Jiyuan oridonin A induces differentiation of acute myeloid leukemia cells including leukemic stem-like cells

Abstract

Acute myeloid leukemia (AML) is an aggressive form of hematological neoplasia characterized by failure of myeloid differentiation. AML is a leading cause of death from leukemia. Cytarabine chemotherapy resistance is a major source of refractory/relapsed AML. A major obstacle to the successful treatment of AML results from residual disease maintained by leukemic stem cells (LSCs), which are mostly resistant to conventional chemotherapy. Here, we determined the effect of a natural compound, Jiyuan oridonin A (JOA), on the differentiation blockade in the M2 subtype [particularly t (8;21)] of AML cells, M3 subtype of AML cells (APL cells), and leukemic stem-like cells both in vitro and in vivo. We found that JOA induced cell differentiation and suppressed the colony formation capacity in various AML cell lines (Kasumi-1, KG-1, MUTZ-8, NB4, and HL-60) without eliciting apoptosis. The mechanism of JOA-induced cell differentiation depends on the specificity of cell type. JOA mediated the differentiation of Kasumi-1 cells by activating the hematopoietic cell lineage signaling pathway, while inhibition of c-MYC was involved in the JOA-induced differentiation of NB4 cells. Moreover, JOA was identified to target leukemic stem-like cells by induced cell differentiation in vivo. These findings demonstrated that JOA could inhibit the proliferation of M2 and M3 subtypes of AML cells and leukemic stem-like cells by overcoming the differentiation blockade, which may offer a novel therapeutic strategy for AML to overcome relapse and drug resistance in patients with AML. Our findings highlight the possibility of using compounds like JOA as a promising differentiation-induced agent for the treatment of AML.

Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A

“…Hence, these findings indicated that the anti-cancer activity of JOA against K562 cells was also likely originated from the inhibition of BCR-ABL/c-MYC signaling. Therefore, the mechanism of JOA-mediated differentiation of BaF3-T315I and K562 cells may be originate from the modulation of BCR-ABL/c-MYC signaling, which is different to that caused to the differentiation of AML cells (25)(26).…”

“…In our previous study [25][26], it was found that JOA triggered cell differentiation of different AML cell lines via specific signaling pathway. In addition, the great success of all-trans retinoic acid improved the prognosis of acute promyelocytic leukemia.…”

“…JOA was derived from Isodon rubescens [24]. In our previous study, it was found that JOA promoted differentiation of AML cells and has anti-cancer activity against these cells [25][26]. It is well known that different tumor cells have different sensitivity to the same drug (compound).…”

“…To investigate the mRNA expression of genes in cells (BaF3-T315I and K562) incubated with JOA, mRNA sequencing was carried out [25][26]. Briefly, quality of extracted RNA was evaluated.…”