Cephalotaxine Esters: Antileukemic Advance or Therapeutic Failure?

Grem, Jean L.; Cheson, Bruce D.; King, Susan A.; Leyland‐Jones, Brian; Suffness, Matthew

doi:10.1093/jnci/80.14.1095

Cited by 38 publications

(29 citation statements)

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“…Although HHT has been reported to be an effective treatment in a portion of patients with AML or CML, the reasons for these different responses are not understood (Grem et al, 1988). Although the mechanisms of action of HHT are not fully understood, apoptotic cells have been detected in HHTtreated patient samples (Visani et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Yin¹,

Wang²,

Zhang³

et al. 2011

Mol Pharmacol

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Homoharringtonine (HHT) has been reported to be effective in a portion of patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). To investigate its mechanism of action, cell growth inhibition and cytotoxicity of HHT were investigated in three AML cell lines, HL-60, NB4, and U937, and in three CML cell lines, K562, KU812, and KCL22. AML cells were more sensitive than CML cells to HHT-induced cytotoxicity. Using HL-60 cells, it was revealed that HHT decreased the levels of myeloid cell leukemia 1 (Mcl-1), X-linked inhibitor of apoptosis protein (XIAP), survivin, and B-cell lymphoma 2 (Bcl-2)-homology domain 3 (BH3)-only proteins as well as the mitochondrial membrane potential. The levels of Bcl-2, Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist/killer (Bak) proteins in HL-60 cells were not changed after HHT treatment. U937, K562, KU812, and KCL22 cells expressed B-cell lymphoma-extra large (Bcl-xL) and were less responsive to HHT-induced apoptosis than HL-60 cells. Silencing Mcl-1 or Bcl-xL, but not XIAP or survivin, enhanced HHT-induced apoptosis in U937 cells. The levels of HHT-induced apoptosis in K562, KCL22, and KU812 cells were inversely correlated with the levels of Bcl-xL but not those of Bcl-2 or Mcl-1. K562 cells expressing high levels of Bcl-xL but no Bcl-2 were less responsive to HHT-induced apoptosis than KCL22 cells that expressed lower levels of Bcl-xL and higher levels of Bcl-2 protein. In K562 cells, knockdown of Bcl-xL, but not of Mcl-1, enhanced HHT-induced apoptosis. Transfection of Bcl-xL into KCL22 cells attenuated HHT-induced apoptosis. These data suggest that Bcl-xL plays a more important role than Bcl-2 and Mcl-1 in protecting against HHT-induced apoptosis.

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Section: Discussionmentioning

confidence: 99%

“…Homoharringtonine [HHT; 4-methyl-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate] is a cephalotaxus alkaloid obtained from Cephalotaxus species, which are evergreen coniferous shrubs (Grem et al, 1988). Extractions of seeds of this genus are toxic to cancer cells and have been used in traditional Chinese medicine (Huang et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Yin¹,

Wang²,

Zhang³

et al. 2011

Mol Pharmacol

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“…1 HHT was first isolated in the 1970s and was found to have natural antitumor and antileukemic activities in in vitro and in vivo studies. 2,3 HHT was initially considered as one of the most effective choices for patients with acute myelocytic leukemia (AML) and chronic myelogenous leukemia (CML) who failed with interferon alpha (IFN-α) therapy and could not tolerate hematopoietic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of magnetic Fe<sub>3</sub>O<sub>4</sub> nanoparticles coloaded with homoharringtonine on human leukemia cells in vivo and in vitro

Chen

Xiong

Yao

et al. 2016

IJN

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Homoharringtonine (HHT), a natural cephalotaxine alkaloid, has been used in the People’s Republic of China for treatment of leukemia for >3 decades. Here, we employed magnetic Fe 3 O 4 nanoparticles (MNP-Fe 3 O 4 ) to improve the therapeutic effect of HHT and investigated its biological effects. Within a certain range of concentrations, the HHT-MNP-Fe 3 O 4 showed a more enhanced inhibitory effect on the selected myeloid leukemia cell lines than HHT alone. Compared with HHT, HHT-MNP-Fe 3 O 4 could induce more extensive apoptosis in leukemia cells, which also showed more pronounced cell arrests at G0/G1 phase. HHT-MNP-Fe 3 O 4 enhanced antitumor activity by downregulating myeloid cell leukemia-1, which could inhibit the activation of caspase-3 and poly-ADP-ribose polymerase. In vivo experiments using tumor-bearing animal models showed that the mean tumor volume with HHT-MNP-Fe 3 O 4 was significantly smaller than that with HHT alone (193±26 mm 3 versus 457±100 mm 3 , P <0.05), while the mean weight was 0.67±0.03 g versus 1.42±0.56 g ( P <0.05). Immunohistochemical study showed fewer myeloid cell leukemia-1-stained cells in mice treated with HHT-MNP-Fe 3 O 4 than with the controls. These findings provide a more efficient delivery system for HHT in the treatment of hematological malignancy.

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“…Phase I trials were later performed in the US using purified alkaloids. Chinese studies were summarised by Grem et al (1988) with data available for 350 patients with leukaemia. Almost 25% of the acute myeloid leukaemia (AML) patients achieved complete remission (CR), but these results were difficult to evaluate (Grem et al, 1988).…”

mentioning

confidence: 99%

“…Chinese studies were summarised by Grem et al (1988) with data available for 350 patients with leukaemia. Almost 25% of the acute myeloid leukaemia (AML) patients achieved complete remission (CR), but these results were difficult to evaluate (Grem et al, 1988). In US, purified HHT was tested first in bolus infusion (Neidhart et al, 1983;Legha et al, 1984;Stewart and Krakoff, 1985) and later replaced by continuous infusion schedule to avert HHT-associated cardiovascular complications (Coonley et al, 1983;Neidhart et al, 1986).…”

mentioning

confidence: 99%

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia

et al. 2006

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To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m À2 day À1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m À2 day À1 . Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m À2 day À1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m À2 , and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m À2 day À1 . The mean half-life of ssHHT was 11.0173.4 h, the volume of distribution at steady state was 271.4 l kg À1 and the plasma clearance was 11.6710.4 l h À1 . Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m À2 day À1 .

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Cephalotaxine Esters: Antileukemic Advance or Therapeutic Failure?

Cited by 38 publications

References 0 publications

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Inhibitory effect of magnetic Fe<sub>3</sub>O<sub>4</sub> nanoparticles coloaded with homoharringtonine on human leukemia cells in vivo and in vitro

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia

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