Skip to main content

Advertisement

SpringerLink
Log in

The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

The effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an hsp90 inhibitor, alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma (ATC) was evaluated. In 8505C and CAL62 cells, after treatment of 17-AAG, cell viability decreased, and the percentage of dead cells increased. 17-AAG did not cause cleavage of caspase-3 protein, and change expression of IAPs. Pretreatment of z-VAD-fmk did not alter cell viability and the percentage of dead cells. In 17-AAG-treated cells, knockdown of p53 rescued growth inhibition, while cycloheximide attenuated cell death. When cells were treated with both 17-AAG and paclitaxel, all of the combination index values were higher than 1, indicating antagonism between 17-AAG and paclitaxel. In 17-AAG- and paclitaxel-treated cells, compared with paclitaxel alone-treated cells, the protein levels of hsp90, hsp70, and hsc70 increased. In conclusion, our results suggest that 17-AAG induces non-apoptotic cell death requiring de novo protein synthesis in ATC cells. Moreover, these results demonstrate that 17-AAG antagonizes paclitaxel with concomitant alterations in hsp90 client proteins in ATC cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

17-AAG:

17-Allylamino-17-demethoxygeldanamycin

Act D:

Actinomycin D

ATC:

Anaplastic thyroid carcinoma

CHX:

Cycloheximide

CI:

Combination index

DMSO:

Dimethylsulfoxide

FTC:

Follicular thyroid carcinoma

hsc70:

Heat-shock cognate 70

hsp70:

Heat-shock protein 70

hsp90:

Heat-shock protein 90

IAP:

Inhibitor of apoptosis protein

MTC:

Medullary thyroid carcinoma

PTC:

Papillary thyroid carcinoma

siRNA:

Small interfering RNA

References

  1. J. Akaishi, K. Sugino, W. Kitagawa, M. Nagahama, K. Kameyama, K. Shimizu, K. Ito, Prognostic factors and treatment outcomes of 100 cases of anaplastic thyroid carcinoma. Thyroid 21, 1183–1189 (2011)

    Article  PubMed  Google Scholar 

  2. T.W. Schulte, L.M. Neckers, The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother. Pharmacol. 42, 273–279 (1998)

    Article  CAS  PubMed  Google Scholar 

  3. C. Prodromou, S.M. Roe, R. O’Brien, J.E. Ladbury, P.W. Piper, L.H. Pearl, Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90, 65–75 (1997)

    Article  CAS  PubMed  Google Scholar 

  4. M.V. Blagosklonny, Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia 16, 455–462 (2002)

    Article  CAS  PubMed  Google Scholar 

  5. L. Neckers, Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol. Med. 8, S55–S61 (2002)

    Article  CAS  PubMed  Google Scholar 

  6. I. Hostein, D. Robertson, F. Distefano, P. Workman, P.A. Clarke, Inhibition of signal transduction by 17-allylamino-7-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res. 61, 4003–4009 (2001)

    CAS  PubMed  Google Scholar 

  7. A. Maloney, P. Workman, HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin. Biol. Ther. 2, 3–24 (2002)

    Article  CAS  PubMed  Google Scholar 

  8. D.K. Marsee, A. Venkateswaran, H. Tao, D. Vadysirisack, Z. Zhang, D.D. Vandre, S.M. Jhiang, Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. J. Biol. Chem. 279, 43990–43997 (2004)

    Article  CAS  PubMed  Google Scholar 

  9. R. Elisei, A. Vivaldi, R. Ciampi, P. Faviana, F. Basolo, F. Santini, C. Traino, F. Pacini, A. Pinchera, Treatment with drugs able to reduce iodine efflux significantly increases the intracellular retention time in thyroid cancer cells stably transfected with sodium iodide symporter complementary deoxyribonucleic acid. J. Clin. Endocrinol. Metab. 91, 2389–2395 (2006)

    Article  CAS  PubMed  Google Scholar 

  10. M. Braga-Basaria, E. Hardy, R. Gottfried, K.D. Burman, M. Saji, M.D. Ringel, 17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels. J. Clin. Endocrinol. Metab. 89, 2982–2988 (2004)

    Article  CAS  PubMed  Google Scholar 

  11. K.B. Ain, M.J. Egorin, P.A. DeSimone, Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 10, 587–594 (2000)

    Article  CAS  PubMed  Google Scholar 

  12. N. Sain, B. Krishnan, M.G. Ormerod, A. De Rienzo, W.M. Liu, S.B. Kaye, P. Workman, A.L. Jackman, Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol. Cancer Ther. 5, 1197–1208 (2006)

    Article  CAS  PubMed  Google Scholar 

  13. D.A. Proia, J. Sang, S. He, D.L. Smith, M. Sequeira, C. Zhang, Y. Liu, S. Ye, D. Zhou, R.K. Blackman, K.P. Foley, K. Koya, Y. Wada, Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models. Invest. New Drugs 30, 2201–2209 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. T.H. Kim, S.Y. Lee, J.H. Rho, N.Y. Jeong, Y.H. Soung, W.S. Jo, D.Y. Kang, S.H. Kim, Y.H. Yoo, Mutant p53 (G199 V) gains antiapoptotic function through signal transducer and activator of transcription 3 in anaplastic thyroid cancer cells. Mol. Cancer Res. 7, 1645–1654 (2009)

    Article  CAS  PubMed  Google Scholar 

  15. S.Y. Park, S.J. Cho, H.C. Kwon, K.R. Lee, D.K. Rhee, S. Pyo, Caspase-independent cell death by allicin in human epithelial carcinoma cells: involvement of PKA. Cancer Lett. 224, 123–132 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. S. Sperandio, K. Poksay, I. de Belle, M.J. Lafuente, B. Liu, J. Nasir, D.E. Bredesen, Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ. 11, 1066–1075 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Y.S. Chung, S. Cho, H.J. Ryou, H.-G. Jee, J.Y. Choi, K. Yoon, H.J. Choi, K.E. Lee, Y.-J. Suh, S.K. Oh, Y.-K. Youn, Is there a treatment advantage when paclitaxel and lovastatin are combined to dose anaplastic thyroid carcinoma cell lines? Thyroid 21, 735–744 (2011)

    Article  CAS  PubMed  Google Scholar 

  18. M.G. Catalano, R. Poli, M. Pugliese, N. Fortunati, G. Boccuzzi, Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines. Endocr. Relat. Cancer 14, 839–845 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. J.-W. Park, M.W. Yeh, M.G. Wong, M. Lobo, W.C. Hyun, Q.-Y. Duh, O.H. Clark, The heat shock protein 90-binding geldanamycin inhibits cancer cell proliferation, down-regulates oncoproteins, and inhibits epidermal growth factor induced invasion in thyroid cancer cell lines. J. Clin. Endocrinol. Metab. 88, 3346–3353 (2003)

    Article  CAS  PubMed  Google Scholar 

  20. R.E. Schweppe, J.P. Klopper, C. Korch, U. Pugazhenthi, M. Benezra, J.A. Knauf, J.A. Fagin, L.A. Marlow, J.A. Copland, R.C. Smallridge, B.R. Haugen, Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J. Clin. Endocrinol. Metab. 93, 4331–4341 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. L.M. Hawkins, A.A. Jayanthan, A. Narendran, Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. Pediatr. Res. 57, 430–437 (2005)

    Article  CAS  PubMed  Google Scholar 

  22. G.V. Georgakisa, Y. Lia, G.Z. Rassidakisb, L.J. Medeirosb, A. Younes, The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression. Exp. Hematol. 34, 1670–1679 (2006)

    Article  Google Scholar 

  23. L. Whitesell, R. Bagatell, R. Falsey, The stress response: implications for the clinical development of hsp90 inhibitors. Curr. Cancer Drug Targets 3, 349–358 (2003)

    Article  CAS  PubMed  Google Scholar 

  24. G. Jego, A. Hazoume, R. Seigneuric, C. Garrido, Targeting heat shock proteins in cancer. Cancer Lett. 332, 275–285 (2013)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012R1A1A2008786) to S.J. Lee, Republic of Korea.

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Disclosure

The authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea

    Si Hyoung Kim, Jun Goo Kang, Chul Sik Kim, Sung-Hee Ihm, Moon Gi Choi, Hyung Joon Yoo & Seong Jin Lee

Authors
  1. Si Hyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Goo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chul Sik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sung-Hee Ihm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Moon Gi Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyung Joon Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seong Jin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seong Jin Lee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, S.H., Kang, J.G., Kim, C.S. et al. The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells. Endocrine 48, 886–893 (2015). https://doi.org/10.1007/s12020-014-0371-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0371-2

Keywords

Search

Navigation