Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma.

[primary effusion lymphoma]

Sphingosine kinase (SPHK ) is overexpressed by a variety of cancers , and its phosphorylation of sphingosine results in accumulation of sphingosine-1 -phosphate (S 1 P ) and activation of antiapoptotic signal transduction . Existing data indicate a role for S 1 P in viral pathogenesis , but roles for SPHK and S 1 P in virus-associated cancer progression have not been defined . Rare pathologic variants of diffuse large B-cell lymphoma arise preferentially in the setting of HIV infection , including primary effusion lymphoma (PEL ), a highly mortal tumor etiologically linked to the Kaposi 's sarcoma -associated herpesvirus (KSHV ). We have found that ABC 294640 , a novel clinical-grade small molecule selectively targeting SPHK (SPHK 2 > SPHK 1 ), induces dose-dependent caspase cleavage and apoptosis for KSHV (+) patient-derived PEL cells , in part through inhibition of constitutive signal transduction associated with PEL cell proliferation and survival . These results were validated with induction of PEL cell apoptosis using SPHK 2 -specific siRNA , as well as confirmation of drug-induced SPHK inhibition in PEL cells with dose-dependent accumulation of proapoptotic ceramides and reduction of intracellular S 1 P . Furthermore , we demonstrate that systemic administration of ABC 294640 induces tumor regression in an established human PEL xenograft model . Complimentary ex vivo analyses revealed suppression of signal transduction and increased KSHV lytic gene expression within drug-treated tumors , with the latter validated in vitro through demonstration of dose-dependent viral lytic gene expression within PEL cells exposed to ABC 294640 . Collectively , these results implicate interrelated mechanisms and SPHK 2 inhibition in the induction of PEL cell death by ABC 294640 and rationalize evaluation of ABC 294640 in clinical trials for the treatment of KSHV-associated lymphoma .

Diseases
Validation

Diseases presenting "as well as confirmation of drug-induced sphk inhibition in pel cells with dose-dependent accumulation of proapoptotic ceramides and reduction of intracellular s1p" symptom

primary effusion lymphoma

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