Analogs of Vitamin E Epitomized by α-Tocopheryl Succinate for Pancreatic Cancer Treatment

Greco, Eliana; Basso, Daniela; Fadi, Elisa; Padoan, Andrea; Fogar, Paola; Zambon, Carlo–Federico; Navaglia, Filippo; Bozzato, Dania; Moz, Stefania; Pedrazzoli, Sergio; Plebani, Mario

doi:10.1097/mpa.0b013e3181c8b48c

Cited by 9 publications

(15 citation statements)

References 39 publications

(43 reference statements)

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“…In another recent study, Greco did not show any apoptotic changes until 30-h incubation with 80 lM VES. Greco et al (2010) also observed mild sensitivity to VES at 100 lM concentration, which was close to our apoptotic-inducing concentration in PANC-1 cells (Greco et al 2010). Other than PANC-1, the cell lines used by Greco et al were different than used in our study and might explain the differences in results.…”

Section: Discussioncontrasting

confidence: 53%

“…Earlier studies on the effects of VES on pancreatic cancer cells have reported contradictory results (Greco et al 2010;Heisler et al 2000;Ohlsson et al 2004). Ohlsson et al (2004) found that pancreatic cell lines are insensitive to VES; however, the maximum concentration used in this study was low at 1 lM (Ohlsson et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Limited studies have been performed to examine the effects of vitamin E and its analogs in pancreatic cancer cells (Greco et al 2010;Heisler et al 2000;Ohlsson et al 2004). A few studies have indicated that vitamin E does not inhibit the growth of pancreatic cancer cell line (Greco et al 2010;Ohlsson et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells

et al. 2011

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Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Identifying novel chemotherapeutic and chemopreventive approaches is critical in the prevention and treatment of cancers such as pancreatic cancer. Vitamin E succinate (VES) is a redox-silent analog of the fat-soluble vitamin alphatocopherol. In the present study, we explored the antiproliferative action of VES and its effects on inhibitor of apoptosis proteins in pancreatic cancer cells. We show that VES inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. Further, we demonstrate that VES downregulates the expression of survivin and X-linked inhibitor of apoptosis proteins. The apoptosis induced by VES was augmented by siRNA-mediated inhibition of survivin in PANC-1 cells. In summary, our results suggest that VES targets survivin signaling and induces apoptosis in pancreatic cancer cells.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells

et al. 2011

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“…Looking into earlier clinical trials on dietary antioxidants in cancer condition, we have not received encouraging results. 47,48 Moreover, NAC treatment leads to the attenuation of apoptotic functions of ROS inducers, further emphasizing toward the optimization of antioxidant therapies against PC. 49 However, due to observed overexpression of HIF-1α even under normoxic condition, current study encourages HIF-1α targeting, which will led to the downregulation of multiple oncogenic proteins, including mucins.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival

et al. 2016

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Pancreatic cancer (PC) and associated pre-neoplastic lesions have been reported to be hypoxic, primarily due to hypovascular nature of PC. Though the presence of hypoxia under cancerous condition has been associated with the overexpression of oncogenic proteins (MUC1), multiple emerging reports have also indicated the growth inhibitory effects of hypoxia. In spite of being recognized as the top-most differentially expressed and established oncogenic protein in PC, MUC4 regulation in terms of micro-environmental stress has not been determined. Herein, for the first time, we are reporting that MUC4 protein stability is drastically affected in PC, under hypoxic condition in a hypoxia inducible factor 1α (HIF-1α)-independent manner. Mechanistically, we have demonstrated that hypoxia-mediated induction of reactive oxygen species (ROS) promotes autophagy by inhibiting pAkt/ mTORC1 pathway, one of the central regulators of autophagy. Immunohistofluorescence analyses revealed significant negative correlation (P-value = 0.017) between 8-hydroxy guanosine (8-OHG) and MUC4 in primary pancreatic tumors (n = 25). Moreover, we found pronounced colocalization between MUC4 and LAMP1/LC3 (microtubule-associated protein 1A/1B-light chain 3) in PC tissues and also observed their negative relationship in their expression pattern, suggesting that areas with high autophagy rate had less MUC4 expression. We also found that hypoxia and ROS have negative impact on overall cell growth and viability, which was partially, though significantly (P < 0.05), rescued in the presence of MUC4. Altogether, hypoxia-mediated oxidative stress induces autophagy in PC, leading to the MUC4 degradation to enhance survival, possibly by offering required metabolites to stressed cells.

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“…MiaPaCa2, β‐TC6, and HepG2 were cultured in Dulbecco's modified eagle medium (DMEM) (Gibco/BRL) supplemented with 10% (MiaPaCa2 and HepG2) or 15% (β‐TC6) FCS, 2% L ‐glutamine and 0.1% Gentamycin. BxPC3 cells were transfected with the expression vector pBK‐cytomegalovirus (CMV)‐SMAD4/DPC4, as previously described (Greco et al, 2010). One SMAD4/DPC4‐expressing clone (BxPC3‐SMAD4+) was used for S100A8 real time PCR analysis.…”

Section: Methodsmentioning

confidence: 99%

Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N‐terminal peptide (NT‐S100A8)

Basso

Greco

Padoan

et al. 2010

Journal Cellular Physiology

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After isolating NT-S100A8 from pancreatic cancer (PC) tissue of diabetic patients, we verified whether this peptide alters PC cell growth and invasion and/or insulin release and [Ca(2+)](i) oscillations of insulin secreting cells and/or insulin signaling. BxPC3, Capan1, MiaPaCa2, Panc1 (PC cell lines) cell growth, and invasion were assessed in the absence or presence of 50, 200, and 500 nM NT-S100A8. In NT-S100A8 stimulated β-TC6 (insulinoma cell line) culture medium, insulin and [Ca(2+)] were measured at 2, 3, 5, 10, 15, 30, and 60 min, and [Ca(2+)](i) oscillations were monitored (epifluorescence) for 3 min. Five hundred nanomolars NT-S100A8 stimulated BxPC3 cell growth only and dose dependently reduced MiaPaCa2 and Panc1 invasion. Five hundred nanomolars NT-S100A8 induced a rapid insulin release and enhanced β-TC6 [Ca(2+)](i) oscillations after both one (F = 6.05, P < 0.01) and 2 min (F = 7.42, P < 0.01). In the presence of NT-S100A8, [Ca(2+)] in β-TC6 culture medium significantly decreased with respect to control cells (F = 6.3, P < 0.01). NT-S100A8 did not counteract insulin induced phosphorylation of the insulin receptor, Akt and IκB-α, but it independently activated Akt and NF-κB signaling in PC cells. In conclusion, NT-S100A8 exerts a mild effect on PC cell growth, while it reduces PC cell invasion, possibly by Akt and NF-κB signaling, NT-S100A8 enhances [Ca(2+)](i) oscillations and insulin release, probably by inducing Ca(2+) influx from the extracellular space, but it does not interfere with insulin signaling.

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Analogs of Vitamin E Epitomized by α-Tocopheryl Succinate for Pancreatic Cancer Treatment

Abstract: Only a minority of PC cells are sensitive to the antiproliferative effects of alpha-TOS, any sensitivity appearing to be correlated with SMAD4/DPC4 homozygous deletion and Bax/Bak expression.

Cited by 9 publications

References 39 publications

Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells

Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells

Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival

Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N‐terminal peptide (NT‐S100A8)

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