Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells

Abstract

Semisynthetic homoharringtonine (ssHHT) is now being evaluated in phase II clinical trials for the treatment of chronic myelogenous leukemia and acute myelogenous leukemia patients. Here, we examined the mechanism of the apoptosis induced by ssHHT in myeloid leukemia cells. First, we have shown that ssHHT induces apoptosis in HL60 and HL60/MRP cell lines in a time-and dosedependent manner, and independently of the expression of Bax. The decrease of mitochondrial membrane potential and the release of cytochrome c were observed in the apoptotic cells induced by ssHHT. To unveil the relationship between ssHHT and the mitochondrial disruption, we have shown that ssHHT decreased myeloid cell leukemia-1 (Mcl-1) expression and induced Bcl-2 cleavage in HL60 and HL60/MRP cell lines. The Bcl-2 cleavage could be inhibited by the Z-VAD.fmk caspase inhibitor. However, Mcl-1 turnover was very rapid and occurred before caspase activation. The Mcl-1 turnover was only induced by ssHHT and cycloheximide, but not by daunorubicin and cytosine arabinoside, and could be restored by proteasome inhibitors. Second, we confirmed that ssHHT rapidly induced massive apoptosis in acute myelogenous leukemia patient cells. We have also confirmed the release of cytochrome c and a rapid turnover of Mcl-1 in these patient cells, taking place only in apoptotic cells induced by ssHHT but not in cells undergoing spontaneous apoptosis. Finally, we have shown that ssHHT inhibits protein synthesis in both cell line and patient cells. We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia. [Mol Cancer Ther 2006; 5(3):723 -31]

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

“…52 This phenomenon occurred in the absence of Bcl-2, Bax, Bcl-x L , mitogen-activated protein kinase, and AKT down-regulation before 8 hours posttreatment. These effects were replicated in primary cells obtained from patients with AML 51 and patients with CML. 53 However, other reports have indicated that the proapoptotic activity of HHT may involve not only the activation of caspase-9, caspase-3, and PARP but also the activation of caspase-8, thus involving both intrinsic and extrinsic apoptotic pathways, as demonstrated in human myeloma cell lines and tumor cells from patients with recurrent/refractory multiple myeloma.…”

“…sHHT currently is known as omacetaxine The mechanism of action of omacetaxine involves induction of apoptosis in a Bax-independent fashion through mitochondrial disruption and the release of cytochrome c, leading to caspase-9 and caspase-3 activation in HL60 and HL60/MRP myeloid leukemia cell lines. 51 However, omacetaxine did not activate caspase-8 or promote BH3-interacting domain death agonist (Bid) cleavage. The early event that triggered omacetaxine mepesuccinate-induced apoptosis was the down-regulation of Mcl-1, which originally was identified as an antiapoptotic Bcl-2 family protein during differentiation of myeloid cells.…”

Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors

“…Franck E. Nicolini, 1 H. Jean Khoury, 2 Luke Akard, 3 Delphine Rea, 4 Hagop Kantarjian, 5 Michele Baccarani, 6 Janis Leonoudakis, 7 Adam Craig, 8 Annie-Claude Benichou, 8 …”

Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors

“…24 To define the role of proteasomal degradation for the OM-induced cCRbc-downregulation in hematopoietic cells, we performed combination experiments with the proteasome-inhibitor MG-132 and OM. For this end we treated Ba/F3p210 cells with 10 mM MG-132 1 h prior adding 50 nM of OM.…”