title: RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3.
abstract: Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second highest cause of cancer-related mortality. We identified an RNA helicase gene, DDX3 (DDX3X), which is overexpressed in prostate cancers, and whose expression is directly correlated with high Gleason scores. Knockdown of DDX3 in the aggressive prostate cancer cell lines DU145 and 22Rv1 resulted in significantly reduced clonogenicity. To target DDX3, we rationally designed a small molecule, RK-33, which docks into the ATP-binding domain of DDX3. Functional studies indicated that RK-33 preferentially bound to DDX3 and perturbed its activity. RK-33 treatment of prostate cancer cell lines DU145, 22Rv1, and LNCaP (which have high DDX3 levels) decreased proliferation and induced a G1phase cell-cycle arrest. Conversely, the low DDX3-expressing cell line, PC3, exhibited few changes following RK-33 treatment. Importantly, combination studies using RK-33 and radiation exhibited synergistic effects both in vitro and in a xenograft model of prostate cancer demonstrating the role of RK-33 as a radiosensitizer. Taken together, these results indicate that blocking DDX3 by RK-33 in combination with radiation treatment is a viable option for treating locally advanced prostate cancer. Cancer Res; 76(21); 6340-50. ©2016 AACR.
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Farhad
authors.initials: F
authors.lastname: Vesuna
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Saritha
authors.initials: S
authors.lastname: Tantravedi
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Guus M
authors.initials: GM
authors.lastname: Bol
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marise R
authors.initials: MR
authors.lastname: Heerma van Voss
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Katriana
authors.initials: K
authors.lastname: Nugent
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Reem
authors.initials: R
authors.lastname: Malek
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland. vraman2@jhmi.edu.|Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D004249:DNA Damage; D006657:Histones / Q000032:analysis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: C000603512:3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one; D001381:Azepines; C468783:H2AX protein, human; D006657:Histones; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases