Sorafenib, a potential therapy for Chronic lymphocytic leukemia patients

by Selleckchem | Oct 13 2011

Chronic lymphocytic leukemia (CLL) is a common leukemia which causes a slow increase in white blood cells called B lymphocytes, or B cells. This cancer mostly affects adults, around age 70, and leads to approximately 5000 deaths annually. The frontline therapy for CLL mainly use several chemotherapy drugs alone or in combination, such as fludarabine, chlorambucil, cyclophosphamide, and rituximab. Besides, bone marrow or stem cell transplantation may be used in younger patients with advanced or high-risk CLL.
More recently, some new therapy against CLL have been reported to block the pro-survival interaction of CLL cells with their microenvironment and the associated signaling pathways. And it is observed that in vitro, spontaneous or drug-induced apoptosis of CLL cells can inhibited by accessory cells including NLCs and MSCs, suggesting that CLL cells may receive survival signals from these accessory cells. Moreover, exposure of CLL cells to factors from cells of the microenvironment leads to activation of the ERK signaling pathway, which is thus an protential drug target.
Sorafenib (Nexavar) Chemical Structure

     Sorafenib (Nexavar) is a novel, small molecular inhibitor of RAF/MEK/ERK cascade inhibitor, and shows a broad-spectrum antitumor activity in a variety of cancers. Sorafenib can cause apoptosis in leukemia cell lines, and has been used in clinical trials for its efficacy in the treatment of some solid tumors.
     In a recent paper, Fecteau et al.found Sorafenib caused apoptosis of CLL cells even in the presence of NLCs and MSCs, and sorafenib-mediated cytotoxicity also led to apoptosis of CLL cells from fludarabine-resistant patients, in the protective environment. In further mechanism study, sorafenib might induce apoptosis of CLL cells by inhibition of the RAF/MEK/ERK pathway and Mcl-1 downregulation[2].
     Taken together, sorafenib can inhibit apoptosis protection of CLL cells by environment, and thus may be a potential second-line therapy for fludarabine-resistant patients.

Reference
[1]. Blood 2005; 106: 1824-1830.
[2]. Molecular Medicine 2011.

Cat.No.	Product Name	Information
S1040	Sorafenib tosylate	Sorafenib tosylate is a multikinase inhibitor of Raf-1 and B-Raf with IC50 of 6 nM and 22 nM in cell-free assays, respectively. Sorafenib Tosylate inhibits VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-KIT with IC50 of 90 nM, 20 nM, 57 nM, 59 nM and 68 nM, respectively. Sorafenib Tosylate induces autophagy and apoptosis and activates ferroptosis with anti-tumor activity.
S1491	Fludarabine	Fludarabine is a STAT1 activation inhibitor which causes a specific depletion of STAT1 protein (and mRNA) but not of other STATs. Also a DNA synthesis inhibitor in vascular smooth muscle cells. Fludarabine induces apoptosis.
S1217	Cyclophosphamide	Cyclophosphamide(NSC 26271,Endoxan, Cytoxan, Neosar, Procytox, Revimmune, Cytophosphane) is a nitrogen mustard alkylating agent from the oxazophorines group.