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

Abstract

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.

Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells

“…Consistent with the results of RNA-Seq, RT-PCR and western blot analyses also showed upregulated expression of GLI1 and p-AKT in the AML-RR patients. An in vitro study showed that inhibition of GLI1 depressed p-AKT activation and increased Ara-C sensitivity in leukemia cells, which is consistent with previous reports121527. These results indicated that these pathways might play important roles in the progression and drug resistance of leukemia.…”

Targeting cancer stem cells and signaling pathways by resveratrol and pterostilbene

“…An additional mechanism linked to the resveratrol mediated inhibition of LSCs involves the interleukin‐6 (IL‐6) and sonic hedgehog (Shh) signaling axis. IL‐6 and Shh molecules are important to maintain the growth and expansion of LSCs . Recently, Su and coworkers have identified that the IL‐6 in plasma, Shh pre‐proteins, C‐ and N‐terminal Shh peptides in bone marrow and peripheral blood mononuclear cells in patients with AML are much higher than those in healthy individuals.…”

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

“…Other studies have shown that Hh signaling is essential for the survival and drug resistance of leukemia cells [22, 23]. Interestingly, a recent report has demonstrated that inhibition of the Hh pathway with LDE225 sensitizes AML cells to 5-azacytidine, and a clinical trial based on these results is ongoing [24].…”