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Platelet factor 4 and other CXC chemokines support the survival of normal
hematopoietic cells and reduce the chemosensitivity of cells to cytotoxic
agents
ZC Han, M Lu, J Li, M Defard, B Boval, N Schlegel and JP Caen
Institut des Vaisseaux et du Sang, University of Paris VII, France.
The effects of platelet factor 4 (PF4) on the viability and
chemosensitivity of normal hematopoietic cells and cancer cell lines were
studied to determine the mechanisms whereby PF4 functions as either an
inhibitor or a protector and to evaluate its clinical significance. Two
other chemokines, interleukin-8 (IL-8) and neutrophil- activating peptide-2
(NAP-2), were also studied in comparison to PF4. Using a tetrazolium salt
assay for cell viability, we observed that PF4 at 1 to 50 microg/mL
supported the viability of normal human bone marrow cells. Approximately
45% of cells cultured for 48 hours survived, whereas 80% or more survived
in the presence of PF4 5 microg/mL. PF4 also supported the viability of
CD34+ cord blood (CB) cells and protected them from apoptosis induced by
transforming growth factor beta1 (TGFbeta1) and cytotoxic drugs.
Pretreatment of CD34+ cells by PF4, but not by TGFbeta1, caused an increase
in the number of megakaryocyte colonies after these cells were replated in
secondary cultures. Flow cytometry analysis showed that when CD34+ cells
were preincubated with PF4 or TGFbeta1 for 12 days in hematopoietic growth
factor-rich medium, an increased number of remaining CD34+ cells was
observed only for PF4-treated cells. Furthermore, PF4 significantly reduced
the chemosensitivity of bone marrow cells, as shown by its ability to
increase the 50% inhibition concentration (IC50) of several cytotoxic
agents. Like PF4, IL-8 and NAP-2 at 0.1, 0.6, and 1 microg/mL supported the
survival of myeloid progenitors, including colony-forming units
granulocyte, erythroblast, monocyte, megakaryocyte (CFU-GEMM),
CFU-megakaryocyte (CFU-MK), CFU-granulocyte/macrophage (CFU-GM), and
burst-forming units-erythroblast (BFU-E), and reduced their sensitivity to
the toxicity of etoposide (ETP). Protamine sulfate at 1 to 100 microg/mL
showed no such activity of PF4. Interestingly, the three chemokines failed
to affect significantly the viability and chemosensitivity of three
leukemic and two other tumor cell lines. Based on these results, we
conclude for the first time that PF4 and IL- 8 and NAP-2 support the
survival of normal hematopoietic precursors and protect them from the
toxicity of chemotherapeutic agents. Because such activities are unique to
normal hematopoietic cells but not to the cancer cell lines evaluated, a
potential clinical application of these molecules in the treatment of
cancer is suggested.
Volume 89,
Issue 7,
pp. 2328-2335,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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