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. 2013 Nov;27(11):2262-4.
doi: 10.1038/leu.2013.138. Epub 2013 May 3.

Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo

R Soderquist  1 , D J P Bates, A V Danilov, A Eastman
Affiliations

Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo

R Soderquist et al. Leukemia. 2013 Nov.
No abstract available

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Gossypol overcomes stroma-mediated resistance to ABT-737 in CLL cells treated ex vivo at concentrations minimally toxic to normal lymphocytes and platelets. (a) Gossypol induces NOXA and sensitizes CLL cells to ABT-737 ex vivo. CLL cells from consenting patients were isolated using a ficol extraction protocol and incubated with ABT-737 and gossypol as indicated for 6 h ex vivo. Cells were then incubated with Hoechst 33342 and scored for condensed chromatin via microscopy. Survival is expressed as the percentage of cells which do not exhibit condensed chromatin. Error bars represent one S.E.M. (n=5–11). NOXA induction following ex vivo incubation with gossypol in a representative CLL patient was detected by western blotting, with actin as a loading control (inset). (b) Co-culture of CLL cells with CD154-expressing stroma upregulates BCLXL and BFL1. CLL cells isolated from five patients were co-cultured on CD154-expressing stromal cells for 24 h CLL cells were then gently removed from stroma and passed through an 8 micron filter to remove any residual stromal cells. Purified CLL cells were lysed (urea lysis buffer) and analyzed for MCL1, BCLXL, BFL1, BCL2 and actin (loading control) via western blotting. (c) Gossypol resensitizes CLL cells to ABT-737 in a stroma co-culture model. Isolated CLL cells were co-cultured on CD154-expressing stroma for 24 h, and then incubated for 6 h as indicated and scored for % survival (n=5–11). (d) Normal lymphocytes are resistant to ABT-737 and gossypol combinations. Lymphocytes were isolated from healthy individuals via ficol extraction, treated for 6 h as indicated and scored for % survival (n=2). (e) Gossypol does not increase platelet death induced by ABT-737. Platelets from a healthy donor were isolated via centrifugation and treated for 6 h as indicated. Caspase-dependent cleavage of gelsolin was used as a marker of apoptosis in platelets. DMSO (0.1%) was used as a vehicle control.
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References

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