Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer
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Ho Kyung Seo1, Kyung-Ohk Ahn2, Nae-Rae Jung3, Ji-Sun Shin3, Weon Seo Park1, Kang Hyun Lee1, Sang-Jin Lee3, and Kyung-Chae Jeong2
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
Kyung-Chae Jeong, e-mail: [email protected]
Sang-Jin Lee, e-mail: [email protected]
Key words: Bladder cancer, c-Myc, inhibitor, gemcitabine, gemcitabine resistance
Received: October 28, 2013 Accepted: December 12, 2013 Published: January 16, 2014
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.
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