Am J Cancer Res 2012;2(1):75-92
Review Article
Targeted ovarian cancer treatment: the TRAILs of resistance
Nadzeya Goncharenko-Khaider, Denis Lane, Isabelle Matte, Claudine Rancourt, Alain Piché
Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord,
Sherbrooke, Canada J1H 5N4
Received October 3, 2011; accepted October 29, 2011; Epub November 21, 2011; Published January 22, 2012
Abstract: Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond
to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line
therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy
combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only
be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will
translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group
of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be
required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal
cells. Death receptor ligands such as TRAIL rely on the activation of apoptotic signaling pathway to destroy tumor cells. TRAIL
induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1
(TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal
amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm
for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells.
There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will
enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly
desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In
particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their
potential implication in the clinical outcome. (AJCR0000090).
Keywords: Ovarian cancer, death receptors, resistance, TRAIL
Full Text PDF
Address all correspondence to:
Alain Piché, M.D., M.Sc.
Département de Microbiologie et Infectiologie
Université de Sherbrooke,
3001, 12ième Avenue Nord
Sherbrooke, Québec
Canada J1H 5N4
Tel : (819) 564-5321
FAX : (819) 564-5392
e-mail : Alain.Piche@USherbrooke.ca
Review Article
Targeted ovarian cancer treatment: the TRAILs of resistance
Nadzeya Goncharenko-Khaider, Denis Lane, Isabelle Matte, Claudine Rancourt, Alain Piché
Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord,
Sherbrooke, Canada J1H 5N4
Received October 3, 2011; accepted October 29, 2011; Epub November 21, 2011; Published January 22, 2012
Abstract: Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond
to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line
therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy
combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only
be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will
translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group
of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be
required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal
cells. Death receptor ligands such as TRAIL rely on the activation of apoptotic signaling pathway to destroy tumor cells. TRAIL
induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1
(TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal
amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm
for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells.
There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will
enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly
desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In
particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their
potential implication in the clinical outcome. (AJCR0000090).
Keywords: Ovarian cancer, death receptors, resistance, TRAIL
Full Text PDF
Address all correspondence to:
Alain Piché, M.D., M.Sc.
Département de Microbiologie et Infectiologie
Université de Sherbrooke,
3001, 12ième Avenue Nord
Sherbrooke, Québec
Canada J1H 5N4
Tel : (819) 564-5321
FAX : (819) 564-5392
e-mail : Alain.Piche@USherbrooke.ca
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