The Potential of Vitamin D-Regulated Intracellular Signaling Pathways as Targets for Myeloid Leukemia Therapy

Abstract

The current standard regimens for the treatment of acute myeloid leukemia (AML) are curative in less than half of patients; therefore, there is a great need for innovative new approaches to this problem. One approach is to target new treatments to the pathways that are instrumental to cell growth and survival with drugs that are less harmful to normal cells than to neoplastic cells. In this review, we focus on the MAPK family of signaling pathways and those that are known to, or potentially can, interact with MAPKs, such as PI3K/AKT/FOXO and JAK/STAT. We exemplify the recent studies in this field with specific relevance to vitamin D and its derivatives, since they have featured prominently in recent scientific literature as having anti-cancer properties. Since microRNAs also are known to be regulated by activated vitamin D, this is also briefly discussed here, as are the implications of the emerging acquisition of transcriptosome data and potentiation of the biological effects of vitamin D by other compounds. While there are ongoing clinical trials of various compounds that affect signaling pathways, more studies are needed to establish the clinical utility of vitamin D in the treatment of cancer.

The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

“…AML blasts and cell lines derived from them can be induced to differentiate by several compounds including VDDs, alone or in combination [11, 16, 25–27]. However, cell differentiation may be masked by cytotoxicity, particularly for the determination of cell surface protein markers such as CD11b and CD14.…”

Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia

“…9,10,18 Gocek et al reviewed the potential therapeutic effects of calcitriol in acute myeloid leukemia (AML), which are achieved by inducing differentiation and inhibiting proliferation of the AML blasts. 19 While this potential therapeutic response is promising, the high amount of vitamin D supplement needed to see these effects in patients can cause calciotropic effects, therefore vitamin D analogs may be a better alternative. 10 Vitamin D analogs are currently being developed and utilized in clinical trials to circumvent the adverse effects of large doses of vitamin D. 20 Our present study was prompted by anecdotal evidence from T-LGLL patients stating that voluntary vitamin D supplementation improved their complete blood count parameters, namely absolute neutrophil count.…”

Current Understandings of Myeloid Differentiation Inducers in Leukemia Therapy

“…Although the underlying mechanism of action remains unknown, vitamin K2 has also been reported to induce apoptosis and differentiation [67]. 1,25D induces monocyte/macrophagelike differentiation, and cell cycle arrest through activating various kinase pathways including mitogen-activated kinases, c-Jun NH2-terminal kinases, and p38 mitogenactivated kinases [68]. 1,25D also modulates the expres-DOI: 10.1159/000510980 sion of several miRNAs [68].…”