The role of notch in the cardiovascular system

Potential adverse effects of investigational notch inhibitors

Paola Rizzo, Donato Mele, Cristiana Caliceti, Micaela Pannella, Cinzia Fortini, Anthony George Clementz, Marco Bruno Morelli, Giorgio Aquila, Pietro Ameri, Roberto Ferrari

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalFrontiers in Oncology
Volume4
DOIs
StatePublished - Jan 13 2015
Externally publishedYes

Fingerprint

Cardiovascular System
Neoplasms
Angiogenesis Modulating Agents
Amyloid Precursor Protein Secretases
Heart Neoplasms
Neoplastic Stem Cells
Cardiac Myocytes
Protein-Tyrosine Kinases
Therapeutics
Parturition
Neoplasm Metastasis
Recurrence

Keywords

  • Cancer therapy
  • Cardiac remodeling
  • Cardiotoxicity
  • Endothelial dysfunctions
  • Notch inhibitors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rizzo, P., Mele, D., Caliceti, C., Pannella, M., Fortini, C., Clementz, A. G., ... Ferrari, R. (2015). The role of notch in the cardiovascular system: Potential adverse effects of investigational notch inhibitors. Frontiers in Oncology, 4, 1-11. https://doi.org/10.3389/fonc.2014.00384

The role of notch in the cardiovascular system : Potential adverse effects of investigational notch inhibitors. / Rizzo, Paola; Mele, Donato; Caliceti, Cristiana; Pannella, Micaela; Fortini, Cinzia; Clementz, Anthony George; Morelli, Marco Bruno; Aquila, Giorgio; Ameri, Pietro; Ferrari, Roberto.

In: Frontiers in Oncology, Vol. 4, 13.01.2015, p. 1-11.

Research output: Contribution to journalArticle

Rizzo, P, Mele, D, Caliceti, C, Pannella, M, Fortini, C, Clementz, AG, Morelli, MB, Aquila, G, Ameri, P & Ferrari, R 2015, 'The role of notch in the cardiovascular system: Potential adverse effects of investigational notch inhibitors', Frontiers in Oncology, vol. 4, pp. 1-11. https://doi.org/10.3389/fonc.2014.00384
Rizzo, Paola ; Mele, Donato ; Caliceti, Cristiana ; Pannella, Micaela ; Fortini, Cinzia ; Clementz, Anthony George ; Morelli, Marco Bruno ; Aquila, Giorgio ; Ameri, Pietro ; Ferrari, Roberto. / The role of notch in the cardiovascular system : Potential adverse effects of investigational notch inhibitors. In: Frontiers in Oncology. 2015 ; Vol. 4. pp. 1-11.
@article{1c26196bf5ba44de8e8e5acec360f90e,
title = "The role of notch in the cardiovascular system: Potential adverse effects of investigational notch inhibitors",
abstract = "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.",
keywords = "Cancer therapy, Cardiac remodeling, Cardiotoxicity, Endothelial dysfunctions, Notch inhibitors",
author = "Paola Rizzo and Donato Mele and Cristiana Caliceti and Micaela Pannella and Cinzia Fortini and Clementz, {Anthony George} and Morelli, {Marco Bruno} and Giorgio Aquila and Pietro Ameri and Roberto Ferrari",
year = "2015",
month = "1",
day = "13",
doi = "10.3389/fonc.2014.00384",
language = "English (US)",
volume = "4",
pages = "1--11",
journal = "Frontiers in Oncology",
issn = "2234-943X",
publisher = "Frontiers Media S. A.",

}

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

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

VL - 4

SP - 1

EP - 11

JO - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

ER -