期刊
JOURNAL OF CLINICAL MEDICINE
卷 9, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/jcm9092740
关键词
beta-adrenergic receptor antagonist; ICI-118; 551; propranolol; HIF; ccRCC; VHL; anticarcinogenic
资金
- Ministry of Economy and Competitivity [SAF2017-83351-R]
- Madrid Regional Government IMMUNOTHERCAN [B2017/BMD-3733-2]
- Spanish Alliance of VHL patients
- CIBERER
Von Hippel-Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of beta 2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL-/- ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2 alpha, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2 alpha and NFB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.
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