Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

  • Authors:
    • Ajay P. Singh
    • Thilo S. Lange
    • Kyu K. Kim
    • Laurent Brard
    • Timothy Horan
    • Richard G. Moore
    • Nicholi Vorsa
    • Rakesh K. Singh
  • View Affiliations

  • Published online on: October 6, 2011     https://doi.org/10.3892/ijo.2011.1225
  • Pages: 99-108
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

Related Articles

Journal Cover

January 2012
Volume 40 Issue 1

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

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Singh AP, Lange TS, Kim KK, Brard L, Horan T, Moore RG, Vorsa N and Singh RK: Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells. Int J Oncol 40: 99-108, 2012
APA
Singh, A.P., Lange, T.S., Kim, K.K., Brard, L., Horan, T., Moore, R.G. ... Singh, R.K. (2012). Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells. International Journal of Oncology, 40, 99-108. https://doi.org/10.3892/ijo.2011.1225
MLA
Singh, A. P., Lange, T. S., Kim, K. K., Brard, L., Horan, T., Moore, R. G., Vorsa, N., Singh, R. K."Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells". International Journal of Oncology 40.1 (2012): 99-108.
Chicago
Singh, A. P., Lange, T. S., Kim, K. K., Brard, L., Horan, T., Moore, R. G., Vorsa, N., Singh, R. K."Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells". International Journal of Oncology 40, no. 1 (2012): 99-108. https://doi.org/10.3892/ijo.2011.1225