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Autologous plasma activates Akt/protein kinase B and enhances basal survival and resistance to DNA damage‐induced apoptosis in B‐chronic lymphocytic leukaemia cells
Author(s) -
Wickremasinghe R. Gitendra,
Ganeshaguru Kanagasabai,
Jones Dylan T.,
Lindsay Caroline,
Spanswick Victoria J.,
Hartley John A.,
Wadhwa Meenu,
Thorpe Robin,
Hoffbrand A. Victor,
Prentice H. Grant,
Mehta Atul B.
Publication year - 2001
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2001.02978.x
Subject(s) - protein kinase b , apoptosis , biology , cancer research , pi3k/akt/mtor pathway , microbiology and biotechnology , immunology , biochemistry
We have studied the actions of autologous plasma on both basal and DNA damage‐induced apoptosis in B‐chronic lymphocytic leukaemia (B‐CLL) cells. Apoptosis was quantified using morphological criteria and Western blot analysis for the apoptosis‐specific p85 fragment of poly(ADP ribose) polymerase. Cell viability was estimated using the methyl thiazol tetrazolium bromide dye reduction assay. Plasma cultures showed lower rates of basal apoptosis as well as a decreased cytotoxic response to chlorambucil and γ‐radiation compared with cultures in fetal calf serum. Experiments using neutralizing antibodies suggested that the protective actions of plasma could not be accounted for by interleukin 4, the interferons α or γ or stromal cell‐derived factor 1, each of which have been shown to protect B‐CLL cells from apoptosis in vitro . Plasma addition to B‐CLL cells resulted in rapid activation of the Akt protein kinase, a key signalling enzyme that has been implicated in anti‐apoptotic signalling. LY294002, an inhibitor of phosphatidylinositol 3′‐kinase, blocked Akt activation by plasma. To the best of our knowledge, this is the first report to show that factors present in plasma promote basal survival of B‐CLL cells and resistance to cytotoxic drugs via stimulation of the Akt cytoprotective‐signalling pathway. Pharmacological blockade of this pathway may have potential in the development of novel therapeutic strategies for B‐CLL treatment.