A Green Tea Polyphenol, Epigallocatechin-3-Gallate, Induces Selective Apoptosis in Multiple Myeloma Cells: Mechanism of Action and Therapeutic Potential.

Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea, induces dose and time dependent cell death in both IL-6-dependent and independent multiple myeloma cell lines and primary patient cells, with minimal or no effect on the growth of normal cells. The cell death is apoptotic as determined by annexin V staining and is not inhibited by IL-6. Evaluation of molecular mechanism of action by gene expression profiling indicated that EGCG had a profound effect on transcription of major regulatory genes involved in distinct pathways controlling cell growth arrest and apoptosis: Exposure of myeloma cells to EGCG induced the expression of: 1) Fas ligand, Fas, and caspase 4, the initiators and mediators of death receptor dependent apoptosis; 2) death-associated protein kinase 2, a multifunctional pro-apoptotic protein kinase; 3) P53-like proteins, p73, p63; 4) CARD10 and CARD14, positive regulators of apoptosis and NF-kappaB activation; and 5) Cyclin-dependent kinase inhibitors, p16 and p18. In a subset of these selected genes, the expression data is also confirmed with western blot analyses. We have also demonstrated that the transcript and protein levels of a metastasis associated laminin receptor 1 are significantly elevated in myeloma cell lines and patient samples compared to normal cells. RNAi mediated inhibition of laminin receptor 1, abrogated EGCG-induced apoptosis in myeloma cells thus indicating that the profound anti-cancer effect of this compound is probably mediated through this receptor. The selective expression of this receptor explains the selective activity of EGCG in multiple myeloma cells without adversely affecting normal cells.

Taken together these data confirm significant and selective anti-cancer activity of EGCG, a natural product, in MM and provides the basis for its clinical evaluation.