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Effects and Mechanisms of the Combination of Suberoylanilide Hydroxamic Acid and Bortezomib on the Anticancer Property of Gemcitabine in Pancreatic Cancer

Lee, Jun Kyu MD, PhD*; Ryu, Ji Kon MD, PhD; Yang, Ki Young MD; Woo, Sang Myung MD; Park, Joo Kyung MD; Yoon, Won Jae MD; Lee, Sang Hyub MD, PhD; Jeong, Kyoung-Sin; Kim, Yong-Tae MD, PhD; Yoon, Yong Bum MD, PhD

doi: 10.1097/MPA.0b013e3182156d5a
Original Articles
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Objectives: Earlier studies that dealt with the combination therapy of gemcitabine and histone deacetylation inhibitors for pancreatic cancer revealed unsatisfactory results. The activation of nuclear factor κB (NF-κB) was referred as one of the attributable causes, and we attempted to overcome this resistance by the addition of a proteasome inhibitor.

Methods: The influences of suberoylanilide hydroxamic acid (vorinostat, SAHA), a histone deacetylase inhibitor, and bortezomib, a novel selective antagonist of 26S proteasome, with or without gemcitabine on cell growth and apoptosis and the expressions of related proteins were observed in pancreatic cancer cell lines (MiaPaCa-2 and ASPC-1). The xenograft model of pancreatic cancer was used to notice effects in vivo.

Results: Vorinostat and bortezomib had independent inhibitory effects and potentiated the antitumor property of gemcitabine in vitro. In the xenograft model, more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone. The down-regulation of pAkt and suppression of NF-κB activity was induced by the triple combination.

Conclusions: The triple combination of vorinostat, bortezomib, and gemcitabine resulted in the strongest antitumor effects both in vitro and in vivo and pAkt and NF-κB seems to be involved in this process.

From the *Department of Internal Medicine, Dongguk University Ilsan Hospital, Graduate School of Medicine, Dongguk University, Seoul; †Department of Internal Medicine, Seoul National University Hospital, Liver Research Institute, College of Medicine, Seoul National University, Seoul; and ‡Department of Internal Medicine, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea.

Received for publication August 2, 2010; accepted February 11, 2011.

Reprints: Ji Kon Ryu, MD, PhD, Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, 110-744, Seoul, Republic of Korea (e-mail: jkryu@snu.ac.kr).

This study was supported in part by the Seoul National University College of Medicine Research Fund (800-2008-0572).

All the experimental works presented in this article were carried out at the Liver Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea.

© 2011 Lippincott Williams & Wilkins, Inc.