Published online 16 June 2009
Haematologica, Vol 94, Issue 7, 928-934 doi:10.3324/haematol.2008.003996
Copyright © 2009 by Ferrata Storti Foundation
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Acute Leukemia

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

Patries M. Herst1, Joanne E. Davis2, Paul Neeson2, Michael V. Berridge1, David S. Ritchie2

1 Malaghan Institute of Medical Research, Wellington, New Zealand and
2 Haematology and Immunology Translational Research Laboratory, The Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Correspondence: Patries M. Herst, Malaghan Institute of Medical Research, PO Box 7060, Wellington 6005, New Zealand. E-mail:pherst{at}malaghan.org.nz

Background: The redox-active isoflavene anti-cancer drug, phenoxodiol, has previously been shown to inhibit plasma membrane electron transport and cell proliferation and promote apoptosis in a range of cancer cell lines and in anti-CD3/anti-CD28-activated murine splenocytes but not in non-transformed WI-38 cells and human umbilical vein endothelial cells.

Design and Methods: We determined the effects of phenoxodiol on plasma membrane electron transport, MTT responses and viability of activated and resting human T cells. In addition, we evaluated the effect of phenoxodiol on the viability of leukemic cell lines and primary myeloid and lymphoid leukemic blasts.

Results: We demonstrated that phenoxodiol inhibited plasma membrane electron transport and cell proliferation (IC50 46 µM and 5.4 µM, respectively) and promoted apoptosis of rapidly proliferating human T cells but did not affect resting T cells. Phenoxodiol also induced apoptosis in T cells stimulated in HLA-mismatched allogeneic mixed lymphocyte reactions. Conversely, non-proliferating T cells in the mixed lymphocyte reaction remained viable and could be restimulated in a third party mixed lymphocyte reaction, in the absence of phenoxodiol. In addition, we demonstrated that leukemic blasts from patients with primary acute myeloid leukemia (n=22) and acute lymphocytic leukemia (n=8) were sensitive to phenoxodiol. The lymphocytic leukemic blasts were more sensitive than the myeloid leukemic blasts to 10 µM phenoxodiol exposure for 24h (viability of 23±4% and 64±5%, respectively, p=0.0002).

Conclusions: The ability of phenoxodiol to kill rapidly proliferating lymphocytes makes this drug a promising candidate for the treatment of pathologically-activated lymphocytes such as those in acute lymphoid leukemia, or diseases driven by T-cell proliferation such as auto-immune diseases and graft-versus-host disease.

Key words: phenoxodiol, anti-leukemic, proliferating T cells, auto-immune disease, graft-versus-host disease.