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

Ajay P. Singh, Thilo S. Lange, Kyu K. Kim, Laurent Brard, Timothy Horan, Richard G. Moore, Nicholi Vorsa, Rakesh K. Singh

Research output: Contribution to journalArticle

24 Scopus citations

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 (Δψm) 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.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalInternational journal of oncology
Volume40
Issue number1
DOIs
StatePublished - Jan 1 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • Apoptosis
  • Cell cycle
  • Cranberry
  • Cyclophosphamide
  • Proanthocynidine
  • TNFα

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