Apigenin inhibits proliferation and induces apoptosis through targeting the trinity of CK2, Cdc37 and Hsp90.
2011 BioMed Research
- Abstract -
Background: Multiple myeloma (MM) is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common ﬂavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined.
Results: in this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells, but not against normal peripheral blood mononuclear cells.
Together inase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the l~lsp9O/Cdc37/client complex and induced the degradation of multiple kinase clients, including R|Pi, Src, Raf-i, Cdl<4 and AKT.
By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-KB. The treatment also down regulated the expression of the antiapoptotic proteins Mcl—i, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells.
In addition, apigenin had a greater effects in depleting Hsp9O clients when used in combination with the Hsp9O inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat.
Conclusions: Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2—Cdc37-Hsp9O, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.