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

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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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Abbreviations

AML:

Acute myeloid leukemia

LPS:

Lipopolysaccharide

TNF-α:

Tumor necrosis factor-α

IFNs:

Interferons

Shh:

Sonic hedgehog

Ptch-1:

Patched 1

Ptch-2:

Patched 2

Smo:

Smoothened

Gli:

Glioma-associated oncogene homolog

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Acknowledgements

This work was supported by funding from the National Health Research Institutes (NHRI-EX100-10025SI), National Science Council (NSC-100-2314-B-001- 002, NSC-97-2321-B-001-022-MY3, NSC-100-2321-B-001-039-, and NSC-101-2311-B-182-001-), summit project, Academia Sinica, National Taiwan University Hospital (99-M-1474), the Chang Gung Memorial Hospital (CMRP–D190213), and the Taiwan Ministry of Education (EMRP-D1B0221). We thank the fluorescence microscope core facility of Genomics Research Center for their technical assistance. We also thank the Taiwan Mouse Clinic, which is funded by the National Research Program for Biopharmaceuticals (NRPB) at the National Science Council of Taiwan, for technical support.

Competing interests

The authors declare that they have no competing interests.

Author’s contributions

Contribution: FLL, SYC, and JL design the experiment, analyze the data, supervised the project and wrote the manuscript. CCY, HHC, TYG, HCH, CHC, and MSC performed the experiments and analyzed the data. HEL and SL contributed to collecting the AML clinical samples and analyzing the data. HCW, WSH, and MHW provide reagents and data discussion. SCS contributed to writing the manuscript. All authors read and approved the final draft of the manuscript.

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Correspondence to Jean Lu.

Additional information

Ching-Chia Yu, Huei-Hsuan Chiu, Hsingjin Eugene Liu and Shao-Yin Chen contributed equally to this study.

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Lu, F.L., Yu, CC., Chiu, HH. et al. Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons. Invest New Drugs 31, 823–832 (2013). https://doi.org/10.1007/s10637-012-9908-5

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  • DOI: https://doi.org/10.1007/s10637-012-9908-5

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