Specific killing of multiple myeloma cells by (-)-epigallocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications.
Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea, is an antioxidant with chemopreventive and chemotherapeutic actions. Based on its ability to modulate growth factor-mediated cell proliferation, we evaluated its efficacy in multiple myeloma (MM). EGCG induced both dose- and time-dependent growth arrest and subsequent apoptotic cell death in MM cell lines including IL-6-dependent cells and primary patient cells, without significant effect on the growth of peripheral blood mononuclear cells (PBMCs) and normal fibroblasts. Treatment with EGCG also led to significant apoptosis in human myeloma cells grown as tumors in SCID mice. EGCG interacts with the 67-kDa laminin receptor 1 (LR1), which is significantly elevated in myeloma cell lines and patient samples relative to normal PBMCs. RNAi-mediated inhibition of LR1 resulted in abrogation of EGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCG activity in MM while sparing PBMCs. Evaluation of changes in gene expression profile indicates that EGCG treatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing the expression of death-associated protein kinase 2, the initiators and mediators of death receptor-dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positive regulators of apoptosis and NF-kappaB activation (CARD10, CARD14), and cyclin-dependent kinase inhibitors (p16 and p18). Expression of related genes at the protein level were also confirmed by Western blot analysis. These data demonstrate potent and specific antimyeloma activity of EGCG and provide the rationale for its clinical evaluation.
Shammas
Masood A
MA
Veterans Administration Boston Health Care System, and Dana Farber Cancer Institute/Harvard Medical School, 44 Binney Street, D1B25, Boston, MA 02115, USA.
Neri
Paola
P
Koley
Hemanta
H
Batchu
Ramesh B
RB
Bertheau
Robert C
RC
Munshi
Vidit
V
Prabhala
Rao
R
Fulciniti
Mariateresa
M
Tai
Yu Tzu
YT
Treon
Steven P
SP
Goyal
Raj K
RK
Anderson
Kenneth C
KC
Munshi
Nikhil C
NC
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002392:Catechin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D008517:Phytotherapy; D034741:RNA, Small Interfering / Q000235:genetics; D017474:Receptors, Laminin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013662:Tea / Q000737:chemistry; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D017474:Receptors, Laminin; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate