Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Differential Sensitivities of Human Multidrug-resistant Cancer Cells to BIIB021 and Modulation of Hsp90 Inhibitors by NSAIDs and Niclosamide

항암제 다제내성(MDR) 암세포의 Hsp90 저해제 BIIB021에 대한 감수성의 차이 및 NSAIDs 및 Niclosamide에 의한 Hsp90 저해제의 활성 변화

  • Moon, Hyun-Jung (Department of Biochemistry, Pusan National University School of Medicine) ;
  • Lee, Su-Hoon (Department of Biochemistry, Pusan National University School of Medicine) ;
  • Kim, Sun-Hee (Department of Biochemistry, Pusan National University School of Medicine) ;
  • Kang, Chi-Dug (Department of Biochemistry, Pusan National University School of Medicine)
  • 문현정 (부산대학교 의학전문대학원 의과학과 생화학교실) ;
  • 이수훈 (부산대학교 의학전문대학원 의과학과 생화학교실) ;
  • 김선희 (부산대학교 의학전문대학원 의과학과 생화학교실) ;
  • 강치덕 (부산대학교 의학전문대학원 의과학과 생화학교실)
  • Received : 2018.06.29
  • Accepted : 2018.08.17
  • Published : 2018.10.30
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Abstract

The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant (MDR) human cancer cells, although BIIB021 was shown to be active in first-generation Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant MDR cells. MCF7-MDR and HeyA8- MDR cells were more resistant to BIIB021 than their parental counterparts, indicating that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins. We revealed that dimethyl-celecoxib (DMC), one of the non-steroidal anti-inflammatory drugs (NSAIDs), potentiated cytotoxicity of BIIB021 against both BIIB021-resistant and BIIB021-sensitive MDR cells. The effectiveness of NSAIDs involving celecoxib and DMC in combination with BIIB021 led to the autophagic degradation/down-regulation of mutant p53 (mutp53) that overexpressed MDR cells and the suppression of Hsp70 induction. This resulted in sensitization of MDR cells to BIIB021. Moreover, autophagy induction by sulindac sulfide, another type of NSAID, and niclosamide, an FDA-approved anthelmintic drug, potentiated 17-AAG-mediated autophagic degradation/down-regulation of mutp53 and c-Myc, client proteins of Hsp90. Therefore, our results suggest that NSAIDs and niclosamide positively enhance the anticancer activity of Hsp90 inhibitors through an autophagic pathway. They may also be new candidates for sensitizing MDR cells to Hsp90 inhibitors.

열 충격 단백질인 heat shock protein 90 (Hsp90)은 종양 형성 과정에서 중요한 역할을 하고 있으며, 이에 따라 1세대 및 2세대 Hsp90저해제들이 개발되어, 다양한 암에서의 항암 효과가 보고되어 있다. 2세대 Hsp90저해제로 개발된 BIIB021는 1세대 Hsp90저해제인 17-allylamino-17-demethoxygeldanamycin (17-AAG)에 내성을 나타내는 항암제 다제내성(MDR) 암세포에 감수성을 가진다고 알려져 있지만, 본 연구에서 BIIB021에 내성인 MDR세포로서, MCF7-MDR 및 HeyA8-MDR세포가 해당됨을 밝혔다. BIIB021 감수성을 증강시키는 물질로 비스테로이드성 항염증약물(NSAID)인 dimethyl-celecoxib (DMC)의 BIIB021의 효과 증강 활성을 BIIB021-내성 및 -감수성 MDR 세포에서 확인하였다. MDR세포에 NSAID와 BIIB021의 병합 처리한 경우, NSAID의 자가분해(autophagy) 유도 활성에 의해 MDR세포에서 과잉 발현하는 변이형 mutant p53 (mutp53)을 분해할 뿐만 아니라 BIIB021 처리로 유도되는 Hsp70 발현을 억제하므로써, 암세포의 BIIB021 내성을 극복할 수 있는 활성을 나타내었다. 또한 NSAID 물질인 sulindac sulfate 및 FDA 승인 약물인 niclosamide 도 자가분해 유도 활성으로 Hsp90의 타켓 단백질 인 mutp53 및 c-Myc의 분해를 유도하므로서, 17-AAG 효과를 증강시켰다. 그러므로 본 연구에서는 새로운 BIIB021에 대한 효과 증강 및 내성 극복 물질로서, NSAIDs 및 niclosamide를 발굴하였으며, 이들 물질의 자가분해 경로 활성화에 의하여, BIIB021 효과를 극대화 시킴을 밝혔다.

Keywords

References

  1. Bansal, T., Jaggi, M., Khar, R. K. and Talegaonkar, S. 2009. Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy. J. Pharm Pharm Sci. 12, 46-78.
  2. Cheng, B. X., Morales, L. D., Zhang, Y. H., Mito, S. and Tsin, A. 2017. Niclosamide induces protein ubiquitination and inhibits multiple pro-survival signaling pathways in the human glioblastoma U-87 MG cell line. PLoS One 12, e0184324. https://doi.org/10.1371/journal.pone.0184324
  3. Dickson, M. A., Okuno, S. H., Keohan, M. L., Maki, R. G., D'Adamo, D. R., Akhurst, T. J., Antonescu, C. R. and Schwartz, G. K. 2013. Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Ann. Oncol. 24, 252-257. https://doi.org/10.1093/annonc/mds275
  4. Fischer, V., Einolf, H. J. and Cohen, D. 2005. Efflux transporters and their clinical relevance. Mini Rev. Med. Chem. 5, 183-195. https://doi.org/10.2174/1389557053402756
  5. Gottesman, M. M., Fojo, T. and Bates, S. E. 2002. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48-58. https://doi.org/10.1038/nrc706
  6. Hsieh, Y. C., Athar, M. and Chaudry, I. H. 2009. When apoptosis meets autophagy: deciding cell fate after trauma and sepsis. Trends Mol. Med. 15, 129-138. https://doi.org/10.1016/j.molmed.2009.01.002
  7. Kim, S. H., Kang, J. G., Kim, C. S., Ihm, S. H., Choi, M. G., Yoo, H. J. and Lee, S. J. 2016. Synergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/Akt/ mTOR and NF-kappa B signal pathways in thyroid carcinoma cells. Biomed. Pharmacother. 83, 22-32. https://doi.org/10.1016/j.biopha.2016.06.014
  8. Li, Y. H., Li, P. K., Roberts, M. J., Arend, R. C., Samant, R. S. and Buchsbaum, D. J. 2014. Multi-targeted therapy of cancer by niclosamide: A new application for an old drug. Cancer Lett. 349, 8-14. https://doi.org/10.1016/j.canlet.2014.04.003
  9. Liggett, J. L., Zhang, X. B., Eling, T. E. and Baek, S. J. 2014. Anti-tumor activity of non-steroidal anti-inflammatory drugs: Cyclooxygenase-independent targets. Cancer Lett. 346, 217-224. https://doi.org/10.1016/j.canlet.2014.01.021
  10. Lundgren, K., Zhang, H., Brekken, J., Huser, N., Powell, R. E., Timple, N., Busch, D. J., Neely, L., Sensintaffar, J. L., Yang, Y. C., McKenzie, A., Friedman, J., Scannevin, R., Kamal, A., Hong, K., Kasibhatla, S. R., Boehm, M. F. and Burrows, F. J. 2009. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol. Cancer Ther. 8, 921-929.
  11. Maloney, A. and Workman, P. 2002. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin. Biol. Ther. 2, 3-24. https://doi.org/10.1517/14712598.2.1.3
  12. Moon, H. J., Kim, H. B., Lee, S. H., Jeun, S. E., Kang, C. D. and Kim, S. H. 2018. Sensitization of multidrug-resistant cancer cells to Hsp90 inhibitors by NSAIDs-induced apoptotic and autophagic cell death. Oncotarget 9, 11303-11321.
  13. Neckers, L. 2002. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol. Med. 8, S55-S61. https://doi.org/10.1016/S1471-4914(02)02316-X
  14. Saif, M. W., Takimoto, C., Mita, M., Banerji, U., Lamanna, N., Castro, J., O'Brien, S., Stogard, C. and Von Hoff, D. 2014. A Phase 1, Dose-Escalation, pharmacokinetic and pharmacodynamic study of BIIB021 administered orally in patients with advanced solid tumors. Clin. Cancer Res. 20, 445-455.
  15. Shtil, A. A. and Azare, J. 2005. Redundancy of biological regulation as the basis of emergence of multidrug resistance. Int. Rev. Cytol. 246, 1-29.
  16. Taldone, T., Gozman A., Maharaj R. and Chiosis, G. 2008. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr. Opin. Pharmacol. 8, 370-374. https://doi.org/10.1016/j.coph.2008.06.015
  17. Yu, C., Li W. B., Liu J. B., Lu J. W. and Feng, J. F. 2018. Autophagy: novel applications of nonsteroidal anti-inflammatory drugs for primary cancer. Cancer Med. 7, 471-484. https://doi.org/10.1002/cam4.1287
  18. Zhang, H. and Burrows, F. 2004. Targeting multiple signal transduction pathways through inhibition of Hsp90. J. Mol. Med. (Berl). 82, 488-499.
  19. Zhang, H., Neely, L., Lundgren, K., Yang, Y. C., Lough, R., Timple, N. and Burrows, F. 2010. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance. Int. J. Cancer 126, 1226-1234.