Dipyridamole impairs autophagic flux and exerts antiproliferative activity on prostate cancer cells

Thomé, Marcos Paulo Machado; Pereira, Luiza C.; Onzi, Giovana R.; Rohden, Francieli; Ilha, Mariana; Guma, Fátima Theresinha Costa Rodrigues; Wink, Márcia Rosângela; Lenz, Guido

doi:10.1016/j.yexcr.2019.06.001

Cited by 18 publications

(20 citation statements)

References 40 publications

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“…Furthermore, mitochondrial autophagy, a conserved self-digestion process, plays a key role in the maintenance of cell homeostasis, and dysregulation of autophagy often occurs during tumor development ( 5 ). Activation of autophagy not only helps cells to survive in stressful conditions ( 6 ), but can also induce cell death ( 7 ). Therefore, mitochondrial autophagy regulation has been a promising strategy for cancer treatment ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Xie

Zhang

et al. 2020

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) has a worldwide impact on human health, due to its high incidence and mortality. Therefore, identifying compounds to increase patients' survival rate is urgently needed. Mefloquine (MQ) is an FDA-approved anti-malarial drug, which has been reported to inhibit cellular proliferation in several cancers. However, the anti-tumor activities of the drug have not yet been completely defined. In this study, mass spectrometry was employed to profile proteome changes in ESCC cells after MQ treatment. Sub-cellular localization and gene ontology term enrichment analysis suggested that MQ treatment mainly affect mitochondria. The KEGG pathway enrichment map of down-regulated pathways and Venn diagram indicated that all of the top five down regulated signaling pathways contain four key mitochondrial proteins (succinate dehydrogenase complex subunit C (SDHC), succinate dehydrogenase complex subunit D, mitochondrially encoded cytochrome c oxidase III and NADH: ubiquinone oxidoreductase subunit V3). Meanwhile, mitochondrial autophagy was observed in MQ-treated KYSE150 cells. More importantly, patient-derived xenograft mouse models of ESCC with SDHC high expression were more sensitive to MQ treatment than low SDHC-expressing xenografts. Taken together, mefloquine inhibits ESCC tumor growth by inducing mitochondrial autophagy and SDHC plays a vital role in MQ-induced anti-tumor effect on ESCC.

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Section: Introductionmentioning

confidence: 99%

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Xie

Zhang

et al. 2020

Front. Oncol.

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“…A previous study also reported that dipyridamole alone or in combination with methotrexate failed to increase the cytotoxicity in leukemia cells (29). In fact, the small compound of dipyridamole not only inhibits PDE3 and PDE5, but also regulates multiple cell signaling pathways (2,7). Therefore, the anti-cancer effect of dipyridamole used alone or with doxorubicin may largely depend on the cell types and other conditions (30).…”

Section: Discussionmentioning

confidence: 99%

“…Cytotoxicity assay. Based on previous publications (2,7,8), we used 0, 10 and 20 µM dipyridamole in this study. For doxorubicin, we used the same dose of 0, 1.0 and 3.0 µM for HCT-8 cells as our previous study (19).…”

Section: Methodsmentioning

confidence: 99%

“…Dipyridamole, a traditional anti-platelet agent, is an inhibitor of phosphodiesterase enzyme 3 (PDE3) and PDE5, which results in the accumulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (1), consequently increasing protein kinase A (PKA) and PKG, respectively (2). Previous studies have reported that dipyridamole enhances the cytotoxicity of anti-tumor drugs, such as 5-flurouracil (3), cisplatin (4) and methotrexate (5,6), as well as preventing tumor progression (7) and decreasing the proliferative activity of cancer cells (2,8). Although dipyridamole has been reported to inhibit the re-uptake of adenosine and downregulate cyclin D1 and c-Myc levels (7), the precise role and the relevant mechanism of dipyridamole in regulating the proliferation of cancer cells is yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Dipyridamole induces the phosphorylation of CREB to promote cancer cell proliferation

et al. 2021

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Dipyridamole, a traditional anti-platelet drug, has been reported to inhibit the proliferation of cancer cells. The present study aimed to investigate the possibility of dipyridamole as an adjuvant of chemotherapy by enhancing the cytotoxicity of an anti-cancer drug. The cytotoxicity of colorectal cancer cells (HCT-8), CD133 + /CD44 + stem-like subpopulation of HCT-8 cells and lymphoma cells (U937) to dipyridamole and/or doxorubicin was evaluated using MTT proliferation and colony forming assays. The expression levels of phosphorylated cAMP-regulatory element-binding protein (pCREB) and poly(ADP-ribose) polymerase-1 (PARP-1) in cells were analyzed via western blotting and immunofluorescence. The present study reported controversial data regarding the anti-cancer effect of dipyridamole. Dipyridamole increased, rather than inhibited, the proliferation of HCT-8 and U937 cells in a dose-dependent manner. Furthermore, it was found that dipyridamole significantly increased the expression levels of pCREB and PARP-1. However, the combined usage of dipyridamole significantly enhanced the cytotoxicity of doxorubicin to HCT-8 cells at particular doses. Based on the current findings, dipyridamole likely induces the phosphorylation of CREB to promote the proliferation of cancer cells, but may enhance the cytotoxicity of anti-cancer drugs at particular doses.

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“…Compared to the several studies focused on the antioxidant (Ciacciarelli et al, 2015) and anticancer (Liu et al, 2014;Spano et al, 2013;Thomé et al, 2019) properties of DIP, its antiviral activity has been poorly explored. Of pharmacological importance is the fact that antiviral nucleoside analogs use different transporters to enter cells than those targeted by DIP that block nucleoside uptake (Pastor-Anglada et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Dipyridamole as a new drug to prevent Epstein-Barr virus reactivation

et al. 2019

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Epstein-Barr virus (EBV) is a widely distributed gamma-herpesvirus that has been associated with various cancers mainly from lymphocytic and epithelial origin. Although EBV-mediated oncogenesis has been associated with viral oncogenes expressed during latency, a growing set of evidence suggested that antiviral treatments directed against EBV lytic phase may contribute to prevent some forms of cancers, including EBV-positive Post-Transplant Lymphoproliferative Diseases. It is shown here that dipyridamole (DIP), a safe drug with favorable and broad pharmacological properties, inhibits EBV reactivation from B-cell lines. DIP repressed immediate early and early genes expression mostly through its ability to inhibit nucleoside uptake. Considering its wide clinical use, DIP repurposing could shortly be evaluated, alone or in combination with other antivirals, to treat EBVrelated diseases where lytic replication plays a deleterious role.

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Dipyridamole impairs autophagic flux and exerts antiproliferative activity on prostate cancer cells

Cited by 18 publications

References 40 publications

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Dipyridamole induces the phosphorylation of CREB to promote cancer cell proliferation

Dipyridamole as a new drug to prevent Epstein-Barr virus reactivation

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