Ceramide-induced cell death in malignant cells

Carpinteiro, Alexander; Dumitru, Claudia A.; Schenck, M.; Gulbins, Erich

doi:10.1016/j.canlet.2008.02.020

Cited by 109 publications

(80 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several mechanisms are described how ceramides contribute to programmed cell death and how they are associated with typical apoptotic characteristics, such as PARP cleavage, DNA fragmentation, or trypan blue uptake. 33 Besides different stimuli, such as certain signaling molecules (protein kinase C or phospholipase A2), death receptors, UV-light, ␥-irradiation, or chemotherapy, 34 BCR engagement was shown to play a role in ceramide regulation. 33,35 The Burkitt lymphoma cell line Ramos displayed an increase of C16-ceramide after BCR engagement.…”

Section: Discussionmentioning

confidence: 99%

B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides

Schwamb

Feldhaus

Baumann

et al. 2012

Blood

View full text Add to dashboard Cite

Survival of chronic lymphocytic leukemia (CLL) cells is triggered by several stimuli, such as the B-cell receptor (BCR), CD40 ligand (CD40L), or interleukin-4 (IL-4).We identified that these stimuli regulate apoptosis resistance by modulating sphingolipid metabolism. Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of proapoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared with untreated controls. Antiapoptotic glucosylceramide levels were significantly increased after BCR cross-linking. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via UDPglucose ceramide glucosyltransferase (UGCG). Besides specific UGCG inhibitors, our data demonstrate that IgMmediated UGCG expression was inhibited by the novel and highly effective PI3K␦ and BTK inhibitors CAL-101 and PCI-32765, which reverted IgM-induced resistance toward apoptosis of CLL cells. Sphingolipids were recently shown to be crucial for mediation of apoptosis via mitochondria. Our data reveal ABT-737, a mitochondria-targeting drug, as interesting candidate partner for PI3K␦ and BTK inhibition, resulting in synergistic apoptosis, even under protection by the BCR. In summary, we identified the mode of action of novel kinase inhibitors CAL-101 and PCI-32765 by controlling the UGCGmediated ceramide/glucosylceramide equilibrium as a downstream molecular switch of BCR signaling, also providing novel targeted treatment options beyond current chemotherapy-based regimens. (Blood. 2012;120(19):3978-3985) IntroductionDespite recent advances in the treatment of chronic lymphocytic leukemia (CLL) by use of modern chemoimmunotherapies, 1,2 the disease remains incurable for most patients with the exception of those who have the option of an allogeneic transplantation. 3 Moreover, most chemotherapeutic regimens require a certain physical fitness of the patient. Because CLL is a disease of the elderly, there is a need for novel therapeutic concepts, which are able to disrupt resistance to cytostatic drugs. Chemoresistance is thought to be partially the result of malignant cell clones that find a niche within the microenvironment. Resistance might be mediated at least by 3 major stimuli: (1) by engagement of the B-cell receptor (BCR), (2) by CD40 ligand (CD40L)-CD40 interaction, and (3) by stimulation via interleukin-4 (IL-4). 4 Those signals lead via downstream pathways to reduced susceptibility of CLL cells toward chemotherapy within the microenvironment. To some extent, these stimuli share common pathways to mediate survival. 5 As a consequence, the balance between proapoptotic and antiapoptotic signals is disrupted toward pro-survival signals. BCR signaling has been identified as the central and determining factor in CLL. Therefore, novel compounds, which target this pathway, have been developed: CAL-101 as PI3K␦ inhibitor and PCI-32765 as inhibitor of Bruton tyrosine kinase (BTK).Recent data from first trials using CAL-101 and PCI-32765 ind...

show abstract

Section: Discussionmentioning

confidence: 99%

B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides

Schwamb

Feldhaus

Baumann

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…Interestingly, marked deregulation of ribosomal-and translation-related genes in patients with the 5q-syndrome has been shown by our group. 62 Multiple pathways that have an important function in cell survival, differentiation, apoptosis and growth [63][64][65][66] were significantly deregulated in À7/del(7q) MDS, including SAPK/JNK, NF-kB, PI3K/AKT and ceramide signaling pathways. Interestingly, CK2, an enzyme with a master regulatory function in Wnt and NF-kB signaling, is up-regulated in À7/del(7q) MDS by 4twofold.…”

Section: Deregulated Pathways In Myelodysplastic Syndromes a Pellagatmentioning

confidence: 99%

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

et al. 2010

View full text Add to dashboard Cite

To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or À7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with À7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention.

show abstract

“…Thus, ceramide plays an active role in membrane raft clustering [3]. Sphingomyelinase and ceramide are involved in the triggering of apoptosis following a wide variety of triggers including TRAIL, CD95, TNF-receptor, DR5, radiation, cytotoxic substances, bacteria, viruses, development, anti-CD20, and disruption of cellular contact with matrix molecules [4].…”

mentioning

confidence: 99%

The trail to deadly membrane rafts

Läng

2012

J Mol Med

View full text Add to dashboard Cite

Ceramide-induced cell death in malignant cells

Cited by 109 publications

References 82 publications

B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides

B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

The trail to deadly membrane rafts

Contact Info

Product

Resources

About