TY - JOUR
T1 - The role of notch in the cardiovascular system
T2 - Potential adverse effects of investigational notch inhibitors
AU - Rizzo, Paola
AU - Mele, Donato
AU - Caliceti, Cristiana
AU - Pannella, Micaela
AU - Fortini, Cinzia
AU - Clementz, Anthony George
AU - Morelli, Marco Bruno
AU - Aquila, Giorgio
AU - Ameri, Pietro
AU - Ferrari, Roberto
N1 - Publisher Copyright:
© 2015 Rizzo, Mele, Caliceti, Pannella, Fortini, Clementz, Morelli, Aquila, Ameri and Ferrari.
PY - 2015/1/13
Y1 - 2015/1/13
N2 - Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival of cancer stem cells, which are considered responsible for tumor recurrence and metastasis. Additionally, since Delta-like ligand 4 (Dll4)-activated Notch signaling is a major modulator of angiogenesis, anti-Dll4 agents are being investigated to reduce vascularization of the tumor. Notch plays a major role in the heart during the development and, after birth, in response to cardiac damage. Therefore, agents used to inhibit Notch in the tumors (gamma secretase inhibitors and anti-Dll4 agents) could potentially affect myocardial repair. The past experience with trastuzumab and other tyrosine kinase inhibitors used for cancer therapy demonstrates that the possible cardiotoxicity of agents targeting shared pathways between cancer and heart and the vasculature should be considered. To date, Notch inhibition in cancer patients has resulted only in mild gastrointestinal toxicity. Little is known about the potential long-term cardiotoxicity associated to Notch inhibition in cancer patients. In this review, we will focus on mechanisms through which inhibition of Notch signaling could lead to cardiomyocytes and endothelial dysfunctions. These adverse effects could contrast with the benefits of therapeutic responses in cancer cells during times of increased cardiac stress and/or in the presence of cardiovascular risk factor.
AB - Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival of cancer stem cells, which are considered responsible for tumor recurrence and metastasis. Additionally, since Delta-like ligand 4 (Dll4)-activated Notch signaling is a major modulator of angiogenesis, anti-Dll4 agents are being investigated to reduce vascularization of the tumor. Notch plays a major role in the heart during the development and, after birth, in response to cardiac damage. Therefore, agents used to inhibit Notch in the tumors (gamma secretase inhibitors and anti-Dll4 agents) could potentially affect myocardial repair. The past experience with trastuzumab and other tyrosine kinase inhibitors used for cancer therapy demonstrates that the possible cardiotoxicity of agents targeting shared pathways between cancer and heart and the vasculature should be considered. To date, Notch inhibition in cancer patients has resulted only in mild gastrointestinal toxicity. Little is known about the potential long-term cardiotoxicity associated to Notch inhibition in cancer patients. In this review, we will focus on mechanisms through which inhibition of Notch signaling could lead to cardiomyocytes and endothelial dysfunctions. These adverse effects could contrast with the benefits of therapeutic responses in cancer cells during times of increased cardiac stress and/or in the presence of cardiovascular risk factor.
KW - Cancer therapy
KW - Cardiac remodeling
KW - Cardiotoxicity
KW - Endothelial dysfunctions
KW - Notch inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85013080221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013080221&partnerID=8YFLogxK
U2 - 10.3389/fonc.2014.00384
DO - 10.3389/fonc.2014.00384
M3 - Article
AN - SCOPUS:85013080221
SN - 2234-943X
VL - 4
SP - 1
EP - 11
JO - Frontiers in Oncology
JF - Frontiers in Oncology
ER -