Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma

Liu, Shi-He; Yu, Juehua; Creeden, Justin; Sutton, Jeffrey M.; Markowiak, Stephen; Sanchez, Robbi; Nemunaitis, John; Nestor-Kalinoski, Andrea L.; Zhang, Jianting; Damoiseaux, Robert; Erhardt, Paul; Brunicardi, F. Charles

doi:10.1016/j.canlet.2020.08.002

Cited by 12 publications

(7 citation statements)

References 56 publications

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“…Others were mainly about anti-tumor effect, such as inhibition of prostate cancer, colorectal cancer, hepatocellular carcinoma and endometrial cancer, etc [35][36][37][38][39][40][41][42]. In our study, we also found that combination of simvastatin and metformin had a wide range of anti-cancer effects in breast cancer, hepatocellular carcinoma, lung cancer and cervical cancer.…”

Section: Discussionsupporting

confidence: 60%

Effective Suppression of Hypoxia Induced Angiogenesis by Synergism of Simvastatin and Metformin via Inhibiting ET-1-ETBR-Hif1α Signaling Axis

Liu

Wang

Zhang

et al. 2021

Preprint

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Background: Hypoxic stress accelerates metabolic reprogramming to promote malignant progression, which contains huge and interesting drug targets for cancer therapy. According to recently reports and our previously researches, simvastatin (SVA) or metformin (MET), two metabolic relevant drugs, play an important role in inhibiting tumor growth, angiogenesis, improvement hypoxic microenvironment. However, the signal networks of hypoxia induced metabolic reprogramming is enormous and intricacy, blocking a signal target can’t play an effective role in antitumor, whether combination of SVA and MET could exert a more effective antitumor effect is not clear.Methods: The antitumor effect of synergism of SVA and MET were detected in mouse models, breast cancer patient-derived organoid (PDO) and multiple tumor cell lines compared with untreated, SVA or MET alone. Transcriptome sequencing were performed for exploring the possible mechanisms. Inhibition of endothelin 1 (ET-1) induced Hif1α by synergism of SVA and MET were contrasted with bosentan, an ETBR antagonist.Results: Our results show that synergism of SVA and MET can inhibit tumor cell proliferation and promote apoptosis, alleviate hypoxia, decrease angiogenesis and increase vessel normalization within tumor than use of SVA or MET alone. RNA-sequencing result implies that just synergism of SVA and MET can inhibit EDN1 expression, which encodes endothelin 1, an important regulator of angiogenesis and hypoxia-related pathway, but not in use of SVA or MET alone. More specifically, synergism of SVA and MET suppresses the ET-1 induced Hif1α expression by inhibiting ET-1-ETBR signaling pathway and increasing PHD2 expression. In addition, the antitumor effect of synergism of SVA and MET is more efficient than bosentan in tumor cells and breast cancer PDO by inhibiting ET-1-ETBR-Hif1α signaling axis.Conclusions: Thus, our data show that synergism of SVA and MET can be a viable therapy for antitumor.

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Section: Discussionsupporting

confidence: 60%

Effective Suppression of Hypoxia Induced Angiogenesis by Synergism of Simvastatin and Metformin via Inhibiting ET-1-ETBR-Hif1α Signaling Axis

Liu

Wang

Zhang

et al. 2021

Preprint

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“…A previous study examined the combination treatment of MET and SVA in polycystic ovary syndrome 43 . Other studies explored the combination treatment and the related cancer inhibitory activity in prostate cancer, colorectal cancer, hepatocellular carcinoma, and endometrial cancer 44–51 . Our results demonstrated that the MET and SVA combination treatment showed a wide range of anticancer effects in breast cancer, hepatocellular carcinoma, lung cancer, and cervical cancer.…”

Section: Discussionmentioning

confidence: 58%

“… 43 Other studies explored the combination treatment and the related cancer inhibitory activity in prostate cancer, colorectal cancer, hepatocellular carcinoma, and endometrial cancer. 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 Our results demonstrated that the MET and SVA combination treatment showed a wide range of anticancer effects in breast cancer, hepatocellular carcinoma, lung cancer, and cervical cancer. In addition, we confirmed that SVA combined with MET resulted in synergistic antitumor effects compared with the use of SVA or MET alone.…”

Section: Discussionmentioning

confidence: 62%

Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types

et al. 2022

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Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti‐angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic‐related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient‐derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET‐1), an important regulator of angiogenesis and the hypoxia‐related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET‐1‐induced hypoxia‐inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.

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“…Consequently, cells with high OXPHOS dependency were susceptible to treatment with OXPHOS inhibitors metformin or oligomycin [34,35]. In line with this, various in vitro as well as in vivo studies suggested an anti-tumoral effect of metformin [36][37][38][39][40] (Table 1). However, addition of metformin to standard systemic therapy proved to be disappointing in advanced-stage pancreatic cancer [41,42].…”

Section: Metabolic Subtypesmentioning

confidence: 87%

Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

Dujardin

Baginska

Urban

et al. 2021

Cancers

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Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.

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Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma

Cited by 12 publications

References 56 publications

Effective Suppression of Hypoxia Induced Angiogenesis by Synergism of Simvastatin and Metformin via Inhibiting ET-1-ETBR-Hif1α Signaling Axis

Effective Suppression of Hypoxia Induced Angiogenesis by Synergism of Simvastatin and Metformin via Inhibiting ET-1-ETBR-Hif1α Signaling Axis

Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types

Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

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