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Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis.

ABSTRACT: Interactions between the multi-kinase inhibitor sorafenib and MEK1/2 inhibitors were investigated in DLBCL cells. Sorafenib (3-10 microM) triggered apoptosis in multiple GC and ABC lymphoma cells. Unexpectedly, sorafenib did not cause sustained ERK1/2 inactivation, and in SUDHL-6 and -16 cells, triggered ERK1/2 activation. Marginally toxic MEK1/2 inhibitor concentrations (5 microM PD184352) abrogated ERK1/2 activation in sorafenib-treated cells and synergistically potentiated apoptosis. MEK1 shRNA transfection also significantly increased sorafenib-mediated lethality. Sorafenib/PD184352 co-administration accelerated Mcl-1 down-regulation without up-regulating Bim(EL). Finally, ectopic Mcl-1 expression attenuated sorafenib/PD184352-mediated apoptosis. Together, these findings provide a theoretical basis for potentiating sorafenib anti-lymphoma activity by MEK1/2 inhibitors.

SUBMITTER: Nguyen TK

PROVIDER: S-EPMC3150480 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis.

Nguyen Tri K TK Jordan Nicholas N Friedberg Jonathan J Fisher Richard I RI Dent Paul P Grant Steven S

Leukemia research 20100201 3

Interactions between the multi-kinase inhibitor sorafenib and MEK1/2 inhibitors were investigated in DLBCL cells. Sorafenib (3-10 microM) triggered apoptosis in multiple GC and ABC lymphoma cells. Unexpectedly, sorafenib did not cause sustained ERK1/2 inactivation, and in SUDHL-6 and -16 cells, triggered ERK1/2 activation. Marginally toxic MEK1/2 inhibitor concentrations (5 microM PD184352) abrogated ERK1/2 activation in sorafenib-treated cells and synergistically potentiated apoptosis. MEK1 shR ...[more]

PMID: 20117835

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MEK inhibition induces apoptosis in osteosarcoma cells with constitutive ERK1/2 phosphorylation.

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Inhibition of methyltransferases accelerates degradation of cFLIP and sensitizes B-cell lymphoma cells to TRAIL-induced apoptosis.

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| S-EPMC5746389 | biostudies-other

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