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David Kessel - One of the best experts on this subject based on the ideXlab platform.
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Photodynamic therapy: apoptosis, Paraptosis and beyond
Apoptosis, 2020Co-Authors: David KesselAbstract:Photodynamic therapy (PDT) is a light-catalyzed process that can initiate cellular death pathways from the formation of cytotoxic reactive oxygen species at sub-cellular sites. Apoptosis was the first such pathway to be identified. Autophagy can also occur and is often found to be cytoprotective. Another process termed Paraptosis can also have lethal consequences, even in cells with an impaired apoptotic pathway. PDT in vivo can evoke other potentially cytotoxic processes including vascular shutdown and enhanced immunologic recognition of neoplastic cells. Using appropriate photosensitizing agents, sub-cellular PDT targeting can be directed so that the resulting interplay among assorted death and survival pathways will result in an enhanced level of photokilling.
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Paraptosis and photodynamic therapy a progress report
Photochemistry and Photobiology, 2020Co-Authors: David KesselAbstract:Photodamage to the endoplasmic reticulum (ER) can initiate a death pathway termed Paraptosis. The "canonical" model of Paraptosis, initiated by certain drugs and other stimuli, requires a brief interval of protein synthesis, involves the action of MAP kinases and can be followed by biochemical markers. The latter include changes in expression of AIP-1/Alix and IGF-1R proteins and translocation of HMGB-1 from nucleus to plasma membrane. There is also a report indicating that an enhanced level of autophagy can impair death by Paraptosis. The pathway to Paraptosis follows the canonical pathway when ER photodamage is minor (
Paraptosis nor does a brief chilling of cells after irradiation, MAP kinases are not involved, and stimulation of autophagy was not cytoprotective. We had previously speculated that ER protein cross-linking might potentiate Paraptosis (Photochem. Photobiol. 95, 2019, 1239) but this appears to be incorrect. At higher PDT doses, substantial cross-linking of a typical ER protein (BiP, binding immunoglobin protein, an HSP chaperone) was detected and Paraptosis was impaired. This may relate to decreased mobility of cross-linked proteins. Other pathways to cell death were then observed. -
pathways to Paraptosis after er photodamage in ovcar 5 cells
Photochemistry and Photobiology, 2019Co-Authors: David KesselAbstract:A death mode termed Paraptosis is initiated by photodamage to the endoplasmic reticulum (ER). This is characterized by an extensive pattern of cytoplasmic vacuole formation and leads to a gradual loss of cytoplasm and of viability. Many photosensitizers in clinical use target sub-cellular organelles that include the ER and can, therefore, invoke Paraptosis as well as apoptosis. In this study, we explore pathways to Paraptosis in OVCAR-5, an ovarian cancer cell line of human origin. At low PDT doses, the route to Paraptosis follows the pattern that occurs after chemotherapy, that is, a pattern of vacuole formation that can be suppressed by MAPK antagonists or inhibition of new protein synthesis. At PDT doses clinically pertinent for tumor eradication, the pathway to Paraptosis appears to be independent of these factors. In addition to morphologic changes, translocation of the nuclear protein HMGB1(high mobility group protein B1) to the cell periphery has been described as a potential marker for drug-induced Paraptosis. This occurs to only a very minor extent after a lethal PDT dose that targets the ER. It appears that a lethal level of ER photodamage can initiate a different pathway to Paraptosis, perhaps associated with ER protein cross-linking.
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apoptosis Paraptosis and autophagy death and survival pathways associated with photodynamic therapy
Photochemistry and Photobiology, 2019Co-Authors: David KesselAbstract:The ability of photosensitizing agents to create photodamage at specific sub-cellular sites has proved useful for characterizing pathway(s) to cell death and for selecting optimal targets for anti-tumor efficacy. Both apoptosis and autophagy can occur after photodamage directed at mitochondria, lysosomes or the ER, with the balance often a determinant of overall efficacy. A combination of lysosomal + mitochondrial targets is associated with enhanced efficacy. More recently, ER photodamage was found to evoke a mainly unexplored mode of photokilling that involves extensive cytoplasmic vacuole formation but does not represent autophagy. This has been termed ‘Paraptosis’ and appears to be a reaction to the appearance of misfolded ER proteins. This report is designed to summarize current knowledge relating to death pathways and update information relating to Paraptosis as a PDT response.
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photodynamic therapy the role of Paraptosis
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVII, 2018Co-Authors: David Kessel, Wonjin Cho, Hyeong Reh Choi KimAbstract:Apoptosis is a pathway to cell death frequently observed after photodynamic therapy (PDT). Sub-cellular photodamage to mitochondria, lysosomes, the ER, or combinations of these targets, can lead to apoptotic death. We have recently investigated another pathway to cell death after PDT termed ‘Paraptosis’. This is characterized by extensive cytoplasmic vacuolization, does not involve caspase activation or nuclear fragmentation, requires a brief interval of continued protein synthesis and appears to derive from ER stress. Determinants and further characteristics of PDT-derived Paraptosis are explored in the A549 non small-cell lung cancer cell line and in cells derived from head and neck cancer tissues. We provide evidence that ER photodamage and JNK pathway activation are involved in PDT-mediated Paraptosis.
Patrizia Limonta - One of the best experts on this subject based on the ideXlab platform.
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Ca^2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated Paraptosis in melanoma cells
Apoptosis, 2021Co-Authors: Michela Raimondi, Fabrizio Fontana, Monica Marzagalli, Matteo Audano, Giangiacomo Beretta, Patrizia Procacci, Patrizia Sartori, Nico Mitro, Patrizia LimontaAbstract:Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate Paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for Paraptosis induction. Additionally, δ-TT caused Ca^2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca^2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated Paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.
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the emerging role of Paraptosis in tumor cell biology perspectives for cancer prevention and therapy with natural compounds
Biochimica et Biophysica Acta, 2020Co-Authors: Fabrizio Fontana, Michela Raimondi, Monica Marzagalli, Alessandro Di Domizio, Patrizia LimontaAbstract:Abstract Standard anti-cancer therapies promote tumor growth suppression mainly via induction of apoptosis. However, in most cases cancer cells acquire the ability to escape apoptotic cell death, thus becoming resistant to current treatments. In this setting, the interest in alternative cell death modes has recently increased. Paraptosis is a new form of programmed cell death displaying endoplasmic reticulum (ER) and/or mitochondria dilation, generally due to proteostasis disruption or redox and ion homeostasis alteration. Recent studies have highlighted that several natural compounds can trigger Paraptosis in different tumor cell lines. Here, we review the molecular mechanisms underlying paraptotic cell death, as well as the natural products inducing this kind of cell death program. A better understanding of Paraptosis should facilitate the development of new therapeutic strategies for cancer prevention and treatment.
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Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells
'Elsevier BV', 2020Co-Authors: F. Fontana, Monica Marzagalli, M. Raimondi, M. Audano, G. Beretta, P. Procacci, P. Sartori, N. Mitro, Patrizia LimontaAbstract:The therapeutic options for castration-resistant prostate cancer (CRPC) are still limited. Natural bioactive compounds were shown to possess pro-death properties in different tumors. We previously reported that \u3b4-tocotrienol (\u3b4-TT) induces apoptosis, Paraptosis and autophagy in CRPC cells. Here, we investigated whether \u3b4-TT might exert its activity by impairing mitochondrial functions. We demonstrated that, in PC3 and DU145\u202fcells, \u3b4-TT impairs mitochondrial respiration and structural dynamics. In both cell lines, \u3b4-TT triggers mitochondrial Ca2+ and ROS overload. In PC3 cells, both Ca2+ and ROS mediate the \u3b4-TT-related anticancer activities (decrease of cell viability, apoptosis, Paraptosis, autophagy and mitophagy). As expected, in autophagy-defective DU145\u202fcells, Ca2+ overload was involved in \u3b4-TT-induced pro-death effects but not in autophagy and mitophagy. In this cell line, we also demonstrated that ROS overload is not involved in the anticancer activities of \u3b4-TT, supporting a low susceptibility of these cells to ROS-related oxidative stress. Taken together, these data demonstrate that, in CRPC cells, \u3b4-TT triggers cell death by inducing mitochondrial functional and structural impairments, providing novel mechanistic insights in its antitumor activity
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δ‐Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and Paraptosis in prostate cancer cells
'Wiley', 2019Co-Authors: F. Fontana, Monica Marzagalli, M. Raimondi, G. Beretta, P. Procacci, P. Sartori, R.m. Moretti, Montagnani M. Marelli, Patrizia LimontaAbstract:OBJECTIVES: Prostate cancer, after the phase of androgen dependence, may progress to the castration-resistant prostate cancer (CRPC) stage, with resistance to standard therapies. Vitamin E-derived tocotrienols (TTs) possess a significant antitumour activity. Here, we evaluated the anti-cancer properties of δ-TT in CRPC cells (PC3 and DU145) and the related mechanisms of action. MATERIALS AND METHODS: MTT, Trypan blue and colony formation assays were used to assess cell viability/cell death/cytotoxicity. Western blot, immunofluorescence and MTT analyses were utilized to investigate apoptosis, ER stress and autophagy. Morphological changes were investigated by light and transmission electron microscopy. RESULTS: We demonstrated that δ-TT exerts a cytotoxic/proapoptotic activity in CRPC cells. We found that in PC3 cells: (a) δ-TT triggers both the endoplasmic reticulum (ER) stress and autophagy pathways; (b) autophagy induction is related to the ER stress, and this ER stress/autophagy axis is involved in the antitumour activity of δ-TT; in autophagy-defective DU145 cells, only the ER stress pathway is involved in the proapoptotic effects of δ-TT; (c) in both CRPC cell lines, δ-TT also induces an intense vacuolation prevented by the ER stress inhibitor salubrinal and the protein synthesis inhibitor cycloheximide, together with increased levels of phosphorylated JNK and p38, supporting the induction of Paraptosis by δ-TT. CONCLUSIONS: These data demonstrate that apoptosis, involving ER stress and autophagy (in autophagy positive PC3 cells), and Paraptosis are involved in the anti-cancer activity of δ-TT in CRPC cells
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δ tocotrienol induces apoptosis involving endoplasmic reticulum stress and autophagy and Paraptosis in prostate cancer cells
Cell Proliferation, 2019Co-Authors: Fabrizio Fontana, Michela Raimondi, Monica Marzagalli, Giangiacomo Beretta, Patrizia Procacci, Patrizia Sartori, R.m. Moretti, Montagnani M. Marelli, Patrizia LimontaAbstract:Objectives Prostate cancer, after the phase of androgen dependence, may progress to the castration-resistant prostate cancer (CRPC) stage, with resistance to standard therapies. Vitamin E-derived tocotrienols (TTs) possess a significant antitumour activity. Here, we evaluated the anti-cancer properties of δ-TT in CRPC cells (PC3 and DU145) and the related mechanisms of action. Materials and methods MTT, Trypan blue and colony formation assays were used to assess cell viability/cell death/cytotoxicity. Western blot, immunofluorescence and MTT analyses were utilized to investigate apoptosis, ER stress and autophagy. Morphological changes were investigated by light and transmission electron microscopy. Results We demonstrated that δ-TT exerts a cytotoxic/proapoptotic activity in CRPC cells. We found that in PC3 cells: (a) δ-TT triggers both the endoplasmic reticulum (ER) stress and autophagy pathways; (b) autophagy induction is related to the ER stress, and this ER stress/autophagy axis is involved in the antitumour activity of δ-TT; in autophagy-defective DU145 cells, only the ER stress pathway is involved in the proapoptotic effects of δ-TT; (c) in both CRPC cell lines, δ-TT also induces an intense vacuolation prevented by the ER stress inhibitor salubrinal and the protein synthesis inhibitor cycloheximide, together with increased levels of phosphorylated JNK and p38, supporting the induction of Paraptosis by δ-TT. Conclusions These data demonstrate that apoptosis, involving ER stress and autophagy (in autophagy positive PC3 cells), and Paraptosis are involved in the anti-cancer activity of δ-TT in CRPC cells.
Yi Wang - One of the best experts on this subject based on the ideXlab platform.
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celastrol acts synergistically with afatinib to suppress non small cell lung cancer cell proliferation by inducing Paraptosis
Journal of Cellular Physiology, 2021Co-Authors: Chunhau Dai, Yi Wang, Lirong Zhu, Xingping Tang, Yongchang ChenAbstract:Non-small cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs), such as afatinib. Celastrol, a natural compound with antitumor activity, was reported to induce Paraptosis in cancer cells. In this study, intrinsic EGFR-TKI-resistant NSCLC cell lines H23 (EGFR wild-type and KRAS mutation) and H292 (EGFR wild-type and overexpression) were used to test whether celastrol could overcome primary afatinib resistance through Paraptosis induction. The synergistic effect of celastrol and afatinib on survival inhibition of the NSCLC cells was evaluated by CCK-8 assay and isobologram analysis. The Paraptosis and its modulation were assessed by light and electron microscopy, Western blot analysis, and immunofluorescence. Xenografts models were established to investigate the inhibitory effect of celastrol plus afatinib on the growth of the NSCLC tumors in vivo. Results showed that celastrol acted synergistically with afatinib to suppress the survival of H23 and H292 cells by inducing Paraptosis characterized by extensive cytoplasmic vacuolation. This process was independent of apoptosis and not associated with autophagy induction. Afatinib plus celastrol-induced cytoplasmic vacuolation was preceded by endoplasmic reticulum stress and unfolded protein response. Accumulation of intracellular reactive oxygen species and mitochondrial Ca2+ overload may be initiating factors of celastrol/afatinib-induced Paraptosis and subsequent cell death. Furthermore, Celastrol and afatinib synergistically suppressed the growth of H23 cell xenograft tumors in vivo. The data indicate that a combination of afatinib and celastrol may be a promising therapeutic strategy to surmount intrinsic afatinib resistance in NSCLC cells.
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synergistic killing effect of paclitaxel and honokiol in non small cell lung cancer cells through Paraptosis induction
Cellular Oncology, 2021Co-Authors: Jing Ren, Yi Wang, Yumin Zhu, Chenguo Chen, Weiguo Long, Qian JiangAbstract:Purpose Paclitaxel is an anticancer drug for the treatment of non-small cell lung cancer (NSCLC). However, drug-resistance remains a major problem. Honokiol is a natural component which has been found to exhibit anti-tumor activity. Paclitaxel and honokiol have been reported to be able to induce Paraptosis. The aim of this study was to investigate whether honokiol can reverse paclitaxel resistance by inducing Paraptosis in NSCLC cells. Methods NSCLC cell lines H1650 (paclitaxel-sensitive), H1299 and H1650/PTX (intrinsic and acquired paclitaxel-resistant, respectively) were used to assess the cytotoxic effects of paclitaxel and honokiol. Light and transmission electron microscopy were performed to detect cytoplasmic vacuolation. In vitro cell viability and clonogenic survival assays, as well as in vivo xenograft assays were conducted to test synergistic killing effects of paclitaxel and honokiol on NSCLC cells. Western blotting, flow cytometry and immunofluorescence were performed to evaluate Paraptosis-regulating mechanisms. Results We found that combination treatment with paclitaxel and honokiol synergistically killed H1650, H1299 and H1650/PTX cells by inducing Paraptosis, which is characterized by cytoplasmic vacuolation. Moreover, paclitaxel/honokiol treatment resulted in a significant growth delay in H1299 xenograft tumors that showed extensive cytoplasmic vacuolation. Mechanistically, proteasomal inhibition-mediated endoplasmic reticulum (ER) stress and unfolded protein responses leading to ER dilation, and the disruption of intracellular Ca2+ homeostasis and mitochondrial Ca2+ overload resulting in mitochondrial disfunction, were found to be involved in paclitaxel/honokiol-induced Paraptosis. Cellular protein light chain 3 (LC3) may play an important role in paclitaxel/honokiol induced cytoplasmic vacuolation and NSCLC cell death. Conclusions Combination of honokiol and paclitaxel may represent a novel strategy for the treatment of paclitaxel-resistant NSCLC.
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curcuminoid b63 induces ros mediated Paraptosis like cell death by targeting trxr1 in gastric cells
Redox biology, 2019Co-Authors: Xi Chen, Xiaoming Chen, Xi Zhang, Li Wang, Peihai Cao, Vinothkumar Rajamanickam, Huiping Zhou, Yuepiao Cai, Guang Liang, Yi WangAbstract:Gastric cancer is one of the leading causes of cancer-related deaths. Chemotherapy has improved long-term survival of patients with gastric cancer. Unfortunately, cancer readily develops resistance to apoptosis-inducing agents. New mechanisms, inducing caspase-independent Paraptosis-like cell death in cancer cells is presently emerging as a potential direction. We previously developed a curcumin analog B63 as an anti-cancer agent in pre-clinical evaluation. In the present study, we evaluated the effect and mechanism of B63 on gastric cancer cells. Our studies show that B63 targets TrxR1 protein and increases cellular reactive oxygen species (ROS) level, which results in halting gastric cancer cells and inducing caspase-independent paraptotic modes of death. The Paraptosis induced by B63 was mediated by ROS-mediated ER stress and MAPK activation. Either overexpression of TrxR1 or suppression of ROS normalized B63-induced Paraptosis in gastric cancer cells. Furthermore, B63 caused Paraptosis in 5-fluorouracil-resistant gastric cancer cells, and B63 treatment reduced the growth of gastric cancer xenografts, which was associated with increased ROS and Paraptosis. Collectively, our findings provide a novel strategy for the treatment of gastric cancer by utilizing TrxR1-mediated oxidative stress generation and subsequent cell Paraptosis.
Jiaren Liu - One of the best experts on this subject based on the ideXlab platform.
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γ tocotrienol induces Paraptosis like cell death in human colon carcinoma sw620 cells
PLOS ONE, 2013Co-Authors: Jingshu Zhang, Fengshan Wang, Shuqing Jiang, Bingqing Chen, Jiaren LiuAbstract:Colorectal cancer is one of the most serious illnesses among diagnosed cancer. As a new type of anti-cancer composition from tocotrienol-rich fraction of palm oil, γ-tocotrienol is widely used in anti-cancer research. The objectives of this study were to investigate the effects of γ-tocotrienol on human colon cancer SW620 and HCT-8 cells. We showed that treatment with different concentrations of γ-tocotrienol resulted in a dose dependent inhibition of cell growth. Cell death induced by γ-tocotrienol was mediated by a Paraptosis-like cell death in SW620 and HCT-8 cells. Real-time RT-PCR and western blot analyses showed that γ-tocotrienol inhibited the expression level of β-catenin, cyclin D1 and c-jun. These data suggest that a Paraptosis-like cell death induced by γ-tocotrienol in SW620 cells is associated with the suppression of the Wnt signaling pathway, which offers a novel tool for treating apoptosis-resistance colon cancer.
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c-Tocotrienol Induces Paraptosis-Like Cell Death in
2013Co-Authors: Human Colon, Carcinoma Sw Cells, Qing Chen, Jiaren LiuAbstract:Colorectal cancer is one of the most serious illnesses among diagnosed cancer. As a new type of anti-cancer composition from tocotrienol-rich fraction of palm oil, c-tocotrienol is widely used in anti-cancer research. The objectives of this study were to investigate the effects of c-tocotrienol on human colon cancer SW620 and HCT-8 cells. We showed that treatment with different concentrations of c-tocotrienol resulted in a dose dependent inhibition of cell growth. Cell death induced by c-tocotrienol was mediated by a Paraptosis-like cell death in SW620 and HCT-8 cells. Real-time RT-PCR and western blot analyses showed that c-tocotrienol inhibited the expression level of b-catenin, cyclin D1 and c-jun. These data suggest that a Paraptosis-like cell death induced by c-tocotrienol in SW620 cells is associated with the suppression of the Wnt signaling pathway, which offers a novel tool for treating apoptosis-resistance colon cancer
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a Paraptosis like cell death induced by δ tocotrienol in human colon carcinoma sw620 cells is associated with the suppression of the wnt signaling pathway
Toxicology, 2011Co-Authors: Jingshu Zhang, Shuqing Jiang, Bingqing Chen, Yinghua Liu, Chunhua Wang, Jiaren LiuAbstract:Tocotrienol is considered a beneficial effect agent on inhibition of tumor development. In this study, we focused on the effects of δ-tocotrienol and its possible mechanism on induction of death in human colon cancer SW620 cells. δ-Tocotrienol inhibited proliferation of SW620 cell in a dose-dependent manner. Our findings showed that δ-tocotrienol effectively induced Paraptosis-like death in SW620 cells, correlated with the vacuolation that may be from welling and fusion of mitochondria and/or the endoplasmic reticulum (ER) as well as caspase-3 nonactivated. However, there were no changes in apoptosis based on flow cytometry analysis. Of being noted, δ-tocotrienol reduced the expression of β-catenin and wnt-1 proteins by about 50% at the highest dose (20μmol/L). δ-Tocotrienol also decreased cyclin D1, c-jun and MMP-7 protein levels in SW620 cells. Altogether, these data indicate that δ-tocotrienol induces Paraptosis-like cell death, which is associated with the suppression of the Wnt signaling pathway. Thus, our findings may provide a novel application in treatment of human colon carcinoma.
Jingshu Zhang - One of the best experts on this subject based on the ideXlab platform.
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γ tocotrienol induces Paraptosis like cell death in human colon carcinoma sw620 cells
PLOS ONE, 2013Co-Authors: Jingshu Zhang, Fengshan Wang, Shuqing Jiang, Bingqing Chen, Jiaren LiuAbstract:Colorectal cancer is one of the most serious illnesses among diagnosed cancer. As a new type of anti-cancer composition from tocotrienol-rich fraction of palm oil, γ-tocotrienol is widely used in anti-cancer research. The objectives of this study were to investigate the effects of γ-tocotrienol on human colon cancer SW620 and HCT-8 cells. We showed that treatment with different concentrations of γ-tocotrienol resulted in a dose dependent inhibition of cell growth. Cell death induced by γ-tocotrienol was mediated by a Paraptosis-like cell death in SW620 and HCT-8 cells. Real-time RT-PCR and western blot analyses showed that γ-tocotrienol inhibited the expression level of β-catenin, cyclin D1 and c-jun. These data suggest that a Paraptosis-like cell death induced by γ-tocotrienol in SW620 cells is associated with the suppression of the Wnt signaling pathway, which offers a novel tool for treating apoptosis-resistance colon cancer.
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a Paraptosis like cell death induced by δ tocotrienol in human colon carcinoma sw620 cells is associated with the suppression of the wnt signaling pathway
Toxicology, 2011Co-Authors: Jingshu Zhang, Shuqing Jiang, Bingqing Chen, Yinghua Liu, Chunhua Wang, Jiaren LiuAbstract:Tocotrienol is considered a beneficial effect agent on inhibition of tumor development. In this study, we focused on the effects of δ-tocotrienol and its possible mechanism on induction of death in human colon cancer SW620 cells. δ-Tocotrienol inhibited proliferation of SW620 cell in a dose-dependent manner. Our findings showed that δ-tocotrienol effectively induced Paraptosis-like death in SW620 cells, correlated with the vacuolation that may be from welling and fusion of mitochondria and/or the endoplasmic reticulum (ER) as well as caspase-3 nonactivated. However, there were no changes in apoptosis based on flow cytometry analysis. Of being noted, δ-tocotrienol reduced the expression of β-catenin and wnt-1 proteins by about 50% at the highest dose (20μmol/L). δ-Tocotrienol also decreased cyclin D1, c-jun and MMP-7 protein levels in SW620 cells. Altogether, these data indicate that δ-tocotrienol induces Paraptosis-like cell death, which is associated with the suppression of the Wnt signaling pathway. Thus, our findings may provide a novel application in treatment of human colon carcinoma.
