Amphotericin B br Acknowledgements The authors thank Drs C

Acknowledgements The authors thank Drs. C. Klein, I. Canisso and A. Claes with assistance in obtaining tissues. Supported by the Albert G. Clay Endowment, University of Kentucky.
Introduction Neoplastic Amphotericin B often develop drug resistance during tumor progression or cancer treatment (Turner and Reis-Filho, 2012). Several molecular mechanisms can lead to drug resistance, one of which being the modulation of the NF-κB pathway (Turco et al., 2004). The NF-κB family of transcriptional factors can be activated by various stimuli. Upon activation, NF-κB dissociates from the inhibitory IκBα and translocates from the cytoplasm to the nucleus, where it binds to the promoter elements and activates gene expression (Ghosh et al., 1998). The increased activity of NF-κB has been shown in a variety of cancer cell types where its activation contributes to aggressive tumor growth as well as to resistance to chemotherapy or ionizing radiation during cancer treatment. The induction of chemo- and radio-resistance is mediated through numerous NF-κB-regulated genes. This involves overexpression of its downstream targets, such as Bcl-xL, Bcl–2, IAP1, and IAP2, and proliferative genes such as cyclin D1 and COX-2. Components of the NF-κB pathway therefore represent key therapeutic targets (Braun et al., 2006, Orlowski and Baldwin, 2002). Hence, inhibition of the NF-κB pathway leads to apoptosis induced through the collapse of the mitochondrial membrane and the activation of caspase-9. Activation of the mitochondrial apoptotic pathway secondary to the inhibition of NF-κB is a valuable source of cell death induction in cancer cells where the expression of NF-κB is elevated (Karin, 2006, Kim et al., 2006). It has been demonstrated that cancer cells transiently pretreated with a sublethal concentration of doxorubicin became more resistant to doxorubicin upon subsequent challenges. Pretreatment of the cells with common biologic modulators, such as tamoxifen, dexamethasone, and curcumin, overcame the doxorubicin-induced NF-κB activation, indicating that this inhibition may play an important role in sensitizing cancer cells to chemotherapeutic drugs (Chuang et al., 2002). In the course of our previous research, the EP4 receptor has been identified as conveying the growth-inhibitory effects of PGE2 in immature and mature B cells (Murn et al., 2008, Prijatelj et al., 2011). The EP4 receptor is one of the four prostaglandin E (EP) receptors (EP1, EP2, EP3 and EP4) that recognize prostaglandin E2 (PGE2) as its natural binding ligand. Depending on the cell type, activation of the EP4 receptor by PGE2 leads to elevated levels of cAMP and, in some cases, to the activation of cAMP-independent pathways including modulation of the NF-κB transcription factor (Prijatelj et al., 2012). We have, therefore, hypothesized that the EP4 receptor presents a potent therapeutic target for B leukemia and lymphoma treatment. In the present study, we identified a subset of B leukemia and lymphoma cells responding to the growth-inhibitory effects of the selective EP4 receptor agonist, 1-hydroxy prostaglandin E1 (Pge1-OH). Moreover, activation of EP4 receptor by Pge1-OH leads to a decrease in the NF-κB-mediated expression of the antiapoptotic gene Bcl-xL, resulting in an increased sensitivity of cells towards bortezomib- and doxorubicin-induced chemotherapeutic effects.