Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 4/2013

01-08-2013 | PRECLINICAL STUDIES

Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons

Authors: Frank Leigh Lu, Ching-Chia Yu, Huei-Hsuan Chiu, Hsingjin Eugene Liu, Shao-Yin Chen, Shufan Lin, Ting-Yi Goh, Hsin-Chih Hsu, Chih-Han Chien, Han-Chung Wu, Ming-Shan Chen, Scott C. Schuyler, Wu-Shiun Hsieh, Mei-Hwan Wu, Jean Lu

Published in: Investigational New Drugs | Issue 4/2013

Login to get access

Summary

Due to the development of drug resistance, the outcome for the majority of patients with acute myeloid leukemia (acute myelogenous leukemia; AML) remains poor. To prevent drug resistance and increase the therapeutic efficacy of treating AML, the development of new combinatory drug therapies is necessary. Sonic hedgehog (Shh) is expressed in AML biopsies and is essential for the drug resistance of cancer stem cells of AML. AML patients are frequently infected by bacteria and exposed to lipopolysaccharide (LPS). LPS itself, its derivatives, and its downstream effectors, such as tumor necrosis factor-α (TNF-α) and interferons (IFNs), have been shown to provoke anti-tumor effects. The application of a Shh inhibitor against AML cells in the presence of LPS/TNF-α/IFNs has not been investigated. We found that the Shh inhibitor cyclopamine in combination with LPS treatment synergistically induced massive cell apoptosis in THP-1 and U937 cells. The cytotoxic effects of this combined drug treatment were confirmed in 5 additional AML cell lines, in primary AML cells, and in an AML mouse model. Replacing cyclopamine with another Shh inhibitor, Sant-1, had the same effect. LPS could be substituted by TNF-α or IFNs to induce AML cell death in combination with cyclopamine. Our results suggest a potential strategy for the development of new therapies employing Shh antagonists in the presence of LPS/TNF-α/IFNs for the treatment of AML patients.
Appendix
Available only for authorised users
Literature
1.
2.
Maywald O, Buchheidt D, Bergmann J, Schoch C, Ludwig WD, Reiter A, Hastka J, Lengfelder E, Hehlmann R (2004) Spontaneous remission in adult acute myeloid leukemia in association with systemic bacterial infection-case report and review of the literature. Ann Hematol 83(3):189–194PubMedCrossRef
3.
4.
Thompson BS, Chilton PM, Ward JR, Evans JT, Mitchell TC (2005) The low-toxicity versions of LPS, MPL adjuvant and RC529, are efficient adjuvants for CD4+ T cells. J Leukoc Biol 78(6):1273–1280PubMedCrossRef
5.
Hirota K, Oishi Y, Taniguchi H, Sawachi K, Inagawa H, Kohchi C, Soma G, Terada H (2010) Antitumor effect of inhalatory lipopolysaccharide and synergetic effect in combination with cyclophosphamide. Anticancer Res 30(8):3129–3134PubMed
6.
Fujii Y, Yuki N, Takeichi N, Kobayashi H, Miyazaki T (1987) Differentiation therapy of a myelomonocytic leukemia (c-WRT-7) in rats by injection of lipopolysaccharide and daunomycin. Cancer Res 47(6):1668–1673PubMed
7.
Abe S, Yoshioka O, Masuko Y, Tsubouchi J, Kohno M, Nakajima H, Yamazaki M, Mizono D (1982) Combination antitumor therapy with lentinan and bacterial lipopolysaccharide against murine tumors. Gann 73(1):91–96PubMed
8.
Abe S, Tsubouchi J, Takahashi K, Yamazaki M, Mizuno D (1982) Combination therapy of murine tumors with lentinan plus lipopolysaccharide plus cyclophosphamide. Gann 73(6):961–967PubMed
9.
Katoh Y, Katoh M (2009) Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med 9(7):873–886PubMedCrossRef
10.
11.
Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, VanArsdale T, Beachy PA, Reya T (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458(7239):776–779PubMedCrossRef
12.
Bai LY, Chiu CF, Lin CW, Hsu NY, Lin CL, Lo WJ, Kao MC (2008) Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia 22(1):226–228PubMedCrossRef
13.
Kobune M, Takimoto R, Murase K, Iyama S, Sato T, Kikuchi S, Kawano Y, Miyanishi K, Sato Y, Niitsu Y, Kato J (2009) Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci 100(5):948–955PubMedCrossRef
14.
Hofmann I, Stover EH, Cullen DE, Mao J, Morgan KJ, Lee BH, Kharas MG, Miller PG, Cornejo MG, Okabe R, Armstrong SA, Ghilardi N, Gould S, de Sauvage FJ, McMahon AP, Gilliland DG (2009) Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 4(6):559–567PubMedCrossRef
15.
Gao J, Graves S, Koch U, Liu S, Jankovic V, Buonamici S, El Andaloussi A, Nimer SD, Kee BL, Taichman R, Radtke F, Aifantis I (2009) Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 4(6):548–558PubMedCrossRef
16.
Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418(6900):892–897PubMedCrossRef
17.
Marigo V, Johnson RL, Vortkamp A, Tabin CJ (1996) Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev Biol 180(1):273–283PubMedCrossRef
18.
Fischer AH, Jacobson KA, Rose J, Zeller R (2008) Hematoxylin and eosin staining of tissue and cell sections. Cold Spring Harb Protoc 2008(5)
19.
Incardona JP, Gaffield W, Kapur RP, Roelink H (1998) The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125(18):3553–3562PubMed
20.
Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol Biosyst 6(1):44–54PubMedCrossRef
21.
Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406(6799):1005–1009PubMedCrossRef
22.
Wu JY, Xu XF, Xu L, Niu PQ, Wang F, Hu GY, Wang XP, Guo CY (2011) Cyclopamine blocked the growth of colorectal cancer SW116 cells by modulating some target genes of Gli1 in vitro. Hepatogastroenterology 58(110–111):1511–1518PubMed
23.
Pola R, Ling LE, Silver M, Corbley MJ, Kearney M, Blake Pepinsky R, Shapiro R, Taylor FR, Baker DP, Asahara T, Isner JM (2001) The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 7(6):706–711PubMedCrossRef
24.
Kanda S, Mochizuki Y, Suematsu T, Miyata Y, Nomata K, Kanetake H (2003) Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase. J Biol Chem 278(10):8244–8249PubMedCrossRef
25.
Geng L, Cuneo KC, Cooper MK, Wang H, Sekhar K, Fu A, Hallahan DE (2007) Hedgehog signaling in the murine melanoma microenvironment. Angiogenesis 10(4):259–267PubMedCrossRef
26.
Yang Y, Li Q, Deng Z, Zhang Z, Xu J, Qian G, Wang G (2011) Protection from lipopolysaccharide-induced pulmonary microvascular endothelial cell injury by activation of hedgehog signaling pathway. Mol Biol Rep 38(6):3615–3622PubMedCrossRef
27.
Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002) Small molecule modulation of Smoothened activity. Proc Natl Acad Sci U S A 99(22):14071–14076PubMedCrossRef
28.
Wilson CW, Chen MH, Chuang PT (2009) Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS One 4(4):e5182PubMedCrossRef
29.
Treon SP, Anand B, Chou IN, Broitman SA (1992) Growth restraint and differentiation by LPS/TNF-alpha/IFN-gamma reorganization of the microtubule network in human leukemia cell lines. Leukemia 6(Suppl 3):141S–145SPubMed
30.
Treon SP, Anand B, Ulevitch R, Broitman SA (1994) CD14 mediated endogenous TNF-alpha release in HL60 AML cells: a potential model for CD14 mediated endogenous cytokine release in the treatment of AML. Leuk Res 18(1):17–21PubMedCrossRef
31.
Roberts NJ, Zhou S, Diaz LA, Holdhoff M (2011) Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2(10):739–751PubMed
32.
Aiso M, Iizuka Y, Kang HI, Sawada S, Ohshima T, Horie T (1992) The monocyte tumor necrosis factor-alpha production in patients with acute leukemia in complete remission. Med Oncol Tumor Pharmacother 9(4):191–197PubMed
33.
Bardon M, Reisser D (2009) Lipid A in cancer therapy. Adv Exp Med Biol, vol 667
34.
Metadata
Title
Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons
Authors
Frank Leigh Lu
Ching-Chia Yu
Huei-Hsuan Chiu
Hsingjin Eugene Liu
Shao-Yin Chen
Shufan Lin
Ting-Yi Goh
Hsin-Chih Hsu
Chih-Han Chien
Han-Chung Wu
Ming-Shan Chen
Scott C. Schuyler
Wu-Shiun Hsieh
Mei-Hwan Wu
Jean Lu
Publication date
01-08-2013
Publisher
Springer US
Published in
Investigational New Drugs / Issue 4/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-012-9908-5

Other articles of this Issue 4/2013

Investigational New Drugs 4/2013 Go to the issue

SHORT REPORT

Ipilimumab associated hepatitis: imaging and clinicopathologic findings

PHASE I STUDIES

Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a Phase I multicentre trial in patients scheduled for elective breast cancer surgery

PRECLINICAL STUDIES

Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells

PHASE II STUDIES

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies

PHASE II STUDIES

Maintenance single-agent bevacizumab or observation after first-line chemotherapy in patients with metastatic colorectal cancer: a multicenter retrospective study

PHASE II STUDIES

Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML)
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits