNA nanostructures in biological environment, and enable their use in various delivery applications.
  • Myant, Kevin; Qiao, Xi; Halonen, Tuuli; Come, Christophe; Laine, Anni; Janghorban, Mahnaz; Partanen, Johanna I.; Cassidy, John; Ogg, Erinn-Lee; Cammareri, Patrizia; Laitera, Tiina; Okkeri, Juha; Klefstrom, Juha; Sears, Rosalie C.; Sansom, Owen J.; Westermarck, Jukka (2015)
    An understanding of the mechanisms determining MYC's transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells. These data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to an in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects.
  • Kazemi, Soheila; Kawaguchi, Shinsaku; Badr, Christian E.; Mattos, Daphne R.; Ruiz-Saenz, Ana; Serrill, Jeffrey D.; Moasser, Mark M.; Dolan, Brian P.; Paavilainen, Ville O.; Oishi, Shinya; McPhail, Kerry L.; Ishmael, Jane E. (2021)
    Coibamide A is a potent cancer cell toxin and one of a select group of natural products that inhibit protein entry into the secretory pathway via a direct inhibition of the Sec61 protein translocon. Many Sec61 client proteins are clinically relevant drug targets once trafficked to their final destination in or outside the cell, however the use of Sec61 inhibitors to block early biosynthesis of specific proteins is at a pre-clinical stage. In the present study we evaluated the action of coibamide A against human epidermal growth factor receptor (HER, ErbB) proteins in representative breast and lung cancer cell types. HERs were selected for this study as they represent a family of Sec61 clients that is frequently dysregulated in human cancers, including coibamide-sensitive cell types. Although coibamide A inhibits biogenesis of a broad range of Sec61 substrate proteins in a presumed substrate nonselective manner, endogenous HER3 (ErbB-3) and EGFR (ErbB-1) proteins were more sensitive to coibamide A, and the related Sec61 inhibitor apratoxin A, than HER2 (ErbB-2). Despite this rank order of sensitivity (HER3 > EGFR > HER2), Sec61-dependent inhibition by coibamide A was sufficient to decrease cell surface expression of HER2. We report that coibamide Aor apratoxin A-mediated block of HER3 entry into the secretory pathway is unlikely to be mediated by the HER3 signal peptide alone. HER3 (G11L/S15L), that is fully resistant to the highly substrate-selective cotransin analogue CT8, was more resistant than wild-type HER3 but only at low coibamide A (3 nM) concentrations; HER3 (G11L/S15L) expression was inhibited by higher concentrations of either natural product. Timeand concentration-dependent decreases in HER protein expression induced a commensurate reduction in AKT/MAPK signaling in breast and lung cancer cell types and loss in cell viability. Coibamide A potentiated the cytotoxic efficacy of small molecule kinase inhibitors lapatinib and erlotinib in breast and lung cancer cell types, respectively. These data indicate that natural product modulators of Sec61 function have value as chemical probes to interrogate HER/ErbB signaling in treatment-resistant human cancers.
  • Khan, Daulat Haleem; Bashir, Sajid; Correia, Alexandra; Khan, Muhammad Imran; Figueiredo, Patricia; Santos, Hélder A.; Peltonen, Leena (2019)
    The aim of the present study was to prepare niosome formulations for the simultaneous encapsulation, dual drug therapy, of two anticancer drugs by the ecological probe sonication method. Poloxamer and sorbitan monostearate were used as surface active agents in niosomes, and the water soluble doxorubicin and poorly-water soluble paclitaxel were used as anticancer drugs. Thorough physicochemical analysis were performed for the niosomes, and their cytotoxicity and activity were evaluated on MCF-7 and PC3-MM2 cancer cell lines. Prepared niosomes were small in size with sizes ranging from 137 nm to 893 nm, and entrapment efficiencies were high, ranging from 91.24% to 99.99%. During the four weeks stability testing, the particle size remained stable. The niosomal formulations showed in vitro sustained drug release profiles for doxorubicin and clearly increased the dissolution rate of poorly water soluble paclitaxel. The incorporation of both the drugs into niosomes improved cell penetration and antiproliferative activity of the drugs PC3-MM2 cell lines. As a conclusion, doxorubicin and paclitaxel loaded niosome formulations resulted in relatively stable, small sized niosomes with improved drug release profiles, low toxicity, better cell penetration and antiproliferative activity. The niosomes showed synergistic effect due to the presence of both drugs, which can overcome multidrug resistance.