Journal of Veterinary Clinics (한국임상수의학회지)

The Korean Society of Veterinary Clinics (한국임상수의학회)
권호 표지

Antagonic Effects of Dexamethasone on FK506-induced Antitumor Effects in Hep3B Cells

간암세포주(Hep3B cell)에서 FK506의 항암효과에 대한 dexamethasone의 길항효과

  • Park, Hye-Min (College of Veterinary Medicine, Chonbuk National University) ;
  • Lee, Sei-Jin (Korea Basic Science Institute Jeonju Center) ;
  • Kim, Sun-Young (College of Veterinary Medicine, Chonbuk National University) ;
  • Go, Hyeon-Kyu (College of Veterinary Medicine, Chonbuk National University) ;
  • Jeon, Seol-Hee (College of Veterinary Medicine, Chonbuk National University) ;
  • Kim, Shang-Jin (Korean Zoonoses Research Institute, Chonbuk National University) ;
  • Kang, Hyung-Sub (Korean Zoonoses Research Institute, Chonbuk National University) ;
  • Kim, Jin-Shang (Korean Zoonoses Research Institute, Chonbuk National University)
  • 박혜민 (전북대학교 수의과대학) ;
  • 이세진 (한국기초과학지원연구원전주센터) ;
  • 김선영 (전북대학교 수의과대학) ;
  • 고현규 (전북대학교 수의과대학) ;
  • 전설희 (전북대학교 수의과대학) ;
  • 김상진 (전북대학교 인수공통전염병연구소) ;
  • 강형섭 (전북대학교 인수공통전염병연구소) ;
  • 김진상 (전북대학교 인수공통전염병연구소)
  • Accepted : 2011.12.22
  • Published : 2011.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

FK506 is a widespread immunosuppressive drug after liver transplantion in patients with advanced-stage hepatocellular carcinoma. Dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. Our aim was to investigate antitumor effects of FK506 in Hep3B cells, one of differentiated human hepatocellular carcinoma cell lines and inhibitory effects of dexamethsone on FK506- induced antitumor effects. Cell injury was evaluated by biochemical assays as cell viability, lactate dehydrogenase (LDH) and reactive oxygen species (ROS) in Hep3B cells. Intracellular calcium concentration ([$Ca^{2+}$]i) and the level of activation of the c-Jun-N-terminal kinase (JNK) and the Bax protein in cultured Hep3B cells was measured. Exposure of 0.1 ${\mu}M$ FK506 to Hep3B cells led to cell death accompanied by a decrease in cell viability and an increase in LDH, ROS and [$Ca^{2+}$]i. FK506 induced an increase in activity of Bax and JNK protein but inhibited the activity of Bcl-2 protein. Treatment of dexamethsone, per se, had no effects on cell viability, LDH and ROS. However, co-treatment of FK506 and dexamethasone diminished the FK506-induced LDH release, ROS generation and JNK activation. These results demonstrate that FK506 has antitumor effect in Hep3B cells but the combination of FK506 and dexamethasone antagonizes the FK506-induced antitumor effects.

FK506은 말기 간암환자의 간이식 후 널리 사용되는 면역억제제이다. Dexamethasone은 세포독성 암 치료에서 오심 방지, 정상세포의 보호와 기타 이유 등의로 빈번하게 병용처치된다. 본 연구의 목적은 간암세포주(Hep3B)에서 FK506의 항암효과와 FK506에 의한 항암효과에 대한 dexamethasone의 억제효과를 알아보기 위함이다. 세포의 손상은 세포 생존성 평가와 LDH 및 세포내 ROS 양의 측정으로 평가 하였다. 세포내 칼슘 농도([$Ca^{2+}$]i)와 JNK, Bax 단백질의 발현 정도도 평가하였다. FK506의 처치는 Hep3B의 세포사를 유도하였으며 세포생존성의 감소와 LDH, ROS 및 [$Ca^{2+}$]i 를 증가시켰다. FK506은 Bax와 JNK 의 활성을 증가시켰으며 Bcl-2의 활성을 억제하였다. Dexamethasone 처치 그 자체는 세포생존성, LDH와 ROS에 영향을 주지 않았다. 그러나 dexamethasone과 FK506의 병용처치는 FK506에 의한 LDH 방출, ROS 생성 및 JNK의 활성을 감소시켰다. 이 결과는 간암세포주에서 FK506은 항암효과를 가지지만 dexamethasone의 병용처치는 FK506에 의한 항암효과를 길항한다.

Keywords

References

  1. Buttke TM, Sandstrom PM. Oxidative stress as a mediator of apoptosis. Immunol Today 1994; 15: 7-10. https://doi.org/10.1016/0167-5699(94)90018-3
  2. Chen ZS, Zeng FJ, Ming CS, Lin ZB, Zhang WJ, Wei L, Zhu XH, Jiang JP, Chen ZK. The survival and value of liver transplantation for liver carcinoma: a single-center experience. Transplant Proc 2004; 36: 2284-2286. https://doi.org/10.1016/j.transproceed.2004.08.047
  3. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004; 116: 205-219. https://doi.org/10.1016/S0092-8674(04)00046-7
  4. Grabarevic Z, Coric M, Seiwerth S, Dzaja P, Artukovic B, Kurilj AG, Beck A, Hohsteter M, Sostari -Zuckermann IC, Brcic L, Hrstic I. Comparative analysis of hepatocellular carcinoma in men and dogs. Coll Antropol 2009; 33:811-814.
  5. Li D, Ueta E, Kimura T, Yamamoto T, Osaki T. Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination. Cancer Sci 2004; 95: 644-650. https://doi.org/10.1111/j.1349-7006.2004.tb03323.x
  6. Lipton SA, Nicotera P. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium 1998; 23: 165-171. https://doi.org/10.1016/S0143-4160(98)90115-4
  7. Lu YS, Lien HC, Yeh PY, Yeh KH, Kuo ML, Kuo SH, Cheng AL. Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors. World J Gastroenterol 2005; 11: 6373-6380. https://doi.org/10.3748/wjg.v11.i40.6373
  8. Mazzaferro V, Rondinara GF, Rossi G, Regalia E, De Carlis L, Caccamo L, Doci R, Sansalone CV, Belli LS, Armiraglio E. Milan multicenter experience in liver transplantation for hepatocellular carcinoma. Transplant Proc 1994; 26: 3557-3560.
  9. Neuhaus P, Klupp J, Langrehr JM. mTOR inhibitors: An overview. Liver Transpl 2001; 7: 473-484. https://doi.org/10.1053/jlts.2001.24645
  10. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden. Int J Cancer 2001; 94: 153-156. https://doi.org/10.1002/ijc.1440
  11. Petrella A, Ercolino SF, Festa M, Gentilella A, Tosco A, Conzen SD, Parente L: Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction. Eur J Cancer 2006; 42: 3287-3293. https://doi.org/10.1016/j.ejca.2006.07.018
  12. Rutz HP. Effects of corticosteroid use on treatment of solid tumours. Lancet 2002; 360: 1969-1970. https://doi.org/10.1016/S0140-6736(02)11922-2
  13. Rutz HP, Herr I. Interference of glucocorticoids with apoptosis signaling and host-tumor interactions. Cancer Biol Ther 2004; 3: 715-718. https://doi.org/10.4161/cbt.3.8.966
  14. Sakai M, Miyake H, Tashiro S, Okumura Y, Kido H. Inhibitory effect of FK506 and cyclosporine A on the growth and invasion of human liver cancer cells. Med Invest 2003; 51: 63-69.
  15. Yazawa H, Kato T, Nakada T, Sendo F. Glucocorticoid hormone suppression of human neutrophil-mediated tumor cell. cytostasis. Int J Cancer 1999; 81: 74-80. https://doi.org/10.1002/(SICI)1097-0215(19990331)81:1<74::AID-IJC14>3.0.CO;2-S
  16. Yokoyama I, Carr B, Saitsu H, Iwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 1991; 68: 2095-2100. https://doi.org/10.1002/1097-0142(19911115)68:10<2095::AID-CNCR2820681002>3.0.CO;2-Y
  17. Zhang C, Kolb A, Mattern J, Gassler N, Wenger T, Herzer K, Debatin KM, Bu hler M, Friess H, Rittgen W, Edler L, Herr I. Dexamethasone desensitizes hepatocellular and colorectal tumours toward cytotoxic therapy. Cancer Letters 2006; 242: 104-111. https://doi.org/10.1016/j.canlet.2005.10.037