Abstract
Differentiation therapy with all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), has been extremely successful in inducing clinical remission in APL patients. However, the differentiation therapy of ATRA-based treatment has not been effective in other subtypes of AML. In this study, we evaluated a small molecule of ent-kaurene diterpenoid, Jiyuan oridonin A (JOA), on the differentiation blockade in AML cells with the mixed lineage leukemia (MLL) gene rearrangements (MLLr) in MV4-11, MOLM-13 and THP-1 cells. We found that JOA could significantly inhibit the proliferation of MOLM-13, MV4-11 and THP-1 cells. Moreover, JOA promoted cell differentiation coupled with cell-cycle exit at G0/G1 and inhibited the colony- forming capacity of these cells. We showed that the anti-proliferative effect of JOA attributed to cell differentiation is most likely through the martens tretinoin response up pathway in the MOLM-13 cell line, and the hematopoietic cell lineage pathway by the inhibition of c-KIT expression and cell adhesion pathway in the THP-1 cell line. Our findings suggest that JOA could be a novel therapeutic agent against human MLLr acute myeloid leukemia.
Highlights
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common form of acute leukemia in children
We explored whether Jiyuan oridonin A (JOA) possesses anti-leukemia activity against MLLr AML cells including MV4-11, MOLM-13 and THP-1
Cells were treated with different concentrations of JOA or Ara-C (0- 10 mM) for 72 h, and Cell Counting Kit-8 (CCK-8) assay was carried out to test the effect of JOA on cell proliferation as compared to Ara-C
Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common form of acute leukemia in children. AML is a malignancy of hematopoietic stem cell, with distinctive features of excessive proliferation and impaired differentiation [1, 2]. The biology of AML cells is complex and involves multiple interdependent molecular pathways. The traditional chemotherapies are the mainstay of treatment for the past 50 years. A 5-year overall survival (OS) for patients younger than 60 years is about 40%. For those older than 60 years, the Jiyuan Oridonin A
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