Implication of Raft Microdomains in Drug Induced Apoptosis

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Implication of Raft Microdomains in Drug Induced Apoptosis



Anti-Cancer Agents in Medicinal Chemistry, 3(4): 263-270.

Author(s): Christine Bezombes, Guy Laurent and Jean-Pierre Jaffrezou.

Affiliation: INSERM U563-CPTP, Institut Claudius Regaud, 20 rue du Pont St Pierre 31052, Toulouse, France.

Abstract

DNA damaging agents such as 1-β-D-arabinofuranosylcytosine (Ara-C) and daunorubicin (DNR) are widely used in the treatment of acute nonlymphocytic leukemia. These drugs have, of course, been the objects of intense basic research, as well as preclinical and clinical study. Although specific biochemical lesions (DNA damage) have been associated with Ara-C- and DNR-mediated cytotoxicity, the pathways leading to the induction of apoptosis remain ill defined. This standpoint has forced investigators to explore a new concept in cell response to cytotoxic stress: apoptosis signaling. The recent identification of a ceramide (CER) mediated apoptotic signaling pathway triggered by antitumor agents offers a new perspective for the treatment of neoplastic cells. Indeed, these agents have been shown to induce apoptosis through the activation of a sphingomyelinase (SMase) responsible for the hydrolysis of sphingomyelin (SM) and the generation of CER. The latter acts as a potent apoptosis mediator, triggering several downstream signaling pathways among which the stress-activated protein kinase cascade (MEKK1-SEK1-SAP / JNK) plays a critical role in apoptosis induction. However, the spacio-temporal organization of the key early signaling events is unclear. The present review delineates what appears to be a critical factor in apoptosis signaling: sphingomyelin enriched plasma membrane rafts. The apparent topological partitioning between DNA damage and apoptosis signaling (integrated into specialized plasma membrane domains) is discussed.

Keywords:

cancer therapy, resistance, apoptosis signaling.



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Article Details

Volume: 3
Issue Number: 4
First Page: 263
Last Page: 270
Page Count: 8
DOI: 10.2174/1568011033482413
Price: $58
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