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

Abstract

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.

Aqueous Ethanolic Extract of Tinospora cordifolia as a Potential Candidate for Differentiation Based Therapy of Glioblastomas

“…This gene is also reported to inhibit chemotherapy induced apoptosis [72]. Inhibition of bcl-xl both at transcriptional and translational levels by TCE is in line with findings with other natural products showing anticancer properties, like curcumin, andrographolide, and proanthocyanidines [73,74]. Annexin V-FITC/PI staining study further supported this observation as there was increase in early apoptotic cell population which may be due to the induction of differentiation in C6 glioma cells that led cells to undergo programmed cell death.…”

Withania somnifera Water Extract as a Potential Candidate for Differentiation Based Therapy of Human Neuroblastomas

“…Anti-apoptotic functions of bcl-xl are well known. Recent reports on curcumin, andrographolide, cranberry proanthocyanidines have established bcl-xl mediated pro-apoptotic properties of natural compounds [52], [53]. Therefore we evaluated whether ASH-WEX could influence bcl-xl expression in the IMR-32 cells.…”

Evaluation of In Vitro Antioxidant and Anticancer Properties of the Aqueous Extract from the Stem Bark of Stryphnodendron adstringens

“…In this study, the SAAE increased the production of ROS, which may have triggered the dysfunction in mitochondrial membrane potential and apoptotic cell death observed in melanoma cells. Singh et al [69] showed that proanthocyanidins extracted from cranberries have a cytotoxic effect on neuroblastoma cells by increasing ROS production and depolarizing the mitochondrial membrane potential. Furthermore, other extracts and natural compounds have already been described as promising in cancer treatment because they increase ROS and depolarize the mitochondrial membrane potential [70,71,72,73].…”