Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells.
Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of multiple myeloma.
Bhardwaj
Anjana
A
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Sethi
Gautam
G
Vadhan-Raj
Saroj
S
Bueso-Ramos
Carlos
C
Takada
Yasunari
Y
Gaur
Upasna
U
Nair
Asha S
AS
Shishodia
Shishir
S
Aggarwal
Bharat B
BB
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D053668:Syndecan-1 / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D001897:Boronic Acids; D015850:Interleukin-6; D016328:NF-kappa B; D011719:Pyrazines; D050796:STAT3 Transcription Factor; D013267:Stilbenes; D053668:Syndecan-1; D051028:bcl-2-Associated X Protein; D013792:Thalidomide; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D000077185:Resveratrol