Effects of sorafenib on lymphocytic leukemia cells(CLLs)

Fecteau JF, Bharati IS, O’hayre M, Handel TM, Kipps TJ, Messmer D. “Mol Med. 2011 Oct”

We have beforehand demonstrated that sorafenib, a multi-kinase inhibitor, exhibits cytotoxic results on CLL cells. Considering that the cellular microenvironment can defend CLL cells from drug-induced apoptosis. It is important to assess the impact of novel medications in this particular context.

Here we characterized the in vitro cytotoxic results of sorafenib on CLL cells and also the underlying mechanism in the existence of marrow stromal cells (MSCs) and nurse-like cells (NLCs). One simple dose of 10 μM or even the repeated addition of 1 μM sorafenib brought on caspase-dependent apoptosis and decreased levels of phosphorylated B-RAF, C-RAF, ERK, STAT3, and Mcl-1 in CLL cells within the existence of the microenvironment. We present the RAF/MEK/ERK pathway can modulate Mcl-1 expression and contribute to CLL cell viability, therefore associating sorafenib cytotoxicity to its influence on RAF and Mcl-1.

To evaluate when the other targets of sorafenib can have an effect on CLL cell viability and add to sorafenib mediated cytotoxicity, we examined the sensitivity of CLL cells to several kinase inhibitors particular for these targets. Our information display that RAF and VEGFR although not KIT, PDGFR, and FLT3 are essential for CLL cell viability.

Taken with each other, our information suggest that sorafenib exerts its cytotoxic impact most likely through inhibition in the VEGFR and RAF/MEK/ERK pathways, both of which can modulate Mcl-1 expression in CLL cells. Furthermore, sorafenib induced apoptosis of CLL cells from fludarabine refractory patients within the existence of NLCs or MSCs.

Concentrations:

sorafenib, kinase inhibitor, marrow stromal cells (MSCs)

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