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Curcumin induces cell death of the main molecular myeloma subtypes, particularly the poor prognosis subgroups
Patricia Gomez-Bougie1, Maxime Halliez, Sophie Maïga
1a INSERM, UMR892 - CNRS; UMR 6299; Université de Nantes ; Nantes , France.
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 (LD50 < 20.5 μM), 6 HMCLs exhibited intermediate LD50 values (20.5 μM ≤ LD50 < 32.2 μM) and only 7 HMCLs were weakly sensitive (35 < LD50 < 56 μM). Cell lines harboring the t(11;14) translocation were less sensitive (median LD50 32.9 μM) than non-t(11;14) (median LD50 17.9 μM), 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.
Insights
Curcumin shows varied effectiveness against multiple myeloma (MM) cell death, with sensitivity influenced by molecular subgroups. Targeting Mcl-1 may enhance curcumin
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multiple myeloma (MM) is an incurable plasma cell malignancy.
- Curcumin's anti-tumor effects in MM require further investigation due to disease heterogeneity.
- Previous studies used limited MM cell lines, necessitating research into molecular subgroup impacts on curcumin sensitivity.
Purpose of the Study:
- To screen a large panel of human myeloma cell lines (HMCLs) representing main molecular subgroups for curcumin sensitivity.
- To investigate the impact of molecular heterogeneity on curcumin-induced cell death in MM.
- To explore the role of anti-apoptotic Bcl-2 family molecules, particularly Mcl-1, in MM response to curcumin.
Main Methods:
- Screening of 29 human myeloma cell lines (HMCLs) across major molecular subgroups for curcumin sensitivity.
- Assessment of curcumin's half-maximal lethal dose (LD50) in HMCLs.
- Analysis of curcumin sensitivity in relation to specific chromosomal translocations (e.g., t(11;14), t(4;14), t(14;16)) and TP53 status.
- Evaluation of curcumin sensitivity in primary myeloma cells, including those with del(17p).
- Investigation of Bcl-2 family member expression and Mcl-1 knockdown effects on curcumin response.
Main Results:
- Curcumin-induced cell death was heterogeneous across 29 HMCLs, with 16 highly sensitive, 6 intermediate, and 7 weakly sensitive.
- HMCLs with t(11;14) translocation showed less sensitivity (median LD50 32.9 μM) compared to non-t(11;14) cells (median LD50 17.9 μM).
- Curcumin sensitivity was independent of TP53 status but effective in primary myeloma cells, including those with del(17p).
- Down-regulation of Mcl-1 correlated with curcumin-induced cell death, and Mcl-1 knockdown sensitized cells to curcumin.
Conclusions:
- Curcumin exhibits heterogeneous efficacy in inducing cell death across diverse multiple myeloma molecular subgroups.
- Mcl-1 is identified as a key target, as its down-regulation is linked to curcumin sensitivity and Mcl-1 knockdown enhances this effect.
- Results support further clinical trials investigating curcumin in combination with standard therapies for multiple myeloma.
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