The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing's sarcoma cell line, TC-71

  • Authors:
    • M. C. Manara
    • S. Perdichizzi
    • M. Serra
    • R. Pierini
    • S. Benini
    • C. M. Hattinger
    • A. Astolfi
    • R. Bagnati
    • M. D'Incalci
    • P. Picci
    • K. Scotlandi
  • View Affiliations

  • Published online on: December 1, 2005     https://doi.org/10.3892/ijo.27.6.1605
  • Pages: 1605-1616
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Abstract

Identification of new active agents against sarcoma is considered an important challenge in medical oncology. ET-743 (Trabectidin; Yondelis) has recently emerged as the first active drug developed against sarcoma in the last two decades, with promising results especially against soft-tissue sarcoma and Ewing's sarcoma (ES). In this study, we analyzed the molecular mechanisms responsible for resistance to ET-743 in ES cells. Three resistant cell variants (TC/ET 3 nM, TC/ET 6 nM and TC/ET 12 nM) were obtained, showing 28-, 47- and 102-fold increase in ET-743 resistance. Cross-resistance to other drugs was analyzed. Comparative genomic hybridization and cDNA microarray technology were employed to characterize and compare the gene expression profile of two TC/ET variants with the parental cell line. TC/ET cells show a conventional multidrug resistance phenotype and P-glycoprotein overexpression was found to significantly contribute to ET-743 resistance. However, functional studies with the cyclosporine analogue, PSC-833, indicate that other mechanisms are involved in resistance to ET-743. The gene expression profile of TC/ET cells indicated, among up-regulated genes, an increase in expression of insulin-like growth factor receptor-I (IGF-IR) and one of its major intracellular mediators, insulin receptor substrate-1. Functional studies using a neutralizing antibody anti-IGF-IR confirmed involvement of this signaling pathway in resistance to ET-743. Simultaneous blockage of both P-glycoprotein and IGF-IR completely restored sensitivity to ET-743 in ES cells. Overall, these findings provide impetus for future studies testing the therapeutic value of new specific inhibitors of P-glycoprotein and IGF-IR, which could represent a concrete therapeutic option for ES patients refractory to conventional agents.

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December 2005
Volume 27 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Manara, M.C., Perdichizzi, S., Serra, M., Pierini, R., Benini, S., Hattinger, C.M. ... Scotlandi, K. (2005). The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing's sarcoma cell line, TC-71. International Journal of Oncology, 27, 1605-1616. https://doi.org/10.3892/ijo.27.6.1605
MLA
Manara, M. C., Perdichizzi, S., Serra, M., Pierini, R., Benini, S., Hattinger, C. M., Astolfi, A., Bagnati, R., D'Incalci, M., Picci, P., Scotlandi, K."The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing's sarcoma cell line, TC-71". International Journal of Oncology 27.6 (2005): 1605-1616.
Chicago
Manara, M. C., Perdichizzi, S., Serra, M., Pierini, R., Benini, S., Hattinger, C. M., Astolfi, A., Bagnati, R., D'Incalci, M., Picci, P., Scotlandi, K."The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing's sarcoma cell line, TC-71". International Journal of Oncology 27, no. 6 (2005): 1605-1616. https://doi.org/10.3892/ijo.27.6.1605