Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma

  • Authors:
    • Karen S. Koto
    • Pamela Lescault
    • Laurent Brard
    • Kyukwang Kim
    • Rakesh K. Singh
    • Jeff Bond
    • Sharon Illenye
    • Marni A. Slavik
    • Takamaru Ashikaga
    • Giselle L. Saulnier Sholler
  • View Affiliations

  • Published online on: March 10, 2011     https://doi.org/10.3892/ijo.2011.971
  • Pages: 1329-1341
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Abstract

Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common brain tumor found in children. We recently showed that nifurtimox induces production of reactive oxygen species (ROS) and subsequent apoptosis in neuroblastoma cells both in vitro and in vivo. Tetrathiomolybdate (TM) has been shown to decrease cell proliferation by inhibition of superoxide dismutase-1 (SOD1). Since both nifurtimox and TM increase ROS levels in cells, we investigated whether the combination of nifurtimox and TM would act synergistically in medulloblastoma cell lines (D283, DAOY). Genome-wide transcriptional analysis, by hybridizing RNA isolated from nifurtimox and TM alone or in combination treated and control cells (D283) on Affymetrix exon array gene chips was carried out to further confirm synergy. We show that nifurtimox and TM alone and in combination decreased cell viability and increased ROS levels synergistically. Examination of cell morphology following drug treatment (nifurtimox + TM) and detection of caspase-3 activation via Western blotting indicated that cell death was primarily due to apoptosis. Microarray data from cells treated with nifurtimox and TM validated the induction of oxidative stress, as many Nrf2 target genes (HMOX1, GCLM, SLC7A11 and SRXN1) (p<10-5) were upregulated. Other genes related to apoptosis, oxidative stress, DNA damage, protein folding and nucleosome formation were differentially involved in cells following treatment with nifurtimox + TM. Taken together, our results suggest nifurtimox and TM act synergistically in medulloblastoma cells in vitro, and that this combination warrants further studies as a new treatment for medulloblastoma.

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May 2011
Volume 38 Issue 5

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

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Spandidos Publications style
Koto KS, Lescault P, Brard L, Kim K, Singh RK, Bond J, Illenye S, Slavik MA, Ashikaga T, Saulnier Sholler GL, Saulnier Sholler GL, et al: Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma. Int J Oncol 38: 1329-1341, 2011.
APA
Koto, K.S., Lescault, P., Brard, L., Kim, K., Singh, R.K., Bond, J. ... Saulnier Sholler, G.L. (2011). Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma. International Journal of Oncology, 38, 1329-1341. https://doi.org/10.3892/ijo.2011.971
MLA
Koto, K. S., Lescault, P., Brard, L., Kim, K., Singh, R. K., Bond, J., Illenye, S., Slavik, M. A., Ashikaga, T., Saulnier Sholler, G. L."Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma". International Journal of Oncology 38.5 (2011): 1329-1341.
Chicago
Koto, K. S., Lescault, P., Brard, L., Kim, K., Singh, R. K., Bond, J., Illenye, S., Slavik, M. A., Ashikaga, T., Saulnier Sholler, G. L."Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma". International Journal of Oncology 38, no. 5 (2011): 1329-1341. https://doi.org/10.3892/ijo.2011.971