Rizzo Paola, Mele Donato, Caliceti Cristiana, Pannella Micaela, Fortini Cinzia, Clementz Anthony George, Morelli Marco Bruno, Aquila Giorgio, Ameri Pietro, Ferrari Roberto
Department of Medical Sciences, University of Ferrara , Ferrara , Italy ; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara , Ferrara , Italy ; GVM Hospitals , Cotignola , Italy.
Azienda Ospedaliero-Universitaria di Ferrara , Cona , Italy.
Front Oncol. 2015 Jan 13;4:384. doi: 10.3389/fonc.2014.00384. eCollection 2014.
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.
靶向Notch信号通路是一种对癌症患者有前景的新治疗方法。抑制Notch在肿瘤治疗中有效，因为它能减少高增殖性肿瘤细胞，并抑制癌症干细胞的存活，而癌症干细胞被认为与肿瘤复发和转移有关。此外，由于Delta样配体4（Dll4）激活的Notch信号是血管生成的主要调节因子，目前正在研究抗Dll4药物以减少肿瘤的血管形成。Notch在心脏发育过程中起主要作用，出生后在心脏损伤修复中也发挥作用。因此，用于抑制肿瘤中Notch的药物（γ-分泌酶抑制剂和抗Dll4药物）可能会影响心肌修复。过去使用曲妥珠单抗和其他用于癌症治疗的酪氨酸激酶抑制剂的经验表明，应考虑靶向癌症与心脏及血管系统共同通路的药物可能存在的心脏毒性。迄今为止，癌症患者中Notch抑制仅导致轻度胃肠道毒性。关于癌症患者中Notch抑制相关的潜在长期心脏毒性知之甚少。在本综述中，我们将聚焦于Notch信号抑制可能导致心肌细胞和内皮功能障碍的机制。在心脏压力增加和/或存在心血管危险因素时，这些不良反应可能与癌细胞治疗反应的益处相矛盾。
