title: Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer.
abstract: Intravesical instillation of chemotherapeutic agents is a well-established treatment strategy to decrease recurrence following transurethral resection in non-muscle invasive bladder cancer. Gemcitabine is a recently developed treatment option. However, the curative effects of gemcitabine are far from satisfactory due to de novo or acquired drug resistance. In a previous study, we reported that intravesical administration of the c-Myc inhibitor KSI-3716 suppresses tumor growth in an orthotopic bladder cancer model. Here, we explored whether KSI-3716 inhibits gemcitabine-resistant bladder cancer cell proliferation. As expected from the in vitro cytotoxicity of gemcitabine in several bladder cancer cell lines, gemcitabine effectively suppressed the growth of KU19-19 xenografts in nude mice, although all mice relapsed later. Long-term in vitro exposure to gemcitabine induced gemcitabine-specific resistance. Gemcitabine-resistant cells, termed KU19-19/GEM, formed xenograft tumors even in the presence of 2 mg/kg gemcitabine. Interestingly, KU19-19/GEM cells up-regulated c-Myc expression in the presence of the gemcitabine and resisted to the gemcitabine, however was suppressed by the KSI-3716. The sequential addition of gemcitabine and KSI-3716 inhibited gemcitabine-resistant cell proliferation to a great extent than each drug alone. These results suggest that sequential treatment with gemcitabine and KSI-3716 may be beneficial to bladder cancer patients.
authors: Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea.
authors: Ho Kyung
authors: HK
authors: Seo
authors: Kyung-Ohk
authors: KO
authors: Ahn
authors: Nae-Rae
authors: NR
authors: Jung
authors: Ji-Sun
authors: JS
authors: Shin
authors: Weon Seo
authors: WS
authors: Park
authors: Kang Hyun
authors: KH
authors: Lee
authors: Sang-Jin
authors: SJ
authors: Lee
authors: Kyung-Chae
authors: KC
authors: Jeong
mesh_terms: D042462:4-Quinolones / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D042462:4-Quinolones; D000814:Aniline Compounds; D000964:Antimetabolites, Antineoplastic; C587717:KSI-3716; D003841:Deoxycytidine; D000093542:Gemcitabine