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


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 (IC(50) 46 microM and 5.4 microM, 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 muM 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.
Herst
Patries M
PM
Malaghan Institute of Medical Research, Wellington 6005, New Zealand. pherst@malaghan.org.nz
Davis
Joanne E
JE
Neeson
Paul
P
Berridge
Michael V
MV
Ritchie
David S
DS
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D010084:Oxidation-Reduction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014471:Umbilical Veins / Q000473:pathology
D007529:Isoflavones; D013778:Tetrazolium Salts; D013844:Thiazoles; C471183:phenoxodiol; C022616:thiazolyl blue