Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma.

[primary effusion lymphoma]

Primary effusion lymphoma (PEL ) is a subtype of non-Hodgkin 's B-cell lymphoma and is an aggressive neoplasm caused by Kaposi 's sarcoma -associated herpesvirus (KSHV ) in immunosuppressed patients . In general , PEL cells are derived from post-germinal center B-cells and are infected with KSHV . To evaluate potential novel anti-tumor compounds against KSHV-associated PEL , seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL . Herein , we discovered a pyrrolidinium fullerene derivative , 1 ,1 ,1 ',1 '-tetramethyl [60 ]fullerenodipyrrolidinium diiodide , which induced apoptosis of PEL cells via a novel mechanism , the caspase-9 activation by suppressing the caspase-9 phosphorylation , causing caspase-9 inactivation . Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells , and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage . Pyrrolidinium fullerene additionally reduced the Ser 473 phosphorylation of Akt and Ser 196 of procaspase-9 . Ser 473 -phosphorylated Akt (i .e ., activated Akt ) phosphorylates Ser 196 in procaspase-9 , causing inactivation of procaspase-9 . We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells . Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells . In addition , we evaluated whether pyrrolidinium fullerene in combination with the HSP 90 inhibitor (geldanamycin ; GA ) or valproate , potentiated the cytotoxic effects on PEL cells . Compared to treatment with pyrrolidinium fullerene alone , the addition of low -concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene . These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL .

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primary effusion lymphoma

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