Abstract
Resistance to apoptosis remains a significant problem in drug resistance and treatment failure in malignant disease. NO-aspirin is a novel drug that has efficacy against a number of solid tumours, and can inhibit Wnt signaling, and although we have shown Wnt signaling to be important for acute lymphoblastic leukemia (ALL) cell proliferation and survival inhibition of Wnt signaling does not appear to be involved in the induction of ALL cell death. Treatment of B lineage ALL cell lines and patient ALL cells with NO-aspirin induced rapid apoptotic cell death mediated via the extrinsic death pathway. Apoptosis was dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC) incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1). There was no measurable increase in TNF-R1 or TNF-α in response to NO-aspirin, suggesting that the process was ligand-independent. Consistent with this, expression of silencer of death domain (SODD) was reduced following NO-aspirin exposure and lentiviral mediated shRNA knockdown of SODD suppressed expansion of transduced cells confirming the importance of SODD for ALL cell survival. Considering that SODD and caspase-10 are frequently over-expressed in ALL, interfering with these proteins may provide a new strategy for the treatment of this and potentially other cancers.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and remission is almost always attained, up to 20% of children will relapse, with subsequent poor prognosis [1]
We have recently shown that para-NO-ASA suppresses NF-kB signalling in ALL cells and that this is associated with apoptotic cell death [21]
A significant sub-G0/1 peak was detected in all three cell lines, consistent with apoptotic cell death as previously reported in ALL cell lines [21]. para-NO-ASA induced cell death in 5 freshly thawed patient samples (p = 0.016 for 5 mM and 0.006 for 10 mM para-NO-ASA) as well as 4 patient samples that had been expanded in vitro by co-culture with human stromal layers (p = 0.029 for 5 mM and p = 0.0006 for 10 mM para-NO-ASA) (Fig 1C), demonstrating that the effect is not confined to cell lines
Summary
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and remission is almost always attained, up to 20% of children will relapse, with subsequent poor prognosis [1]. We found that para-NO-ASA resulted in caspase-10 dependent cell death. Results para-NO-ASA induces apoptotic cell death in pre-B ALL cell lines
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