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Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer

2014; Impact Journals LLC; Volume: 5; Issue: 2 Linguagem: Inglês

10.18632/oncotarget.1545

1949-2553

Ho Kyung Seo, Kyung-Ohk Ahn, Nae-Rae Jung, Ji‐Sun Shin, Weon Seo Park, Kang Hyun Lee, Sang-Jin Lee, Kyung‐Chae Jeong,

Cancer Mechanisms and Therapy

$('.header-date').hide();$('#titleAuthors').hide(); $('#abstractHeader').hide(); Ho Kyung Seo 1 , Kyung-Ohk Ahn 2 , Nae-Rae Jung 3 , Ji-Sun Shin 3 , Weon Seo Park 1 , Kang Hyun Lee 1 , Sang-Jin Lee 3 , and Kyung-Chae Jeong 2 1 Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Biomolecular Function Research Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 3 Genitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea Correspondence: Kyung-Chae Jeong, e-mail: jeongkc@ncc.re.kr Sang-Jin Lee, e-mail: leesj@ncc.re.kr Key words: Bladder cancer, c-Myc, inhibitor, gemcitabine, gemcitabine resistance Received : October 28, 2013 Accepted : December 12, 2013 Published : January 16, 2014 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.