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  • American Association for Cancer Research (AACR)  (5)
  • 1
    Online Resource
    Online Resource
    Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 2 ( 2009-01-15), p. 416-421
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 2 ( 2009-01-15), p. 416-421
    Abstract: Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC50s & lt;3 μmol/L) than in p53-mutated cell lines (IC50s & gt;17 μmol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)–overexpressing cell lines (decrease in IC50s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1–mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp–mediated drug efflux. In conclusion, nutlin-3–induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. [Cancer Res 2009;69(2):416–21]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-1856
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Online Resource
    Abstract 6387: Inhibition of Lymphoid Enhancer Factor1 (LEF1 ) in acute myeloid leukemia overcomes acquired cytarabine resistance
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6387-6387
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6387-6387
    Abstract: Canonical Wnt-β-catenin signalling is frequently dysregulated in myeloid leukemia. LEF1 (Lymphoid Enhancer Factor 1), a key mediator of Wnt signalling, functions as an interacting partner with β-catenin. Previous studies have shown that LEF1 is associated with leukemic transformation and is an independent prognostic factor in normal karyotype AML. Through high throughput transcriptome profiling between the parental and acquired cytarabine resistant cell lines, we identified that LEF1 to be a potential target mediating this resistance. Here we evaluated the role, of molecular and pharmacological inhibition of LEF1 in overcoming acquired cytarabine resistance. The differential expression of LEF1 in THP1, MV4-11 and U937 parental and Ara-C resistant AML cell lines was checked by quantitative RT-PCR, immunoblot and immunofluorescence. LEF1 knock-out (KO) cells were generated using the CRISPR-Cas9 in the THP1 cytarabine resistant cell line. Lentiviral based over-expression of LEF1 was carried out in THP1 parental cell line to ensure that LEF1 promotes Ara-C resistance. For nuclear translocation of LEF1, the small molecule CHIR99021 was used in over-expressed cells.The knock-out and over-expressed cells were characterized by analysing proliferation, cell cycle and cytotoxicity assay. The effect of pharmacological inhibition of LEF1 using niclosamide was examined by in-vitro-cytotoxicity assay.Although LEF1 transcript expression was high in all the three cytarabine resistant cell lines compared to the parental cell lines, THP1-araC-R cell line showed around ≈ 500-fold change in expression and hence was used for further experiments. THP1-araC-R was marginally cross resistant to both DNR (IC50 Parent -0.19µM, AraC 0.26µM) and ATO (IC50 Parent -2.1µM, AraC & gt;4µM). LEF1 knock-out showed complete absence of LEF1 protein, decreased rate of proliferation and improved sensitivity to Ara-C (Ara-C IC50- 1430 µM in the untransduced vs. 387.4 µM after LEF1 KO). Over-expression of LEF1 with a fold change of ≈1000 followed by enforced nuclear translocation using the small molecule CHIR99021 in parental cell line resulted in increased resistance to Ara-C (IC50 Parental- 50.7µM vs OE CHIR treated 240.05µM). Further, niclosamide, the pharmacological inhibitor of LEF1 was able to re-sensitize the THP1 AraC -resistant cells (IC50: 1430 µM for UT vs 516.8 µM treated with niclosamide). Our results suggest that inhibition of LEF1 by molecular and pharmacological means showed considerable increase in cytarabine sensitivity in-vitro while we are testing its effect in-vivo using a transplantable AML mouse model. Citation Format: Saswati Das, Raveen Stephen Illangeswaran, Daniel Zechariah Paul Jebanesan, Rakhi Thalayatta Vidhyadharan, Nayanthara Karpillymoola Bijukumar, Bharathi Murugan Rajamani, Martin Michaelis, Jindrich Cinatl Jr., Vikram Mathews, Shaji Ramchandran Velayudhan, Poonkuzhali Balasubramanian. Inhibition of Lymphoid Enhancer Factor1(LEF1) in acute myeloid leukemia overcomes acquired cytarabine resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6387.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6387
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Online Resource
    Abstract 1423: Shikonin impairs the growth of docetaxel-resistant prostate cancer cells by necroptosis
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1423-1423
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1423-1423
    Abstract: Introduction: Prostate carcinoma (PCa) is the most common malignancy in men. Androgen-targeted therapy and chemotherapy are currently the treatment of choice for advanced stages. Due to resistance towards these therapies, prognosis remains poor and new treatment options are urgently required. Shikonin (SHI) from Traditional Chinese Medicine (TCM) might be promising, since it induces anti-tumor effects in different tumor entities. However, data on PCa are few, and data on resistant PCa are not existent. Material and Methods: Parental (=sensitive) and docetaxel-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1 - 1.5 μM] for 24, 48, or 72 hours. Untreated cells served as controls. Tumor cell growth, proliferation, cell cycle, and the expression of cell cycle regulating proteins were assessed. Several cell deaths, like apoptosis, necrosis and necroptosis as well as the metabolic activity were evaluated. Results: Time- and dose-dependent exposure to SHI significantly reduced tumor cell growth and proliferation in parental and docetaxel-resistant PCa cells, compared to the untreated controls. This was accompanied by cell cycle arrest in the G2/M phase in parental PC3 and docetaxel-resistant DU145 and S phase arrest in resistant 22Rv1, associated with modulated expression of cell cycle regulating proteins. Significant apoptotic effects were observed in parental and docetaxel-resistant PC3, DU145, 22Rv1, and resistant LNCaP. Moreover, SHI induced necroptosis in all parental and resistant PCa cells, as shown by additional application to the necroptosis inhibitor necrostatin-1. In line with this, RIP-1 expression enhanced under SHI exposure. In contrast, SHI did not alter the metabolic activity of the PCa cells. Conclusion: Significant anti-tumor effects are apparent in parental but also in docetaxel-resistant PCa cells after SHI application. Thus, adding SHI to standard therapies might be a promising treatment strategy for patients with advanced prostate cancer. Further investigations are necessary to verify our findings. Funding: Friedrich-Spicker-Stiftung (2017). Acknowledgments: The main portion of the results presented here are part of the MD thesis of Kira M. Juetter at the Department of Urology and Pediatric Urology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Citation Format: Sascha D. Markowitsch, Kira M. Juetter, Patricia Schupp, Kristine Hausschulte, Olesya Vakhrusheva, Jindrich Cinatl, Martin Michaelis, Thomas Efferth, Axel Haferkamp, Eva Juengel. Shikonin impairs the growth of docetaxel-resistant prostate cancer cells by necroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1423.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1423
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Online Resource
    Cisplatin-Resistant Neuroblastoma Cells Express Enhanced Levels of Epidermal Growth Factor Receptor (EGFR) and Are Sensitive to Treatment with EGFR-Specific Toxins
    American Association for Cancer Research (AACR) ; 2008
    In:  Clinical Cancer Research Vol. 14, No. 20 ( 2008-10-15), p. 6531-6537
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 20 ( 2008-10-15), p. 6531-6537
    Abstract: Purpose: Neuroblastomas frequently show expression of the epidermal growth factor receptor (EGFR) and may therefore be susceptible to EGFR-targeted therapies. Here, EGFR expression and functionality was investigated in parental chemosensitive neuroblastoma cell lines (UKF-NB-3, IMR-32, NLF, SH-SY5Y) and their cisplatin-resistant sublines (UKF-NB-3rCDDP1000, IMR-32rCDDP1000, NLFrCDDP1000, and SH-SY5YrCDDP500). Moreover, the EGFR antibody cetuximab, the EGFR tyrosine kinase inhibitor Tyrphostin B46, and recombinant EGFR-targeted toxins were investigated for their influence on the viability and growth of neuroblastoma cells. Experimental Design: EGFR expression and function was measured by flow cytometry or Western blot. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was examined by immunostaining for active caspase-3 or cleaved poly(ADP-ribose) polymerase. Cellular binding of FITC-labeled immunotoxins was studied by flow cytometry, and cellular uptake was studied by confocal laser scanning microscopy. Results: The EGFR-targeted antibody and growth factor toxins scFv(14E1)- Pseudomonas exotoxin A (ETA) and TGF-α-ETA exerted anti-cancer effects in neuroblastoma cell lines that were insensitive to cetuximab or EGFR tyrosine kinase inhibitors. Furthermore, adaptation of chemosensitive neuroblastoma cells to cisplatin increased EGFR expression and sensitivity to both recombinant toxins. Treatment of chemosensitive neuroblastoma cells with cisplatin reversibly increased EGFR expression, whereas cisplatin-resistant cells showed enhanced EGFR expression independent of the presence of cisplatin. Combination treatment with scFv(14E1)-ETA or TGF-α-ETA and cisplatin exerted significantly improved anticancer effects compared with either single treatment in parental neuroblastoma cells, cisplatin-resistant sublines, and primary cultures. Conclusions: EGFR-targeted cytotoxic reagents such as scFv(14E1)-ETA and TGF-α-ETA represent promising candidates for further development as antineuroblastoma agents, especially in combination with cisplatin.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-0821
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
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    Online Resource
    Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 8 ( 2021-08-01), p. 1923-1937
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 8 ( 2021-08-01), p. 1923-1937
    Abstract: Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. Significance: We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy. This article is highlighted in the In This Issue feature, p. 1861
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-1508
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2607892-2
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