A238: Three dimensional culture sensitizes Multiple Myeloma cells to Histone methyltransferases (HMTases) inhibitor
1Sheffield Hallam University, Sheffield, UK,2The Medical School, Sheffield University, Sheffield, UK
Background: Despite the considerable improvements of the available chemotherapeutic agents, Multiple Myeloma (MM) remains an incurable disease with a high mortality rate. The selective ability of TRAIL to trigger tumour cells to undergo apoptosis while producing negligible effect on the normal cells makes it a future candidate for the resistant MM cells therapy. TRAIL resistance limits its use; however, combined approaches of TRAIL and other therapeutic agents may overcome the TRAIL resistance. In this study, we investigate whether the utilisation of epigenetic modulations (HMTs) inhibitor could enhance TRAIL-induced apoptosis and targets the mechanisms of tumour resistance in both 2D and 3D alginate culture models.
Methods: Six MM lines were challenged with epigenetic modulations (HMTs) inhibitor GSK343,and BIX 01294 either alone or in combination with TRAIL and examined for their synergistic effects on the TRAIL sensitivity in MM cells in both 2D and 3D alginate cell culture models. Apoptosis was assessed using Hoechst 33342 staining of nuclear morphology. Growth inhibition was assessed by CellTiter-Glo® luminescent assay and genes expression was investigated by qRT- PCR.
Results: MMSET positive cells were uniquely sensitive to BIX 01294 trihydrochloride alone. BIX 01294 trihydrochloride synergistically induces apoptosis in combination with TRAIL and reduces cell viability in MMSET negative cells. GSK343 reduces cell viability and the synergistic induction of TRAIL responses was observed in some cell lines independence of MMSET or EZH2 expression. Interestingly, MM cells were more sensitive to anti-tumour agents in 3D Alginate models with potent synergistic effect with TRAIL which is a novel finding.
Conclusions: Epigenetic modulations (HMTs) inhibitor synergistically enhances TRAIL-induced apoptosis in some of the investigated MM cell lines. MM cells were more sensitive to anti-tumour agents in 3D alginate models with synergistic effect with TRAIL. Our findings suggest that combination treatment could be used as a novel anti-tumour agent for MM.