Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

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

Leukemia volume 27, pages 2262–2264 (2013)Cite this article

Subjects

Chronic lymphocytic leukemia (CLL) is characterized by the deregulated accumulation and persistence of B lymphocytes in the blood. Although the exact causes of CLL are unknown, the evasion of apoptosis through the aberrant expression of B-cell lymphoma 2 (BCL2)-family proteins is a common feature.1 A class of compounds, termed Bcl-2 homology domain 3 (BH3) mimetics, has been developed to directly inhibit BCL2 proteins and selectively kill tumor cells. To date, the most successful of these compounds are the BCL2/BCLXL inhibitors ABT-7372 and ABT-263 (navitoclax),3, as well as the BCL2-specific inhibitor ABT-199.4 Results from early clinical trials with navitoclax have demonstrated single-agent efficacy in patients with relapsed or refractory CLL.5 However, there was heterogeneity in response rates between patients and dose-limiting toxicities, including thrombocytopenia and neutropenia, which prevented further dose escalation. In addition, CLL cells residing within various microenvironments (for example, lymph nodes and bone marrow) are resistant to BCL2 inhibitors. This resistance results from the upregulation of additional BCL2 proteins, such as BCLXL, MCL1 and BFL1, the latter two of which are not inhibited by navitoclax, and therefore protect the leukemia cells from apoptosis.6 Additional drugs are needed to enhance the efficacy of navitoclax. Here, we demonstrate that gossypol overcomes stroma-mediated resistance to ABT-737 without enhancing the sensitivity of normal lymphocytes and platelets.

The BH3-only protein, NOXA, is a potent inhibitor of MCL1 and BFL1,7 but has recently been recognized to inhibit BCLXL with lower affinity.8 Therefore, compounds which induce NOXA may inhibit MCL1, BFL1 and BCLXL, thus overcoming the resistance to navitoclax. We previously reported that six putative BH3 mimetics do not directly inhibit BCL2 in cells, but instead activate the integrated stress response, and induce NOXA.9 Of these six compounds, gossypol has advanced into clinical trials in a racemically purified form (AT-101).10 We hypothesized that gossypol, through the induction of NOXA, would sensitize CLL cells to ABT-737.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91: 3379–3389.

    CAS  Google Scholar 

  2. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677–681.

    Article  CAS  Google Scholar 

  3. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008; 68: 3421–3428.

    Article  CAS  Google Scholar 

  4. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013; 19: 202–208.

    Article  CAS  Google Scholar 

  5. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of Navitoclax in patients with relapsed or refractory disease. J Clin Oncol 2012; 30: 488–496.

    Article  CAS  Google Scholar 

  6. Vogler M, Butterworth M, Majid A, Walewska RJ, Sun X-M, Dyer MJS et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009; 113: 4403–4413.

    Article  CAS  Google Scholar 

  7. Gélinas C, White E . BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes Dev 2005; 19: 1263–1268.

    Article  Google Scholar 

  8. Zhang L, Lopez H, George NM, Liu X, Pang X, Luo X . Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways. Cell Death Differ 2011; 18: 864–873.

    Article  CAS  Google Scholar 

  9. Albershardt TC, Salerni BL, Soderquist RS, Bates DJP, Pletnev AA, Kisselev AF et al. Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem 2011; 286: 24882–24895.

    Article  CAS  Google Scholar 

  10. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B . An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 2009; 15: 3172–3176.

    Article  CAS  Google Scholar 

  11. Chen R, Guo L, Chen Y, Jiang Y, Wierda WG, Plunkett W . Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood 2011; 117: 156–164.

    Article  CAS  Google Scholar 

  12. Neron S, Pelletier A, Chevrier M-C, Monier G, Lemieux R, Darveau A . Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand. Immunol Invest 1996; 25: 79–89.

    Article  CAS  Google Scholar 

  13. Mérino D, Khaw SL, Glaser SP, Anderson DJ, Belmont LD, Wong C et al. Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood 2012; 119: 5807–5816.

    Article  Google Scholar 

  14. Meng Y, Tang W, Dai Y, Wu X, Liu M, Ji Q et al. Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther 2008; 7: 2192–2202.

    Article  CAS  Google Scholar 

  15. Tromp JM, Geest CR, Breij ECW, Elias JA, van Laar J, Luijks DM et al. Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia. Clin Cancer Res 2012; 18: 487–498.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by a Translational Research Grant from the Leukemia and Lymphoma Society (AE) and a Cancer Center Support Grant to the Norris Cotton Cancer Center (NIH CA23108).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Giesel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, USA

    R Soderquist, D J P Bates & A Eastman

  2. Norris Cotton Cancer Center, Giesel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, USA

    R Soderquist, D J P Bates, A V Danilov & A Eastman

  3. Department of Medicine, Giesel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, USA

    A V Danilov

Authors
  1. R Soderquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D J P Bates
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A V Danilov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Eastman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Eastman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Soderquist, R., Bates, D., Danilov, A. et al. Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo. Leukemia 27, 2262–2264 (2013). https://doi.org/10.1038/leu.2013.138

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.138

This article is cited by

Search

Advanced search

Quick links