title: Preclinical evaluation of bortezomib/dipyridamole novel combination as a potential therapeutic modality for hematologic malignancies.
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.
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 685-2 Ochang, Cheongwon 363-883, Republic of Korea; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address: AHMEDELSAYEDGODA@pharm.tanta.edu.eg.
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Goda
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 685-2 Ochang, Cheongwon 363-883, Republic of Korea; Department of Molecular and Cellular Biology, Harvard University, Cambridge, USA.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Erikson
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Republic of Korea.
authors.forename: Jong-Seog
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 685-2 Ochang, Cheongwon 363-883, Republic of Korea. Electronic address: bykim@kribb.re.kr.
authors.forename: Bo-Yeon
authors.initials: BY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D004176:Dipyridamole; D000069286:Bortezomib
keywords: Bortezomib; Dipyridamole; ER stress; GSH/ROS; Hematologic malignancies; JAK2; Pro-survival pathways