Leukemic cell differentiation in vivo and in vitro: arrest of proliferation parallels the differentiation induced by the antileukemic drug Harringtonine

Abstract

A variety of chemical agents have been shown to induce differentiation in in vitro cultured neoplastic cell lines. We noted that blast cells in the peripheral blood of acute nonlymphoid leukemia patients treated with the drug Harringtonine appeared to undergo morphological changes that suggested differentiation. In view of the relatively minimal myelotoxicity of Harringtonine, we hypothesized that harringtonine was acting by differentiation-induction, which concomitantly arrested cell division. We tested this hypothesis using two different experimental approaches. First, the promyelocytic leukemic cell line, HL-60, was cultured with Harringtonine and shown to differentiate into a cell, which, by functional cell surface marker and morphological criteria, closely resembled normal monocytes. Furthermore, these changes were accompanied, and indeed slightly preceded by, loss of proliferative capacity. Second, to prove that the leukemic blasts were the cells undergoing the changes observed in vivo, freshly isolated leukemia cell populations were cultured with Harringtonine, and morphological changes paralleling those seen in the patients were observed. Thus, the antileukemic effect of Harringtonine appeared to be due to diversion of the proliferating blast cells into a differentiation pathway, which, as in normal myeloid cells, resulted in the arrest of proliferation.

IL-18-induced interaction between IMP3 and HuR contributes to COX-2 mRNA stabilization in acute myeloid leukemia

“…triggering apoptosis [33,34]. However, patients often fail to undergo complete remission as a result of the occurrence of drug resistance.…”

“…The increase in IL-18R levels, particularly in response to differentiation induction, further provides a stronger antiapoptotic effect in anticancer drug-treated AML cells. However, this suggestion needs to be further verified in vitro and clinically for AML patients treated with anticancer drugs, such as VitD3, harringtonine, and bufalin [33,34], which are involved in the induction of differentiation activity.…”

Low dose cytosine arabinoside: partial remission of acute myeloid leukaemia without evidence of differentiation induction

“…As an initial step in attempting to analyse the effect of ARA-C on patients' leukaemic cells, its action on this cloned cell line was studied. The FCS used in this study was optimized for growth rate, and the doubling time was estimated to be approximately 30 h. The effect of ARA-C was compared with that of Harringtonine (Harr) which we have shown induced monocytic differentiation in HL60 cells (Boyd & Sullivan, 1984). Liquid cultures ( lo5 cells/ml) were established in the presence of ARA-C, Harr or TPA and incubated for 4 d. The cells were then analysed for morphology and non-specific esterase staining.…”

“…The dose-response curve of DNA synthesis inhibition as reported by others (Harris et al, 1979) would tend to favour a differentiation role for LD ARA-C (Cataigne et al, 1983). Indeed we have shown that the predominant mode of action of the antileukaemic drug Harringtonine is by differentiation induction (Boyd & Sullivan, 1984).…”

A phase II study of homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: A pediatric oncology group study

“…Of seven antitumor agents tested in vitro in a human cell line, none was synergistic with HHT [6]. The HL60 human promyelocytic leukemia cell line is sensitive to and undergoes differentiation in the presence of low levels of HHT [7,8].…”