DOI QR코드

DOI QR Code

In vitro Anti-proliferative Characteristics of Flavonoids and Diazepam on MDA-MB-231 Breast Cancer Cells

Flavonoid류와 diazepam의 시험관 내 MDA-MB-231 유방암세포 증식 억제 효과

  • Kim, Ji-Kwan (Department of Pharmacology, School of Medicine, Kyungpook National University) ;
  • Lee, Maan-Gee (Department of Pharmacology and 1Nuclear Medicine, School of Medicine, Kyungpook National University) ;
  • Lee, Jae-Tae (Department of Nuclear Medicine, School of Medicine, Kyungpook National University) ;
  • Ha, Jeoung-Hee (Department of Pharmacology, School of Medicine, Kyungpook National University)
  • 김지관 (경북대학교 의학전문대학원 약리학교실) ;
  • 이만기 (경북대학교 의학전문대학원 약리학교실) ;
  • 이재태 (경북대학교 의학전문대학원 핵의학교실) ;
  • 하정희 (경북대학교 의학전문대학원 약리학교실)
  • Published : 2009.08.30

Abstract

The beneficial use of sedatives is often required for medically ill patients. This study examined the effect of plant flavonoids and diazepam peripheral-type benzodiazepine receptor (PBR) activation and glucose utilization in breast cancer cells, along with their interactions. In estrogen receptor negative MDA-MB-231 cells, the anti-proliferative activity of fisetin (3,7,3',4'-tetrahydroxyflavone) and diazepam was more prominent than in estrogen receptor positive MCF-7 cells. Unlike PBR ligands, treatment with $10^{-6}$ M concentration of diazepam for 3 days exhibited anti-proliferative effects, while similar to apigenin (4',5,7-Trihydroxyflavone) and fisetin, diazepam hardly affected the PBR mRNA expression by MDA-MB-231 cells. Treatment with $10^{-6}$ M concentration of flavonoids and diazepam for 3 days inhibited the glucose utilization of MDA-MB-231 cells. Treatment with $10^{-6}$ M concentration of flavonoids and diazepam for 6 days showed increased cytotoxicity and reduced the PBR mRNA expression of the MDA-MB-231 cells. Apigenin enhanced diazepam-induced anti-proliferative effects on the MDA-MB-231 cells as well. All together, this study showed the in vitro anti-proliferative activity of flavonoids and diazepam on MDA-MB-231 breast cancer cells, plus additive enhancements. In conclusion, this study provides experimental basis for advanced trials in the future.

Flavonoid류와 진정제의 시험관 내 암세포증식억제효과를 관찰하기 위하여, 암세포의 말초형 benzodiazepine 수용체(이하 PBR로 약함) 활성도와 포도당 활용도에 대한 효과를 유방암 세포를 대상으로 검색하였다. 동시에 이미 항암활성이 잘 알려진 flavonoid류와의 상호작용도 관찰하였다. Fisetin (3,7,3',4'-tetrahydroxyflavone)과 diazepam의 암세포 증식 억제 효과는 악성도가 높은 MDA-MB-231 유방암 세포에서 MCF-7 유방암세포보다 저명하게 관찰되었다. MDA-MB-231 유방암세포에서, Apigenin (4',5,7-Trihydroxyflavone)과 fisetin 같은 flavonoid류처럼, $10^{-6}$ M 농도의 dazepam을 3일간 처치하였을 때 암세포 증식 억제효과를 나타내었으며, 이는 PBR 배위자들의 암세포 증식 증진효과와는 차이를 나타낸 것이다. Flavonoid 류처럼, MDA-MB-231 유방암세포에서, $10^{-6}$ M dazepam의 3일간 처치는 암세포의 PBR mRNA 발현에 큰 영향을 미치지 않았다. $10^{-6}$ M diazepam의 6 일간 처치는 암세포의 증식억제 효과가 증가되어 나타났으며, 암세포의 PBR mRNA 발현도 억제되었다. MDA-MB-231 유방암 세포에서, apigenin, fisetin과 diazepam은 포도당 유용도를 억제하였으며, 인슐린에 의한 포도당 유용도 증강효과도 억압하였다. Apigenin은 diazepam의 암세포 증식 억제 효과를 부가적으로 증강시켰다. 요약하면, 본 연구결과는 flavonoid류와 진정제의 시험관내 암세포 증식 억제효과와 부가적인 상호작용을 보여주고 있다. 결론적으로, 본 연구는 향후 좀더 진척된 시험을 위한 실험적인 기반 정보이다.

Keywords

References

  1. Binder, C., L. Binder, D. Marx, A. Schauer, and W. Hiddemann. 1997. Deregulated simultaneous expression of multiple glucose transporter isoforms in malignant cells and tissues. Anticancer Res. 17, 4299-4304
  2. Block, K. I., C. Gyllenhaal, and M. N. Mead. 2004. Safety and efficacy of herbal sedatives in cancer care. Integr. Cancer Ther. 32, 128-148 https://doi.org/10.1177/1534735404265003
  3. Boitano, A., J. A. Ellman, G. D. Glick, and A. W. Jr. Opipari. 2003. The proapoptotic benzodiazepine Bz-423 affects the growth and survival of malignant B cells. Cancer Res. 63, 6870-6876
  4. Brusselmans, K., R. Vrolik, G. Verhoeven, and J. V. Swinnen. 2005. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J. Biol. Chem. 280, 5636-5645 https://doi.org/10.1074/jbc.M408177200
  5. Cardenas, M., M. Marder, V. C. Blank, and L. P. Roguin. 2006. Antitumor activity of some naural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Biol. Med. Chem. 14, 2966-2971 https://doi.org/10.1016/j.bmc.2005.12.021
  6. Corsi, L., E. Geminaniani, R. Avallone, and M. Baraldi. 2005. Nuclear location-dependent role of peripheral benzodiazepine receptor (PBR) in hepatic tumoral cell lines proliferation. Life Sci. 76, 2523-2533 https://doi.org/10.1016/j.lfs.2004.08.040
  7. Decaudin, D. 2004. Peripheral benzodiazepine receptor and its clinical targeting. Anticancer Drugs 15, 737-745 https://doi.org/10.1097/00001813-200409000-00001
  8. Fennell, D. A., M. Corbo, A. Pallaska, and F. E. Cotter. 2001. Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species. Br. J. Cancer 84, 1397-1404 https://doi.org/10.1054/bjoc.2001.1788
  9. Fernandez, S. P., C. Wasoski, L. M. Loscalzo, R. E. Granger, G. A. R. Johnston, A. C. Paladini, and M. Marder. 2006. Central nervous system depressant action of flavonoid glycosides. Eur. J. Pharm. 539, 168-176 https://doi.org/10.1016/j.ejphar.2006.04.004
  10. Ha, J. H., J. T. Lee, I. H. Cho, K. A. Chun, G. E. Park, H. C. Choi, K. Y. Lee, S. H. Kim, K. Suk, I. K. Kim, and M. G. Lee. 2007. Upregulation of PBR mRNA expression in human neuroblastoma cells by flavonoids. Phytomedicine 14, 232-235 https://doi.org/10.1016/j.phymed.2005.11.004
  11. Hans, Z., R. S. Slack, W. Lia, and V. Papadopoulos. 2003. Expression of peripheral benzodiazepine receptor (PBR) in human tumors: relationship to breast, colorectal, and prostate tumor progression. J. Recept. Signal Transduct. Res. 23, 225-238 https://doi.org/10.1081/RRS-120025210
  12. Harmon, A. W. and Y. M. Pate. 2004. Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation. Breast Cancer Res. 85, 103-110 https://doi.org/10.1023/B:BREA.0000025397.56192.e2
  13. Kale, A., S. Gawande, and S. Kotwal. 2008. Cancer phytotherapeutics: role for flavonoids at the cellular level. Phytother. Res. 22, 567-577 https://doi.org/10.1002/ptr.2283
  14. Kim, D. H., J. T. Lee, I. K. Lee, and J. H. Ha. 2008. Comparative anticancer effects of flavonoids and diazepam in cultured cancer cells. Biol. Pharm. Bull. 31, 255-259 https://doi.org/10.1248/bpb.31.255
  15. Kuo, P. C., H. F. Liu, and J. L. Chao. 2004. Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. J. Biol. Chem. 279, 55875-55885 https://doi.org/10.1074/jbc.M407985200
  16. Lima, S. A. C., J. Tavares, and P. Gameiro. 2008. Flurazepam inhibits the P-glycoprotein transport function: an insight to revert multidrug-resistance phenotype. Eur. J. Pharm. 581, 30-36 https://doi.org/10.1016/j.ejphar.2007.11.045
  17. Maaser, K., M. Hopfner, A. Jansen, G. Weisunger, M. Gavish, A. P. Kozikowski, A. Weizman, P. Carayon, E. O. Riecken, M. Zeitz, and H. Scherubi. 2001. Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells. Br. J. Cancer 85, 1771-1780 https://doi.org/10.1054/bjoc.2001.2181
  18. Marder, M. and A. C. Paladini. 2002. GABA (A)-receptor ligands of flavonoid structure. Curr. Top. Med. Chem. 2, 853-867 https://doi.org/10.2174/1568026023393462
  19. Mizoguchi, K., R. Ikeda, H. Shoji, Y. Tanaka, X.-L. Jin, Y. Kase, S. Takeda, W. Maruyama, and T. Tabira. 2009. Saiko-ka-ryudotsu-borei-to, a herbal medicine, prevents chronic stress-induced anxiety in rats: comparision with diazepam. Nat. Med. (Tokyo) 63, 69-74 https://doi.org/10.1007/s11418-008-0281-9
  20. Ognibene, E., P. Bovicelli, W. Adriani, L. Saso, and G. Laviola. 2008. Behavioral effects of 6-bromoflavanone and 5-methoxy-6, 8-dibromoflavanone as anxiolytic compounds. Prog. Neuro-psychoph. 32, 128-134 https://doi.org/10.1016/j.pnpbp.2007.07.023
  21. Oudard, S., L. Miccoli, B. Dutrillaux, and M. F. Poupon. 1998. Targeting the gene of glucose metabolism for the treatment of advanced gliomas. Bull. Cancer 85, 622-626 https://doi.org/10.1016/S0006-8993(00)02633-0|
  22. Pretner, E., H. Amri, W. Li, R. Brown, C. S. Lin, E. Makariou, F. V. Defeudis, K. Drieu, and V. Papadopoulos. 2006. Cancer-related overexpression of the peripheral-type benzodiazepine receptor and cytostatic anticancer effects of Ginkgo biloba extract (Egb 761). Anticancer Res. 26, 9-22
  23. Shaheen, A. A., M. A. Hamdy, A. A. Kheir-Eldin, Pel-Fattah, and A. A. Lindstrom. 1993. Effect of pretreatment with vitamin E or diazepam on brain metabolism of stressed rats. Biochem. Pharmacol. 46, 194-197 https://doi.org/10.1016/0006-2952(93)90367-6
  24. Walter, R. B., B. W. Raden, M. R. Cronk, I. D. Bernstein, F. R. Appelbaum, and D. E. Banker. 2004. The peripheral bezodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin. Blood 103, 4276-4284 https://doi.org/10.1182/blood-2003-11-3825
  25. Wasoski, C., M. Marder, H. Viola, J. H. Medina, and A. C. Paladini. 2002. Isolation & identification of 6-methylapigenin, a competitive ligand for the brain GABA(A) receptors, from Valeriana Wallichii. Planta Med. 68, 934-936 https://doi.org/10.1055/s-2002-34936
  26. Younes, M., R. W. Brown, D. R. Mody, I. Fernandez, and R. Laucirica. 1995. GLUT1 expression in human breast carcinoma: correlation with known prognostic markers. Anticancer Res. 15, 2895-2898
  27. Zhuang, H., R. Hustinx, and A. Alavi. 2006. Effect of diazepam on the efficacy of dual-phase FDG PET imaging. Eur. J. Nucl. Med. Mol. Imaging 33, 228-229 https://doi.org/10.1007/s00259-005-1957-y