title: Targeting phosphodiesterase 3B enhances cisplatin sensitivity in human cancer cells.
abstract: We previously reported that human squamous cell carcinoma (SCC) cell lines refractory to cis-diaminedichloro-platinum II (cisplatin [CDDP]) had significant upregulation of the phosphodiesterase 3B gene (PDE3B), suggesting that inhibiting PDE3B suppresses CDDP resistance. shRNA-mediated PDE3B depletion in CDDP-resistant cells derived from SCC cells and Hela cells and induced CDDP sensitivity and inhibited tumor growth with elevated cyclic GMP induction resulting in upregulation of the multidrug-resistant molecule, but this did not occur in the 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Furthermore, the antitumor growth effect of the combination of a PDE3B inhibitor (cilostazol) and CDDP in vivo was also greater than with either cilostazol or CDDP alone, with a significant increase in the number of apoptotic and cell growth-suppressive cancer cells in CDDP-resistance cell lines. Our results provided novel information on which to base further mechanistic studies of CDDP sensitization by inhibiting PDE3B in human cancer cells and for developing strategies to improve outcomes with concurrent chemotherapy.
authors.affiliation: Department of Clinical Molecular Biology, Graduate School of Medicine, Chiba University Chiba, 260-8670, Japan ; Department of Dentistry-Oral and Maxillofacial Surgery, Chiba University Hospital Chiba, 260-8677, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.forename: Takao
authors.initials: T
authors.lastname: Baba
authors.forename: Katsuya
authors.initials: K
authors.lastname: Usukura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sakuma
authors.forename: Manabu
authors.initials: M
authors.lastname: Iyoda
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ogawara
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077407:Cilostazol; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D012333:RNA, Messenger; D013777:Tetrazoles; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517291:PDE3B protein, human; D006152:Cyclic GMP; D000077407:Cilostazol; D002945:Cisplatin
keywords: Apoptosis; cisplatin sensitivity; multidrug resistance; phosphodiesterase 3B gene