Abstract
CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells. Niclosamide significantly inhibited CREB function and CREB-mediated gene expression in cells, leading to apoptosis and G1/S cell cycle arrest with reduced phosphorylated CREB levels. CREB knockdown protected cells from niclosamide treatment-mediated cytotoxic effects. Furthermore, treatment with a combination of niclosamide and CREB inhibitor XX-650-23 showed an additive anti-proliferative effect, consistent with the hypothesis that niclosamide and XX-650-23 regulate the same targets or pathways to inhibit proliferation and survival of AML cells. Niclosamide significantly inhibited the progression of disease in AML patient-derived xenograft (PDX) mice, and prolonged survival of PDX mice. Niclosamide also showed synergistic effects with chemotherapy drugs to inhibit AML cell proliferation. While chemotherapy antagonized the cytotoxic potential of niclosamide, pretreatment with niclosamide sensitized cells to chemotherapeutic drugs, cytarabine, daunorubicin, and vincristine. Therefore, our results demonstrate niclosamide as a potential drug to treat AML by inducing apoptosis and cell cycle arrest through inhibition of CREB-dependent pathways in AML cells.
Highlights
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that is characterized by the clonal accumulation of immature myeloid progenitors, leading to multilineage cytopenia with a poor outcome [1,2,3,4]
We recently demonstrated the feasibility of targeting cAMP response element binding protein (CREB) for AML treatment using XX-650-23, a small molecule inhibitor of CREB function, which is based on naphthol AS-E phosphate that was first identified as an inhibitor of CREB interaction with its coactivator, CREB Binding Protein (CBP) [17]
We demonstrate that niclosamide inhibits CREB-driven gene expression by preventing CREB activation, thereby disrupting CREB-CREB binding protein (CBP) interaction leading to induction of apoptosis and cell cycle arrest in AML cells
Summary
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that is characterized by the clonal accumulation of immature myeloid progenitors, leading to multilineage cytopenia with a poor outcome [1,2,3,4]. The cAMP response element binding protein (CREB), a stimulus-induced transcription factor that responds rapidly to phosphorylation and co-activator activation, has been implicated in a number of cancers, including leukemia [6,7,8]. Upon phosphorylation at Ser133 in its Kinase Inducible Domain (KID) domain, CREB recruits co-activator CREB binding protein (CBP) through interaction between the KID interacting (KIX) domain and the CREB KID domain [9] to induce expression of CREB-driven genes that regulate cell proliferation, signal www.impactjournals.com/oncotarget transduction, and cell survival [10,11,12]. Overexpression of CREB contributes to transformation of hematopoietic cells. CREB-overexpression in myeloid cells results in a myeloproliferative disorder in CREB-transgenic mice [13]. CREB knockdown inhibits AML cell proliferation, but does not affect normal hematopoietic stem cell activity in mouse transduction and transplantation experiments [14]
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