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

22 Citations (Scopus)

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

Fingerprint

Vaccinium macrocarpon
Neuroblastoma
Cyclophosphamide
Reactive Oxygen Species
Cell Cycle
Down-Regulation
Apoptosis
Death Domain Receptors
G2 Phase
Cyclin D1
Phosphatidylinositol 3-Kinases
Cell Division
Membrane Potentials
Superoxide Dismutase
Glutathione
Proteins
Cell Death
Up-Regulation
Cell Line
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

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

Cite this

Singh, Ajay P. ; Lange, Thilo S. ; Kim, Kyu K. ; Brard, Laurent ; Horan, Timothy ; Moore, Richard G. ; Vorsa, Nicholi ; Singh, Rakesh K. / Purified cranberry proanthocyanidines (PAC-1A) cause proapoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells. In: International journal of oncology. 2012 ; Vol. 40, No. 1. pp. 99-108.
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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.",
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Purified cranberry proanthocyanidines (PAC-1A) cause proapoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells. / Singh, Ajay P.; Lange, Thilo S.; Kim, Kyu K.; Brard, Laurent; Horan, Timothy; Moore, Richard G.; Vorsa, Nicholi; Singh, Rakesh K.

In: International journal of oncology, Vol. 40, No. 1, 01.01.2012, p. 99-108.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Purified cranberry proanthocyanidines (PAC-1A) cause proapoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

AU - Singh, Ajay P.

AU - Lange, Thilo S.

AU - Kim, Kyu K.

AU - Brard, Laurent

AU - Horan, Timothy

AU - Moore, Richard G.

AU - Vorsa, Nicholi

AU - Singh, Rakesh K.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cell cycle

KW - Cranberry

KW - Cyclophosphamide

KW - Proanthocynidine

KW - TNFα

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