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Publications (10 of 166) Show all publications
De Rosa, M., Lu, L., Zamaratski, E., Szałaj, N., Cao, S., Wadensten, H., . . . Karlen, A. (2017). Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB). Bioorganic & Medicinal Chemistry, 25(3), 897-911.
Open this publication in new window or tab >>Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
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2017 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 3, 897-911 p.Article in journal (Refereed) Published
Abstract [en]

Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.

Keyword
Antibacterials, Escherichia coli, Oligopeptides, Solid-phase peptide synthesis, Type I signal peptidase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-314110 (URN)10.1016/j.bmc.2016.12.003 (DOI)000394201900009 ()28038943 (PubMedID)
Funder
Swedish Research Council, 521-2014-6711 521-2013-2904 521-2013-3105 621-2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

Maria De Rosa and Lu Lu contributed equally to this work.

Available from: 2017-01-27 Created: 2017-01-27 Last updated: 2018-01-13Bibliographically approved
Jiang, Y., Marinescu, V. D., Xie, Y., Jarvius, M., Maturi, N. P., Haglund, C., . . . Uhrbom, L. (2017). Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin. Cell reports, 18(4), 977-990.
Open this publication in new window or tab >>Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, 977-990 p.Article in journal (Refereed) Published
Abstract [en]

The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

Keyword
cancer stem cell, cell of origin, central nervous system, drug response, glioblastoma, glioma, mouse model, neural stem cell, oligodendrocyte precursor cell, self-renewal
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319084 (URN)10.1016/j.celrep.2017.01.003 (DOI)000396474300013 ()28122246 (PubMedID)
Funder
Swedish Cancer Society, 110363 140385 150628Swedish Research Council, 90283201 C0259101 B0310101 E0331401Swedish Childhood Cancer Foundation, PROJ11/057 PR2014-0143Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-11-29Bibliographically approved
Strese, S., Hassan, S. B., Velander, E., Haglund, C., Höglund, M., Larsson, R. & Gullbo, J. (2017). In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia. OncoTarget, 8(4), 6341-6352.
Open this publication in new window or tab >>In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, 6341-6352 p.Article in journal (Refereed) Published
Abstract [en]

The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34(+) progenitor cells and a more differentiated CD34(+) derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

Keyword
melflufen, drug development, alkylator, pre-clinical, acute myeloid leukemia
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-317697 (URN)10.18632/oncotarget.13856 (DOI)000393289000079 ()27974676 (PubMedID)
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Herman, S., Emami Khoonsari, P., Aftab, O., Krishnan, S., Strömbom, E., Larsson, R., . . . Gustafsson, M. G. (2017). Mass spectrometry based metabolomics for in vitro systems pharmacology: pitfalls, challenges, and computational solutions.. Metabolomics, 13(7), Article ID 79.
Open this publication in new window or tab >>Mass spectrometry based metabolomics for in vitro systems pharmacology: pitfalls, challenges, and computational solutions.
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2017 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, no 7, 79Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Mass spectrometry based metabolomics has become a promising complement and alternative to transcriptomics and proteomics in many fields including in vitro systems pharmacology. Despite several merits, metabolomics based on liquid chromatography mass spectrometry (LC-MS) is a developing area that is yet attached to several pitfalls and challenges. To reach a level of high reliability and robustness, these issues need to be tackled by implementation of refined experimental and computational protocols.

OBJECTIVES: This study illustrates some key pitfalls in LC-MS based metabolomics and introduces an automated computational procedure to compensate for them.

METHOD: Non-cancerous mammary gland derived cells were exposed to 27 chemicals from four pharmacological classes plus a set of six pesticides. Changes in the metabolome of cell lysates were assessed after 24 h using LC-MS. A data processing pipeline was established and evaluated to handle issues including contaminants, carry over effects, intensity decay and inherent methodology variability and biases. A key component in this pipeline is a latent variable method called OOS-DA (optimal orthonormal system for discriminant analysis), being theoretically more easily motivated than PLS-DA in this context, as it is rooted in pattern classification rather than regression modeling.

RESULT: The pipeline is shown to reduce experimental variability/biases and is used to confirm that LC-MS spectra hold drug class specific information.

CONCLUSION: LC-MS based metabolomics is a promising methodology, but comes with pitfalls and challenges. Key difficulties can be largely overcome by means of a computational procedure of the kind introduced and demonstrated here. The pipeline is freely available on www.github.com/stephanieherman/MS-data-processing.

Keyword
Batch effects, Data handling, Drug metabolism, Mass spectrometry, Metabolomics
National Category
Bioinformatics (Computational Biology)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-323946 (URN)10.1007/s11306-017-1213-z (DOI)000403779800002 ()28596718 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council
Available from: 2017-06-11 Created: 2017-06-11 Last updated: 2018-01-13Bibliographically approved
Karlsson, H., Fryknäs, M., Strese, S., Gullbo, J., Westman, G., Bremberg, U., . . . Nygren, P. (2017). Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity. OncoTarget, 8(18), 30217-30234.
Open this publication in new window or tab >>Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, 30217-30234 p.Article in journal (Refereed) Published
Abstract [en]

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keyword
cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-323035 (URN)10.18632/oncotarget.16324 (DOI)000400456200055 ()28415818 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-11-29Bibliographically approved
Sreedharan, S., Maturi, N. P., Xie, Y., Sundström, A., Jarvius, M., Libard, S., . . . Uhrbom, L. (2017). Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype. Cancer Research (3), 802-812.
Open this publication in new window or tab >>Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 3, 802-812 p.Article in journal (Refereed) Published
Abstract [en]

High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease.

Keyword
pediatric high-grade glioma, glioblastoma, mouse model, cell of origin, glioma stem cell
National Category
Cell and Molecular Biology
Research subject
Biomedical Laboratory Science
Identifiers
urn:nbn:se:uu:diva-310215 (URN)10.1158/0008-5472.CAN-16-2482 (DOI)000393194400020 ()
Funder
Swedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2016-12-13 Created: 2016-12-13 Last updated: 2018-01-13Bibliographically approved
Blom, K., Nygren, P., Larsson, R. & Andersson, C. R. (2017). Predictive Value of Ex Vivo Chemosensitivity Assays for Individualized Cancer Chemotherapy: A Meta-Analysis. SLAS TECHNOLOGY, 22(3), 306-314.
Open this publication in new window or tab >>Predictive Value of Ex Vivo Chemosensitivity Assays for Individualized Cancer Chemotherapy: A Meta-Analysis
2017 (English)In: SLAS TECHNOLOGY, ISSN 2472-6303, Vol. 22, no 3, 306-314 p.Article in journal (Refereed) Published
Abstract [en]

Current treatment strategies for chemotherapy of cancer patients were developed to benefit groups of patients with similar clinical characteristics. In practice, response is very heterogeneous between individual patients within these groups. Precision medicine can be viewed as the development toward a more fine-grained treatment stratification than what is currently in use. Cell-based drug sensitivity testing is one of several options for individualized cancer treatment available today, although it has not yet reached widespread clinical use. We present an up-to-date literature meta-analysis on the predictive value of ex vivo chemosensitivity assays for individualized cancer chemotherapy and discuss their current clinical value and possible future developments.

Keyword
tumor cell, ex vivo, chemotherapy, individualized cancer therapy
National Category
Cancer and Oncology Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-323769 (URN)10.1177/2472630316686297 (DOI)000401736700008 ()28378608 (PubMedID)
Available from: 2017-06-09 Created: 2017-06-09 Last updated: 2017-06-09Bibliographically approved
Blom, K., Senkowski, W., Jarvius, M., Berglund, M., Rubin, J., Lenhammar, L., . . . Larsson, R. (2017). The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation. Immunopharmacology and immunotoxicology, 39(4), 199-210.
Open this publication in new window or tab >>The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation
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2017 (English)In: Immunopharmacology and immunotoxicology, ISSN 0892-3973, E-ISSN 1532-2513, Vol. 39, no 4, 199-210 p.Article in journal (Refereed) Published
Abstract [en]

Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1 beta and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1 beta secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1 release. MBZ-induced IL-1 release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.

Keyword
Repositioning, cancer therapy, monocytes, macrophages, mebendazole
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-329149 (URN)10.1080/08923973.2017.1320671 (DOI)000403934300005 ()28472897 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2018-01-13Bibliographically approved
Segerman, A., Niklasson, M., Haglund, C., Bergström, T., Jarvius, M., Xie, Y., . . . Westermark, B. (2016). Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. Cell reports, 17(11), 2994-3009.
Open this publication in new window or tab >>Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 11, 2994-3009 p.Article in journal (Refereed) Published
Abstract [en]

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-314416 (URN)10.1016/j.celrep.2016.11.056 (DOI)000390894700019 ()
Funder
Knut and Alice Wallenberg Foundation, 2013.0280Swedish Cancer Society, 150670
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
Blom, K., Nygren, P., Alvarsson, J., Larsson, R. & Andersson, C. R. (2016). Ex Vivo Assessment of Drug Activity in Patient Tumor Cells as a Basis for Tailored Cancer Therapy. JALA, 21(1), 178-187.
Open this publication in new window or tab >>Ex Vivo Assessment of Drug Activity in Patient Tumor Cells as a Basis for Tailored Cancer Therapy
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2016 (English)In: JALA, ISSN 2211-0682, Vol. 21, no 1, 178-187 p.Article in journal (Refereed) Published
Abstract [en]

Although medical cancer treatment has improved during the past decades, it is difficult to choose between several first-line treatments supposed to be equally active in the diagnostic group. It is even more difficult to select a treatment after the standard protocols have failed. Any guidance for selection of the most effective treatment is valuable at these critical stages. We describe the principles and procedures for ex vivo assessment of drug activity in tumor cells from patients as a basis for tailored cancer treatment. Patient tumor cells are assayed for cytotoxicity with a panel of drugs. Acoustic drug dispensing provides great flexibility in the selection of drugs for testing; currently, up to 80 compounds and/or combinations thereof may be tested for each patient. Drug response predictions are obtained by classification using an empirical model based on historical responses for the diagnosis. The laboratory workflow is supported by an integrated system that enables rapid analysis and automatic generation of the clinical referral response.

Keyword
tumor cell, ex vivo, chemotherapy, tailored cancer therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-277993 (URN)10.1177/2211068215598117 (DOI)000368772400019 ()26246423 (PubMedID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2016-02-23Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-3427-4128

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