Inhibition of Pancreatic Cancer Cell Proliferation by Propranolol Occurs Through Apoptosis Induction

Dong, Zehua; Ma, Qingyong; Shen, Si-Lian; Hu, Hengtong

doi:10.1097/mpa.0b013e318184f50c

Cited by 99 publications

(52 citation statements)

References 21 publications

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“…Zhang et al also reported that PRO was able to induce apoptosis in the PC-2 human pancreatic cancer cell line at concentrations of 100 μM [51], and reduce invasiveness in MIA PaCa-2 and BxPC-3 cell lines at the same concentration [52]. …”

Section: Pre-clinical Evidence In Cancer - In Vitro and In Vivomentioning

confidence: 99%

“…Zhang et al showed that PRO limited the expansion of the PC-2 pancreatic cancer cell line and that this was due to an increased rate of apoptosis [51]. The pro-apoptotic action of PRO was found to be via blockade of the beta2-adrenergic receptor rather than beta1, as shown by the increased level of apoptosis induced by the selective beta2 antagonist butaxamine and the reduced level due to the beta1 blocker metoprolol.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

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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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Section: Pre-clinical Evidence In Cancer - In Vitro and In Vivomentioning

confidence: 99%

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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“…A number of in vitro studies have demonstrated the anti-proliferative, anti-migratory and cytotoxic properties of propranolol, particularly against lung adenocarcinoma [7, 8], colon carcinoma [9], breast carcinoma [10], nasopharyngeal carcinoma [11], ovarian cancer [12], pancreatic cancer [13-15] and gastric cancer cells [16]. Propranolol was also found to exert potent anti-angiogenic effects in vitro through direct mechanisms on vascular endothelial cells [17, 18] and by decreasing pro-angiogenic signaling in both stromal [19] and cancer cells [11, 20-23].…”

Section: Introductionmentioning

confidence: 99%

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment

et al. 2011

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Recent clinical evidence revealed that the use of beta-blockers such as propranolol, prior to diagnosis or concurrently with chemotherapy, could increase relapse-free and overall survival in breast cancer patients. We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms. In vitro proliferation assay showed that propranolol (from 50-100 μM) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and “normal” cell lines. Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations (<50 μM) but exert no vascular-disrupting activity. Combining chemotherapeutic drugs, such as 5-fluorouracil (5-FU) or paclitaxel, with propranolol at the lowest effective concentration resulted in synergistic, additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of chemotherapy used. Interestingly, breast cancer and vascular endothelial cells were among the most responsive to these combinations. Furthermore, Matrigel assays indicated that low concentrations of propranolol (10 – 50 μM) potentiated the anti-angiogenic effects of 5-FU and paclitaxel. Using an orthotopic xenograft model of triple-negative breast cancer, based on injection of luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice, we showed that propranolol, when used alone, induced only transient anti-tumor effects, if at all, and did not increase median survival. However, the combination of propranolol with chemotherapy resulted in more profound and sustained anti-tumor effects and significantly increased the survival benefits induced by chemotherapy alone (+19% and +79% in median survival for the combination as compared with 5-FU alone and paclitaxel alone, respectively; p<0.05). Collectively our results show that propranolol can potentiate the anti-angiogenic effects and anti-tumor efficacy of chemotherapy. The current study, together with retrospective clinical data, strongly suggests that the use of propranolol concurrently with chemotherapy may improve the outcome of breast cancer patients, thus providing a strong rationale for the evaluation of this drug combination in prospective clinical studies.

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“…Previous studies suggested that β-adrenergic antagonists may suppress cell proliferation and invasion and induce apoptosis in PanCa [14,22], and also β 2 -adrenergic agonist can stimulate the production of cAMP and activation of G-protein effectors Gs [23]. However, the mechanism of PanCa cell death induced by β 2 -adrenergic antagonist is not clear.…”

Section: Introductionmentioning

confidence: 99%

β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

Zhang

Wang

et al. 2011

Mol Cancer

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BackgroundSmoking and stress, pancreatic cancer (PanCa) risk factors, stimulate nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β2-adrenergic antagonist, we hypothesize that blockage of the β2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells.ResultsThe β1 and β2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the β1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells.ConclusionsThe blockage of β2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.

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Inhibition of Pancreatic Cancer Cell Proliferation by Propranolol Occurs Through Apoptosis Induction

Cited by 99 publications

References 21 publications

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

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

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment

β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

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