Curcumin induces cell death of the main molecular myeloma subtypes, particularly the poor prognosis subgroups

Abstract

Multiple myeloma (MM), a plasma cell malignancy, remains incurable despite the development of new therapies. Curcumin anti-tumor effects were previously characterized in multiple myeloma, however only few MM cell lines were included in these studies. Since myeloma is a heterogeneous disease it is important to address the impact of myeloma molecular heterogeneity in curcumin cell death induction. In the present study, a large panel of human myeloma cell lines (HMCLs) (n = 29), representing the main molecular MM subgroups, was screened for curcumin sensitivity. We observed that curcumin cell death induction was heterogeneous, of note 16 HMCLs were highly sensitive to curcumin (LD 50 < 20.5 mM), 6 HMCLs exhibited intermediate LD 50 values (20.5 mM LD 50 < 32.2 mM) and only 7 HMCLs were weakly sensitive (35 < LD 50 < 56 mM). Cell lines harboring the t(11;14) translocation were less sensitive (median LD50 32.9 mM) than non-t(11;14) (median LD50 17.9 mM), which included poor prognosis t(4;14) and t(14;16) cells. Interestingly, curcumin sensitivity was not dependent on TP53 status. For the first time we showed that primary myeloma cells were also sensitive, even those displaying del(17p), another poor prognosis factor. We also unravel the contribution of anti-apoptotic Bcl-2 family molecules in curcumin response. We found that down-regulation of Mcl-1, an essential MM survival factor, was associated with curcumin-induced cell death and its knockdown sensitized myeloma cells to curcumin, highlighting Mcl-1 as an important target for curcumin-induced apoptosis. Altogether, these results support clinical trials including curcumin in association with standard therapy.

Long-term stabilisation of myeloma with curcumin

“… 11 Furthermore, curcumin-induced cell death was not influenced by myeloma molecular heterogeneity. 12 …”

The Pleiotropic Effects of Curcumin.

“…The pleiotropic effects of curcumin can be summarised in the following [6] apoptosis by induction of caspase activity (demethoxycurcumin) [10] Mcl-1 downregulation [12] Radiosensitisation [15] Chemosensitisation [16] Diabetes/metabolic syndrome Improve insulin sensitivity [17] increases the levels of anti inflammatory cytokines like adiponectin [19,20] improved endothelial function [21] decrease in inflammatory cytokines and oxidative stress markers [21] Skin diseases decreases IL-22 levels [23] Osteoarthritis (Curcuma domestica) apoptosis of synovial adherent cells. [30] Neuroprotection Alzheimer disease(in vitro)…”

“…In a study done on HMCL (Human Myeloma cell lines), it was shown that Mcl-1, which is an important protein for myeloma cells to survive in the body, was drastically downregulated in curcumin treated cells [12] .Some subgroups of myeloma cell lines like t(4;14) and t(14;16), which are usually considered as poor prognostic factors were found to be highly sensitive to curcumin [12] .…”

Common genetic variants in 11q13.3 and 9q22.33 are associated with molecular subgroups of multiple myeloma

“…The SNP rs16897930 is located in an intron of PDE10A (phosphodiesterase 10A) and encodes a protein that is important for signal transduction by regulating the intracellular concentration of cyclic nucleotides. The phosphodiesterase encoded by PDE10A gene has recently been shown to be a target of curcumin, a drug that has shown apoptotic effect in myeloma cell lines including those with t(4;14) and t(14;16)(12;13). …”