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

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)823-832
Number of pages10
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
Publication statusPublished - Aug 2013

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Hedgehogs
Myeloid Cells
Acute Myeloid Leukemia
Interferons
Lipopolysaccharides
Cell Death
Tumor Necrosis Factor-alpha
Drug Resistance
Essential Drugs
Therapeutics
U937 Cells
Neoplastic Stem Cells
Apoptosis
Bacteria
Biopsy
Drug Therapy
Cell Line
Pharmaceutical Preparations
cyclopamine
Neoplasms

Keywords

  • Acute myeloid leukemia
  • Cyclopamine
  • Interferon
  • Lipopolysaccharides
  • Sant-1
  • Sonic hedgehog
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons. / Lu, Frank Leigh; Yu, Ching Chia; Chiu, Huei Hsuan; Liu, Hsingjin Eugene; Chen, Shao Yin; Lin, Shufan; Goh, Ting Yi; Hsu, Hsin Chih; Chien, Chih Han; Wu, Han Chung; Chen, Ming Shan; Schuyler, Scott C.; Hsieh, Wu Shiun; Wu, Mei Hwan; Lu, Jean.

In: Investigational New Drugs, Vol. 31, No. 4, 08.2013, p. 823-832.

Research output: Contribution to journalArticle

Lu, FL, Yu, CC, Chiu, HH, Liu, HE, Chen, SY, Lin, S, Goh, TY, Hsu, HC, Chien, CH, Wu, HC, Chen, MS, Schuyler, SC, Hsieh, WS, Wu, MH & Lu, J 2013, 'Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons', Investigational New Drugs, vol. 31, no. 4, pp. 823-832. https://doi.org/10.1007/s10637-012-9908-5
Lu, Frank Leigh ; Yu, Ching Chia ; Chiu, Huei Hsuan ; Liu, Hsingjin Eugene ; Chen, Shao Yin ; Lin, Shufan ; Goh, Ting Yi ; Hsu, Hsin Chih ; Chien, Chih Han ; Wu, Han Chung ; Chen, Ming Shan ; Schuyler, Scott C. ; Hsieh, Wu Shiun ; Wu, Mei Hwan ; Lu, Jean. / Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons. In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 823-832.
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AU - Yu, Ching Chia

AU - Chiu, Huei Hsuan

AU - Liu, Hsingjin Eugene

AU - Chen, Shao Yin

AU - Lin, Shufan

AU - Goh, Ting Yi

AU - Hsu, Hsin Chih

AU - Chien, Chih Han

AU - Wu, Han Chung

AU - Chen, Ming Shan

AU - Schuyler, Scott C.

AU - Hsieh, Wu Shiun

AU - Wu, Mei Hwan

AU - Lu, Jean

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N2 - 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.

AB - 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.

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KW - Interferon

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KW - Sant-1

KW - Sonic hedgehog

KW - Tumor necrosis factor-α

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