Walsby, Elisabeth Jane  ORCID: https://orcid.org/0000-0001-8523-5017, Pearce, Laurence, Burnett, Alan Kenneth, Fegan, Christopher Daniel ORCID: https://orcid.org/0000-0001-9685-0621 and Pepper, Christopher John
2012.
The Hsp90 inhibitor NVP-AUY922-AG inhibits NF-κB signaling, overcomes microenvironmental cytoprotection and is highly synergistic with fludarabine in primary CLL cells.
Oncotarget
3
(5)
, pp. 525-534.
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Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of multiple over-expressed signaling proteins that promote growth and survival in cancer cells. Chronic lymphocytic leukaemia (CLL) is characterized by increased expression of several Hsp90 client proteins making it a potentially susceptible to Hsp90 inhibition. In this study we showed that the novel Hsp90 inhibitor NVP-AUY922-AG was cytotoxic to primary CLL cells in vitro (LD50=0.18µM±0.20). Importantly, its toxicity was preserved under cytoprotective co-culture conditions that rendered fludarabine ineffective. At the molecular level, NVP-AUY922-AG depleted the expression of multiple Hsp90 client proteins including Akt and activators of NF-κB, IKKα and IKKβ. Consistent with this inhibition profile, NVP-AUY922-AG resulted in decreased transcription of the NF-B target genes MCL1, CFLAR, BIRC5. In contrast, fludarabine significantly induced the transcription of MCL1 and BIRC5. Given the anti-apoptotic nature of these genes and the role they play in fludarabine resistance, we considered that the combination of NVP-AUY922-AG with fludarabine might resensitize CLL cells to the effects of fludarabine. In keeping with this hypothesis, the combination of NVP-AUY922-AG and fludarabine was highly synergistic (mean CI=0.110.06) and this synergy was enhanced in co-culture (mean CI=0.06±0.08). Furthermore, the combination maintained the decrease in MCL1, CFLAR and BIRC5 transcription suggesting that the ability of NVP-AUY922-AG to modulate expression of these genes may contribute to the efficacy of this drug under cytoprotective co-culture conditions and for its remarkable synergy with fludarabine. Taken together these findings indicate that Hsp90 inhibition is an attractive therapeutic strategy in CLL.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Subjects: | R Medicine > R Medicine (General) |
| Uncontrolled Keywords: | Hsp90 ; CLL ; apoptosis ; synergy ; NF-κB |
| Publisher: | Impact Journals LLC |
| ISSN: | 1949-2553 |
| Related URLs: | |
| Last Modified: | 24 Oct 2022 10:17 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/43725 |
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