Curcumin Supresess Growth and Induces Apoptosis of Primary Effusion Lymphoma Cells.

Kaposi ‘s sarcoma-associated herpesvirus (KSHV or HHV8) has also been implicated in primary effusion lymphoma (PEL). KSHV/HHV8 has been shown to activate a number of growth and survival signaling pathways, including PI3-kinase and JAK/STAT, and protect cells from programmed cell death. Indeed Stat-3 is constitutively phosphorylated/activated in PEL cells and plays a role in their survival and proliferation. Curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga had very little or no toxicity in human cells and has been shown to have anti-tumor activity in vitro. We describe here that curcumin at 20 μM concentration inhibits cell proliferation in several PEL cell lines (BC1 64 + 1%, BC3 67 + 2%, BCBL1 62 +3% inhibition of growth) and induces apoptosis (BC1 51+ 5%, BC3 47 + 6%, BCBL1 48 + 4 % apoptosis cells). To characterize better the mechanism of action of curcumin, we studied the JAK/STAT pathway and the apoptotic cascade. Curcumin suppressed the constitutively active Stat3 transcription factor in a dose dependent manner. Curcumin also induced loss of mitochondrial membrane potential, as determined by JC1 staining with subsequent activation of capase-3 followed by polyadenosin-5′-diphosphate-ribose polymerase (PARP) cleavage. In addition, zVAD-fmk, a universal inhibitor of caspases prevented caspase-3 activation as well as PARP cleavage induced by curcumin treatment. IL-10 is a major autocrine growth factor for PEL cell survival. We quantified by ELISA the secretion of IL-10 in PEL cells and found that curcumin abrogated IL-10 secretion. Taken together, our findings suggest that curcumin suppresses constitutively active Stat-3 in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. These results provide the molecular basis and preliminary data for new treatment strategies that may incorporate curcumin in regimens for PEL.