RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase

Lee, Kyung-Hun; Hur, Hyung-Seok; Im, Seock-Ah; Lee, Juhee; Kim, Hwang-Phill; Yoon, Young-Kwang; Han, Sae-Won; Song, Sang-Hyun; Oh, Do-Youn; Kim, Tae-You; Bang, Yung-Jue

doi:10.1016/j.canlet.2010.07.020

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Volume 299, Issue 1 , Pages 22-28, 18 December 2010

RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase

Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- These authors equally contributed to this work as first authors.
Hyung-Seok Hur
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- These authors equally contributed to this work as first authors.
Seock-Ah Im
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Corresponding author at: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, Republic of Korea. Tel.: +82 2 2072 0850; fax: +82 2 762 9662.
Juhee Lee
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Hwang-Phill Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Young-Kwang Yoon
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Sae-Won Han
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Sang-Hyun Song
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Do-Youn Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Tae-You Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Republic of Korea
Yung-Jue Bang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Corresponding author at: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, Republic of Korea. Tel.: +82 2 2072 2390; fax: +82 2 762 9662.

Received 19 February 2010; received in revised form 22 June 2010; accepted 22 July 2010. published online 20 August 2010.

Abstract

We evaluated RAD001, an inhibitor of the mammalian target of rapamycin (mTOR) in human gastric cancer cell lines and determined the molecular mechanisms. RAD001 has marked growth inhibitory activity against the SNU-1 and SNU-216 cells. It inhibited phosphorylation of mTOR and S6K, and induced G1 cell cycle arrest. Synergistic growth-inhibitory effects in combination with 5-fluorouracil (5-FU) was identified. Furthermore, RAD001 conferred sensitivity to 5-FU-resistant cell lines by downregulating thymidylate synthase (TS). In conclusion, RAD001 showed growth inhibitory activity against gastric cancer cells and acted synergistically with cytotoxic agents such as 5-FU by downregulating TS.