Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study

Lin, Chin‐Sheng; Lin, Wei‐Shiang; Lin, Cheng‐Li; Kao, Chia‐Hung

doi:10.1016/j.ijcard.2015.02.015

Cited by 56 publications

(48 citation statements)

References 29 publications

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“…Carvedilol's cancer preventative attributes were further confirmed in vitro and in vivo . Consistently, a recent population‐based cohort study reported that long‐term use of carvedilol is associated with reduced risk of many types of cancer …”

Section: Introductionsupporting

confidence: 66%

“…23,24 Consistently, a recent population-based cohort study reported that long-term use of carvedilol is associated with reduced risk of many types of cancer. 25 To identify the mechanisms underlying the cancer preventive activity of carvedilol on JB6 P+ cells, the present study determined whether carvedilol is able to activate ERK in JB6 P+ cells and further addressed the question why as an ERK activator carvedilol does not promote but oppositely prevent EGF-induced transformation. Other biased and unbiased β-blockers were used for comparison with carvedilol in some of the experiments.…”

mentioning

confidence: 99%

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Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

Cleveland

Yeung

Huang

et al. 2018

Molecular Carcinogenesis

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Recent studies suggest that the β-blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few β-blockers identified as biased agonist based on an ability to promote β-arrestin-mediated processes such as ERK phosphorylation. To understand the role of phosphoproteomic signaling in carvedilol's anticancer activity, the mouse epidermal JB6 P+ cells treated with EGF, carvedilol, or their combination were analyzed using the Phospho Explorer Antibody Array containing 1318 site-specific and phospho-specific antibodies of over 30 signaling pathways. The array data indicated that both EGF and carvedilol increased phosphorylation of ERK's cytosolic target P70S6 K while its nuclear target ELK-1 were activated only by EGF; Furthermore, EGF-induced phosphorylation of ELK-1 and c-Jun was attenuated by carvedilol. Subcellular fractionation analysis indicated that ERK nuclear translocation induced by EGF was blocked by co-treatment with carvedilol. Western blot and luciferase reporter assays confirmed that the biased β-blockers carvedilol and alprenolol blocked EGF-induced phosphorylation and activation of c-Jun/AP-1 and ELK-1. Consistently, both carvedilol and alprenolol strongly prevented EGF-induced neoplastic transformation of JB6 P+ cells. Remarkably, oral carvedilol treatment significantly inhibited the growth of A375 melanoma xenograft in SCID mice. As nuclear translocation of ERK is a key step in carcinogenesis, inhibition of this event is proposed as a novel anticancer mechanism for biased β-blockers such as carvedilol.

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Section: Introductionsupporting

confidence: 66%

mentioning

confidence: 99%

Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

Cleveland

Yeung

Huang

et al. 2018

Molecular Carcinogenesis

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“…In this respect PRO has a similar selectivity to some other clinically used beta-blocker drugs, particularly pindolol and carvedilol and there exists some evidence that these particular drugs may also have potential in repurposing [92–93]. There are a number of distinct putative mechanisms of action that have been investigated in relation to the anticancer effects of PRO, many of them associated with the beta2-adrenoreceptor pathway and which may be particularly important in the context of the metastatic process [94].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Pantziarka

Bouche

Sukhatme³

et al. 2016

ecancer

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Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

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“…A subsequent preclinical study showed that propranolol combined with ionizing radiation reduced tumour growth and volume in a gastric adenocarcinoma mouse model . Carvedilol, which acts as an antagonist at both β1,2‐ARs and α1‐ARs, has also been shown to reduce cancer risk and exhibit anti‐tumour activity in some epithelial tumours . Like propranolol, carvedilol may also increase the efficacy of chemotherapy in some drug‐resistant tumours .…”

Section: Inroductionmentioning

confidence: 99%

The adrenergic receptor antagonists propranolol and carvedilol decrease bone sarcoma cell viability and sustained carvedilol reduces clonogenic survival and increases radiosensitivity in canine osteosarcoma cells

Duckett

Phung

Linh-Trung

et al. 2019

Vet Comparative Oncology

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Adrenergic receptor (AR) expression has been demonstrated at several sites of primary and metastatic tumour growth and may influence proliferation, survival, metastasis and angiogenesis. AR antagonists like propranolol and carvedilol inhibit proliferation, induce apoptosis and synergize with chemotherapy agents in some cancers. Radiation resistance is mediated in many cells by upregulation of pro‐survival pathways, which may be influenced by ARs. Studies evaluating AR antagonists combined with radiation are limited. The purpose of this study was to determine the effect of propranolol and carvedilol on viability and radiosensitivity in sarcoma cell lines. The hypothesis was that propranolol and carvedilol would increase radiosensitivity in four primary bone sarcoma cell lines. Single agent propranolol or carvedilol inhibited cell viability in all cell lines in a concentration‐dependent manner. The mean inhibitory concentrations (IC50) for carvedilol were approximately 4‐fold lower than propranolol and may be clinically relevant in vivo. Immunoblot analysis confirmed AR expression in both human and canine sarcoma cell lines; however, there was no correlation between baseline AR protein expression and radiosensitivity. Short duration treatment with carvedilol and propranolol did not significantly affect clonogenic survival. Prolonged exposure to propranolol and carvedilol significantly decreased the surviving fraction of canine osteosarcoma cells after 3Gy radiation. Based on our results and possible in vivo activity in dogs, further studies investigating the effects of carvedilol on sarcoma are warranted.

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Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study

Cited by 56 publications

References 29 publications

Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

The adrenergic receptor antagonists propranolol and carvedilol decrease bone sarcoma cell viability and sustained carvedilol reduces clonogenic survival and increases radiosensitivity in canine osteosarcoma cells

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