Alantolactone selectively ablates AML stem and progenitor cells

Leukemic Stem Cells (LSCs), are implicated in the disease initiation and conservation of malignant cells. LSCs are particularly problematic as like healthy hematopoietic stem cells (HSCs) they can self-renew and undergo quiescence . Furthermore, in Acute Myeloid Leukemia (AML) LSCs can resist conventional treatments. Worse still, small populations of LSCs can maintain the disease.

Consequently, there is a need to find agents that are efficacious against LSCs in order to reduce rates of resistance and relapse in AML.

Alantolactone is a eudesmane-type sesquiterpene lactone and the active ingredient in frankincense. This agent has been reported to induce apoptosis of CD34+CD38 cells in primary AML samples.

Ding Y et al. conducted the first study to investigate the potential anti-cancer activity of alantolactone in Acute Myeloid Leukemia stem and progenitor cells both in vitro and in vivo. The key published results showed that alantolactone demonstrated anti-leukemia activity through its inhibition of HL60 and K562 cells in vitro. Interestingly alantolactone didn’t affect normal colony formation. In summation the findings of this study suggest that alantolactone may provide a novel target to help to improve patient outcomes in AML. The study was published in J Hematol Oncol. in September 2016.

Please find the abstract and the published results below:

Abstract

BACKGROUND:

The poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity.

METHODS:

The aim of the present study was to identify alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of alantolactone in vitro and in vivo.

RESULTS:

The present study is the first to demonstrate that alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-alantolactone, a water-soluble prodrug of alantolactone, could suppress tumor growth in vivo.

CONCLUSIONS:

Based on these results, we propose that alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents.