Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons
Journal
Investigational New Drugs
Journal Volume
31
Journal Issue
4
Pages
823-832
Date Issued
2013
Author(s)
Yu C.-C.
Chiu H.-H.
Liu H.E.
Chen S.-Y.
Lin S.
Goh T.-Y.
Hsu H.-C.
Chien C.-H.
Wu H.-C.
Chen M.-S.
Schuyler S.C.
Hsieh W.-S.
Lu J.
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. ? 2012 Springer Science+Business Media New York.
SDGs
Other Subjects
alpha interferon; antineoplastic agent; caspase 3; caspase 7; cyclopamine; gamma interferon; lipopolysaccharide; protein Patched 1; protein Patched 2; sant 1; Smoothened protein; sonic hedgehog antagonist; sonic hedgehog protein; transcription factor Gli1; transcription factor Gli2; tumor necrosis factor alpha; unclassified drug; acute granulocytic leukemia; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer cell destruction; cancer inhibition; cell survival; cell viability; concentration response; controlled study; drug cytotoxicity; drug effect; drug mechanism; drug potentiation; human; human cell; intracellular signaling; leukemia cell; mouse; nonhuman; priority journal; protein cleavage; protein expression; protein function; tumor volume; Animals; Cell Count; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Hedgehog Proteins; Humans; Interferons; Leukemia, Myeloid, Acute; Lipopolysaccharides; Mice; Mice, SCID; Piperazines; Pyrazoles; Tumor Necrosis Factor-alpha; Veratrum Alkaloids; Xenograft Model Antitumor Assays
Type
journal article