ArticleMolecular oncology2015
Preclinical evaluation of bortezomib/dipyridamole novel combination as a potential therapeutic modality for hematologic malignancies.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Amelioration of gentamicin-induced acute kidney injury by trifluoperazine: in vivo mechanistic insights.Scientific reports · 2026Article
- Synergistic effects of HDAC inhibitor tucidinostat and ENT inhibitor dipyridamole in T-cell malignancies.Scientific reports · 2026Article
- Endoplasmic Reticulum Stress Contributed to Dipyridamole-Induced Impaired Autophagic Flux and Glioma Apoptosis.International journal of molecular sciences · 2022Article
- 3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia.Leukemia · 2022Article
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- HIF-1α and RKIP: a computational approach for pancreatic cancer therapy.Molecular and cellular biochemistry · 2020Article
- Enhanced anticancer activity of combined treatment of imatinib and dipyridamole in solid Ehrlich carcinoma-bearing mice.Naunyn-Schmiedeberg's archives of pharmacology · 2020Article
- 6,7-Dihydroxy-2-(4'-hydroxyphenyl)naphthalene induces HCT116 cell apoptosis through activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway.Drug design, development and therapy · 2019Article
- HIF-1α pathway: role, regulation and intervention for cancer therapy.Acta pharmaceutica Sinica. B · 2015Review
- Anticancer drugs for the modulation of endoplasmic reticulum stress and oxidative stress.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Review
- Rituximab and bortezomib (RB): a new effective regimen for refractory or relapsed indolent lymphomas.Medical oncology (Northwood, London, England) · 2015Article
- Preclinical evaluation of bortezomib/dipyridamole novel combination as a potential therapeutic modality for hematologic malignancies.Molecular oncology · 2015Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Novel combinations aiming at maximizing the efficacy of bortezomib are highly valued in the clinic. Therefore the current study investigated the outcomes of combining bortezomib with dipyridamole, a well-known antiplatelet. The co-treatment exerted a synergistic lethality in a panel of human leukemia/lymphoma cell lines of different origin. Mechanistically, dipyridamole did not modulate the proteasome inhibitory activity of bortezomib. However, dipyridamole triggered an endoplasmic reticulum (ER) stress, and co-treatment with bortezomib resulted in higher levels of ER stress than either monotherapies. Relieving ER stress with the protein translation inhibitor, cycloheximide suppressed cell death. Moreover, the enhanced ER stress by the co-treatment was associated with an aggravation of reactive oxygen species (ROS) generation and glutathione (GSH) depletion. Replenishing GSH pools significantly scavenged ROS and rescued the cells. Importantly, the cytotoxicity of the co-treatment was executed mainly via the mitochondrial apoptotic pathway with an efficient suppression of the key anti-apoptotic regulators, Mcl-1, Bcl-xl, Bcl-2 and XIAP, driving the independence of the co-treatment-induced apoptosis of a single apoptotic trigger. Furthermore, the intrinsic potential of bortezomib to inhibit important pro-survival pathways was enhanced by dipyridamole in a GSH/ROS-dependent manner. Interestingly, dipyridamole abrogated JAK2 phosphorylation indirectly and selectively in cancer cells, and the co-treatment-induced cytotoxicity was preserved in a model of stromal-mediated chemoresistance. In nude mice, the antitumor activity of the co-treatment surpassed that of bortezomib monotherapy despite that synergy was lacking. In summary, findings of the present study provided a preclinical rationale which warrants further clinical evaluation of bortezomib/dipyridamole novel combination in hematologic malignancies.
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