Identification of novel drug combinations for haematological malignancies
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TNF-related apoptosis ligand (TRAIL) is a tumour selective cytokine with potential anti-cancer activity which is currently in clinical trials. Haematological malignancies along with several other cancers have showed varied sensitivity to TRAIL treatment. In vitro and in vivo studies have shown that TRAIL-resistant tumour cells can be sensitised to TRAIL by various chemotherapeutic agents. This has opened up new possibilities for combination therapies. Proteasome inhibitors have previously been used in this way. MLN4924 is an investigational inhibitor of NEDD8 activating enzyme (NAE), which is part of the ubiquitin proteasome pathway. MLN4924 is currently in Phase 1 trials (Millennium Pharmaceuticals, Inc.). MLN4924 binds to NAE and forms an MLN4924-NEDD8 adduct in place of an NEDD8 adenylate thus locking the enzyme in an inactive state. As a consequence, MLN4924 inhibits the NEDD8-dependent activation of a subset of ubiquitin E3 ligases known as cullin ring ligases (CRLs). When CRL neddylation is disrupted, so is the ubiquitin-dependent turnover of CRL substrates, many of which have important roles in cellular processes associated with cancer cell growth and survival pathways including DNA replication and NFkB activity. Targeting the activity of a specific subset of E3 ligases is particularly attractive because there is the potential to selectively block the degradation of certain cellular proteins and possibly avoid unwanted effects on other proteins. We sought to investigate the apoptotic effect MLN4924 in combination with TRAIL may have in multiple myeloma (MM), acute myeloid leukaemia (AML), and diffuse large B cell lymphoma (DLBCL) cell lines. It emerged that MLN4924 and TRAIL have a synergistic effect in a number of AML and MM cell lines. Examples of combination index values obtained for these cell lines include AML2-0.07; MOLM13-0.69; ML1-0.55. In an attempt to identify the mechanism of action we found that MLN4924 induces the expression of Bim and Noxa, pro-apoptotic, BH3-only members of the Bcl-2 protein family. MLN4924 did not significantly affect the expression of apoptotic regulators acting at the TRAIL death receptors, including c-FLIP, pro-caspase-8, cIAP1/2, DR4, DR5, DcR1 or DcR2. Through study of the known transcription factors regulated after MLN4924 treatment, it was found that treatment with MLN4924 led to the induction of p53 and C/EBP alpha in OCI AML2 cells. Inhibition of p53 action with Nutlin3 could sensitise the AML cells to TRAIL-induced apoptosis. Silencing of c/EBP aplha partly reversed the synergism observed between MLN4924 and TRAIL thus identifying it as a key player in the mechanism of sensitisation in OCI AML2 cells. In addition we have observed that p53 and c/EBP alpha most likely behave in a feedback loop fashion. OCI-M2 xenografts treated with a biweekly dose of MLN4924 (on days 1 and 4, each week for 3 weeks) combined with daily dosage of recombinant human TRAIL (days 1-5 each week for 3 weeks) resulted in very significant reduction in tumour volume. In conclusion, this study shows that MLN4924 can sensitise AML and potentially MM cells to TRAIL induced apoptosis to trigger very robust anti-tumour effects by increasing c/EBP alpha and p53 levels. An additional study focused on examining the apoptotic effect of a novel compound on AML cells. This compound was generated by the chemistry department at NUIG. It induces apoptosis in AML cells whilst sparing normal cells. We have identified the serotonin receptors as a possible mechanism through which this compound can induce apoptosis.
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