title: A novel small molecule hybrid of vorinostat and DACA displays anticancer activity against human hormone-refractory metastatic prostate cancer through dual inhibition of histone deacetylase and topoisomerase I.
abstract: Vorinostat, which is an extensively studied inhibitor against histone deacetylase (HDAC), shows limited clinical activity to solid tumors. WJ35435, a new hybrid of vorinostat and DACA (a topoisomerase inhibitor) potently inhibited HDAC activity (in particular HDAC1 and HDAC6) in kinase assay and cell-based examination. The anti-HDAC effect was confirmed by the induction of histone H3 acetylation and phosphorylation, α-tubulin acetylation and γ-H2AX formation. WJ35435 showed better potency than vorinostat and DACA against PC-3 and DU-145, two human hormone-refractory metastatic prostate cancer (HRMPC) cell lines, but not benign prostate cells. WJ35435 at differential concentrations induced G1- or G2-phase arrest of the cell cycle in HRMPCs but not in benign prostate cells. WJ35435 induced the formation of topoisomerase I-DNA cleavable complexes but not type-IIα or -IIβ. Topoisomerase activity assay confirmed the selective inhibition of topoisomerase I. WJ35435 induced profound DNA damage using comet tailing assay. WJ35435 was less effective than camptothecin and etoposide in inducing the phosphorylation and activation of Chk1, Chk2 and RPA32 which were crucial coordinators in DNA repair pathway, indicating a low DNA repair activity to WJ35435 action. Furthermore, WJ35435 showed an in vivo antitumor activity. A synergistic apoptosis (combination index=0.55) was obtained in combination between WJ35435 and MG-132 (a proteasome inhibitor). In summary, WJ35435 is a dual-targeted anticancer hybrid induces anti-HDAC and anti-topoisomerase I activities that cause DNA damage associated with a low DNA repair capability, and induce cell cycle arrest at G1- and G2-phase. Ultimately, WJ35435 inhibits cell proliferation and induces apoptosis of HRMPCs.
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Yu
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.affiliation: Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Chao
authors.affiliation: Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Liu
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan.
authors.forename: Jui-Ling
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei, Taiwan.
authors.forename: Tsia-Kun
authors.initials: TK
authors.lastname: Li
authors.affiliation: Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: wjhuang@tmu.edu.tw.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan. Electronic address: jhguh@ntu.edu.tw.
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000166:Acridines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D059004:Topoisomerase I Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D059005:Topoisomerase II Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000591651:N-hydroxy-6-(4-carbamoylacridinyl)hexanamide; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000077337:Vorinostat; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: DACA; DNA damage; DNA repair; Hybrid; Vorinostat