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Prohibitin (PHB) is a pleiotropic molecule with a variety of known functions and subcellular locations. PHB's function in breast cancer is poorly understood. Herein, we report that PHB is expressed in cancer types of diverse origin including breast cancer. The cancer patients with changes in PHB were reported to have significantly reduced 'overall survival' in comparison to the cases without alterations in PHB. The expression of PHB was increased by H 2 O 2 and also by Moringin (MG), which is an isothiocyanate derived from the seeds of Moringa oleifera. MG interacted with PHB, DRP1, and SLP2 and inhibited the growth of MCF-7 and MDAMB-231 cells. The isothiocyanate triggered apoptosis in breast cancer cells as revealed by AO/PI assay, phosphatidylserine externalization, cell cycle analysis and DAPI staining. MG induced proapoptotic proteins expression such as cytochrome c, p53, and cleaved caspase-7. Further, cell survival proteins such as survivin, Bcl-2, and Bcl-xL were suppressed. A depolarization of membrane potential suggested that the apoptosis was triggered through mitochondria. The isothiocyanate suppressed the cancer cell migration and interacted with NF-κB subunits. MG suppressed p65 nuclear translocation induced by TNF-α. The reactive oxygen species generation was also induced by the isothiocyanate in breast cancer cells. MG also modulated the expression of lncRNAs. Collectively, the functions of PHB in breast cancer growth is evident from this study. The activities of MG against breast cancer might result from its ability to modulate multiple cancer-related targets., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Although over 100 species of Curcuma are reported, only Curcuma longa is extensively studied. Curcuma raktakanda , a poorly studied species, is most commonly distributed in the Kerala state of India. For the first time, we examined the efficacy of different fractions (acetone, hexane, and ethyl acetate) of C. raktakanda against glioma, cervical, and breast cancer cell lines. As determined by mitochondrial reductase activity assay, the viability of cancer cells was decreased in a concentration-dependent manner by the three fractions. The half maximal inhibitory concentration (IC-50) values after the treatment of C-6 glioma cells for 48 h was found to be 32.97 µg/mL (acetone extract), 40.63 µg/mL (hexane extract), and 51.65 µg/mL (ethyl acetate extract). Of the three fractions, the acetone fraction was more effective. The long-term colony formation of cancer cells was significantly suppressed by the acetone fraction. Analyses using DAPI (4',6-diamidino-2-phenylindole) staining, AO/PI (acridine orange/propidium iodide) staining, DNA laddering, and sub-G1 population revealed that the acetone extract induced apoptosis in glioma cells. The extract induced reactive oxygen species generation and suppressed the expression of cell survival proteins. The migration of cancer cells was also suppressed by the acetone extract. The gas chromatography-mass spectrometry (GC-MS) analysis indicated that tetracontane, dotriacontane, hexatriacontane, pentacosane, hexacosane, and eicosane are the major components in the acetone extract. Collectively, the extract from C. raktakanda exhibited anti-carcinogenic activities in cancer cells. We are exploring whether the phytoconstituents, individually, or collectively contribute to the anti-cancer activities of C. raktakanda ., Competing Interests: The authors declare no conflict of interest.

Aim: TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), is a selective killer of tumor cells, although its potential is limited by the development of resistance. In this article, we investigated whether the polyherbal preparation Zyflamend(®) can sensitize tumor cells to TRAIL., Results: We found that Zyflamend potentiated TRAIL-induced apoptosis in human cancer cells. Zyflamend manifested its effects through several mechanisms. First, it down-regulated the expression of cell survival proteins known to be linked to resistance to TRAIL. Second, Zyflamend up-regulated the expression of pro-apoptotic protein, Bax. Third, Zyflamend up-regulated the expression of death receptors (DRs) for TRAIL. Up-regulation of DRs was critical as gene-silencing of these receptors significantly reduced the effect of Zyflamend on TRAIL-induced apoptosis. The up-regulation of DRs was dependent on CCAAT/enhancer-binding protein-homologous protein (CHOP), as Zyflamend induced CHOP, its gene-silencing abolished the induction of receptors, and mutation of the CHOP binding site on DR5 promoter abolished Zyflamend-mediated DR5 transactivation. Zyflamend mediated its effects through reactive oxygen species (ROS), as ROS quenching reduced its effect. Further, Zyflamend induced DR5 and CHOP and down-regulated the expression of cell survival proteins in nude mice bearing human pancreatic cancer cells., Innovation: Zyflamend can sensitize tumor cells to TRAIL through modulation of multiple cell signaling mechanisms that are linked to ROS., Conclusion: Zyflamend potentiates TRAIL-induced apoptosis through the ROS-CHOP-mediated up-regulation of DRs, increase in pro-apoptotic protein and down-regulation of cell survival proteins.

Cholangiocarcinoma (CCA) is a tumor with poor prognosis that is resistant to all currently available treatments. Whether curcumin, a nutraceutical derived from turmeric (Curcuma longa), has potential therapeutic activity against human CCA was investigated using three CCA cell lines (KKU100, KKU-M156 and KKU-M213). Examination of mitochondrial dehydrogenase activity, phosphatidylserine externalization, esterase staining, caspase activation and poly-adenosine diphosphate ribose polymerase cleavage demonstrated that curcumin inhibited proliferation of and induced apoptosis in these biliary cancer cells. Colony-formation assay confirmed the growth-inhibitory effect of curcumin on CCA cells. When examined for the mechanism, curcumin was found to activate multiple cell signaling pathways in these cells. First, all CCA cells exhibited constitutively active nuclear factor (NF)-κB, and treatment with curcumin abolished this activation as indicated by DNA binding, nuclear translocation and p65 phosphorylation. Second, curcumin suppressed activation of signal transducer and activator of transcription-3 as indicated by decreased phosphorylation at both tyrosine(705) and serine(727) and inhibition of janus kinase-1 phosphorylation. Third, curcumin induced expression of peroxisome proliferator-activated receptor gamma. Fourth, curcumin upregulated death receptors, DR4 and DR5. Fifth, curcumin suppressed the Akt activation pathway. Sixth, curcumin inhibited expression of cell survival proteins such as B-cell lymphoma-2, B-cell leukemia protein xL, X-linked inhibitor of apoptosis protein, c-FLIP, cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2 and survivin and proteins linked to cell proliferation, such as cyclin D1 and c-Myc. Seventh, the growth inhibitory effect of curcumin was enhanced in the IκB kinase-deficient cells, the enzyme required for nuclear factor-kappaB activation. Overall, our results indicate that curcumin mediates its antiproliferative and apoptotic effects through activation of multiple cell signaling pathways, and thus, its activity against CCA should be further investigated.

The present study investigated the apoptosis and DNA damage inducing potential of chlorpyrifos (CP) in Drosophila melanogaster. Third instar larvae of Drosophila were treated with different concentrations of CP (0.015-15.0 microg/L) for 2-48 h. Reactive oxygen species (ROS) generation, oxidative stress markers, DNA damage and apoptotic cell death end points were measured in them. A significant increase in DNA damage was concomitant with apoptotic mode of cell death in 15.0 microg/L CP-treated organisms for 24 and 48 h. Depolarization in mitochondrial membrane potential and increased casapase-3 and caspase-9 activities in these organisms indicated both as potential targets of CP. A significant positive correlation was observed among ROS generation, apoptosis and DNA damage. The study suggests that (i) ROS may be involved in inducing apoptosis and DNA damage in the CP-exposed larvae of Drosophila and (ii) D. melanogaster may be used as an alternative in vivo animal model for xenobiotics hazard assessment., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Leachate is a complex chemical mixture of chemicals produced as a result of leaching of solid wastes. The potential toxicity of leachates is a major environmental health concern. The present study evaluated the role of ROS in tannery leachates induced Hsp70 expression, antioxidant enzymes and apoptosis in Drosophila. Different concentrations (0.05-2.0%) of leachates prepared from tannery waste at different pH (7.00, 4.93 and 2.88) were mixed with Drosophila food and fed to the larvae for 2-48 h to examine the different stress and apoptotic markers. A concentration- and time-dependent significant increase in Hsp70 expression, ROS generation, antioxidant enzymes activities and MDA content were observed in the exposed larvae. Activities of antioxidant enzymes were delayed compared with Hsp70 expression and MDA level in the exposed organisms. Apoptotic cell death was observed in the exposed larvae at higher concentrations concurrent with a significant regression in Hsp70 along with a higher level of ROS generation. A positive correlation drawn between ROS generation and apoptotic markers and a negative correlation between apoptotic markers and Hsp70 expression at these concentrations indicated the important role of ROS in the induction of cellular damage in the exposed organisms. There was a significant generation of ROS in the larvae exposed to 0.5% of leachates which did not interfere with the protection of their cells by Hsp70 and antioxidant enzymes. However, generation of significantly higher levels of ROS in the larvae exposed to 1.0% and 2.0% leachates may decrease Hsp70 expression thus leading to mitochondria-mediated caspase-dependent apoptotic cell death., (Copyright 2008 John Wiley & Sons, Ltd.)

The study was aimed to investigate the effect of leachates of solid waste from a flashlight battery factory and a pigment plant on 70 kDa heat shock protein (Hsp70) expression, generation of reactive oxygen species (ROS), antioxidant enzymes activities and apoptosis in Drosophila. Third instar larvae of Drosophila melanogaster transgenic for hsp70 (hsp70-lacZ) were fed on diet mixed with leachates of solid wastes (0.05-2.0%, v/v) released from two industrial plants at three different pHs (7.00, 4.93 and 2.88) for 2-48 h. A concentration- and time-dependent significant change in Hsp70 expression, ROS generation, antioxidant enzymes activities and MDA content was observed in the exposed larvae preceding the antioxidant enzymes activities. Mitochondria-mediated, caspase-dependent apoptotic cell death in the larvae exposed to 1.0 and 2.0% leachates of flashlight battery factory was concurrent with a significant regression in Hsp70 expression and a higher ROS generation. A positive correlation drawn between ROS generation and apoptotic markers and a negative correlation between apoptotic markers and Hsp70 expression in these groups indicated the important role of ROS in the leachate-induced cellular damage. Hsp70 along with antioxidant enzymes offered protection to the organisms exposed to all the tested concentrations of the leachates of pigment plant waste and 0.5% leachate of flashlight battery factory in a cooperative manner when ROS generation was less induced. Conversely, higher levels of ROS generation in the organisms treated with 1.0 and 2.0% leachate of flashlight battery factory after 24 and 48 h resulted in regression of Hsp70 expression in them leading to cell death. The study suggests that (1) leachates of flashlight battery factory waste more adversely affected the organisms in comparison to the leachates of pigment plant waste. (2) Hsp70 may be used as a biomarker of cellular damage in organisms exposed to leachates. (3) Cell based assays using D. melanogaster as an in vivo model may provide important mechanistic information about the adverse effect of xenobiotics.

In recent years, triple‐negative breast cancer (TNBC) has emerged as the most aggressive subtype of breast cancer and is usually associated with increased mortality worldwide. The severity of TNBC is primarily observed in younger women, with cases ranging from approximately 12%–24% of all breast cancer cases. The existing hormonal therapies offer limited clinical solutions in completely circumventing the TNBC, with chemoresistance and tumor recurrences being the common hurdles in the path of TNBC treatment. Accumulating evidence has correlated the dysregulation of long noncoding RNAs (lncRNAs) with increased cell proliferation, invasion, migration, tumor growth, chemoresistance, and decreased apoptosis in TNBC. Various clinical studies have revealed that aberrant expression of lncRNAs in TNBC tissues is associated with poor prognosis, lower overall survival, and disease‐free survival. Due to these specific characteristics, lncRNAs have emerged as novel diagnostic and prognostic biomarkers for TNBC treatment. However, the underlying mechanism through which lncRNAs perform their actions remains unclear, and extensive research is being carried out to reveal it. Therefore, understanding of mechanisms regulating the modulation of lncRNAs will be a substantial breakthrough in effective treatment therapies for TNBC. This review highlights the association of several lncRNAs in TNBC progression and treatment, along with their possible functions and mechanisms. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide and even develops resistance to chemotherapeutic agents over time. As a result survival for patients with CRC remains poor.Method: We investigated both in vitro and in vivo effects of γ-tocotrienol (γ-T3) alone and in combination with capecitabine. Apoptosis and cytotoxicity assays were performed by MTT and FACS analysis, whereas expression of proteins was investigated using western blotting and immunohistochemistry.Results: The γ-T3 inhibited the proliferation of CRC cells with wild-type or mutated KRAS. It also induced apoptosis, inhibited colony formation, and suppressed key regulators of cell survival, cell proliferation, invasion, angiogenesis, and metastasis. Furthermore, γ-T3 enhanced the anticancer effects of capecitabine in CRC cells. In a nude mouse xenograft model of human CRC, oral administration of γ-T3 inhibited tumour growth and enhanced the antitumour efficacy of capecitabine. Western blot and immunohistochemical analysis results indicated that expression of Ki-67, cyclin D1, MMP-9, CXCR4, NF-κB/p65, and VEGF was lower in tumour tissue from the combination treatment group. Combination treatment also downregulated NF-κB and NF-κB-regulated gene products.Conclusions: Our findings suggest that γ-T3 inhibited the growth of human CRC and sensitised CRC to capecitabine by regulating proteins linked to tumourigenesis. [ABSTRACT FROM AUTHOR]

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown efficacy in a phase 2 clinical trial, development of resistance to TRAIL by tumor cells is a major roadblock. We investigated whether azadirone, a limonoidal tetranortriterpene, can sensitize human tumor cells to TRAIL. Results indicate that azadirone sensitized cancer cells to TRAIL. The limonoid induced expression of death receptor (DR) 5 and DR4 but did not affect expression of decoy receptors in cancer cells. The induction of DRs was mediated through activation of ERK and through up-regulation of a transcription factor CCAAT enhancer-binding protein homologous protein (CHOP) as silencing of these signaling molecules abrogated the effect of azadirone. These effects of azadirone were cancer cell-specific. The CHOP binding site on the DR5 gene was required for induction of DR5 by azadirone. Up-regulation of D Rs was mediated through the generation of reactive oxygen species (ROS) as ROS scavengers reduced the effect of azadirone on ERK activation, CHOP up-regulation, DR induction, and TRAIL sensitization. The induction of DRs by this limonoid was independent of p53, but sensitization to TRAIL was p53-dependent. The limonoid down-regulated the expression of cell survival proteins and up-regulated the proapoptotic proteins. The combination of azadirone with TRAIL was found to be additive at concentrations lower than IC50, whereas at higher concentrations, the combination was synergistic. Overall, this study indicates that azadirone can sensitize cancer cells to TRAIL through ROS-ERK-CHOP-mediated up-regulation of DR5 and DR4 signaling, down-regulation of cell survival proteins, and up-regulation of proapoptotic proteins. [ABSTRACT FROM AUTHOR]

Abstract: The major goal of cancer drug discovery is to find an agent that is safe and affordable, yet effective against cancer. Here we show that morin (3,5,7,2′,4′-pentahydroxyflavone) has potential against cancer cells through suppression of the signal transducer and activator of transcription 3 (STAT3) pathway, which is closely linked to the transformation, survival, proliferation, and metastasis of cancer. We found that morin completely suppressed inducible and constitutively activated STAT3 and blocked the nuclear translocation of STAT3 and its DNA binding in multiple myeloma and head and neck squamous carcinoma cells. Morin inhibited activated Src, JAK-1, and JAK-2, all of which are linked to STAT3 activation, while up-regulating a protein inhibitor of activated STAT3, PIAS3. Pervanadate reversed the effects of morin on STAT3 phosphorylation, indicating the role of a protein tyrosine phosphatase. Furthermore, morin induced SHP1 expression at both the mRNA and protein levels, and silencing of SHP1 abrogated the effect of morin on STAT3 phosphorylation, indicating that morin mediates its effects on STAT3 through SHP1. Suppression of STAT3 correlated with the down-regulation of various gene products linked to tumor survival, proliferation, and angiogenesis and led to sensitization of tumor cells to thalidomide and bortezomib. Comparing the activities of morin with those of four structurally related flavonols demonstrated the importance of hydroxyl groups in the B ring in inhibiting STAT3 activation. These findings suggest that morin suppresses the STAT3 pathway, leading to the down-regulation of STAT3-dependent gene expression and chemosensitization of tumor cells. [Copyright &y& Elsevier]

Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and co-workers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF super-family members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the Insights gained regarding the roles of this molecule and its related family members in normal physiology and disease. [ABSTRACT FROM AUTHOR]

TNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G1 fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer cells. Gene silencing of the receptors reduced the effect of limonoid on TRAIL-induced apoptosis. Using pharmacological inhibitors, we found that activation of ERK and p38 MAPK was required for DR up-regulation by nimbolide. Gene silencing of ERK abolished the enhancement of TRAIL-induced apoptosis. Moreover, our studies indicate that the limonoid induced reactive oxygen species production, which was required for ERK activation, up-regulation of DRs, and sensitization to TRAIL; these effects were mimicked by H2O2. In addition, nimbolide down-regulated cell survival proteins, including I-FLICE, cIAP-1, cIAP-2, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis protein, and up-regulated the pro-apoptotic proteins p53 and Bax. Interestingly, p53 and Bax up-regulation by nimbolide was required for sensitization to TRAIL but not for DR up-regulation. Overall, our results indicate that nimbolide can sensitize colon cancer cells to TRAIL-induced apoptosis through three distinct mechanisms: reactive oxygen species- and ERK-mediated up-regulation of DR5 and DR4, down-regulation of cell survival proteins, and up-regulation of p53 and Bax. [ABSTRACT FROM AUTHOR]

Because tumors develop resistance to chemotherapeutic agents, the cancer research community continues to search for effective chemosensitizers. One promising possibility is to use dietary agents that sensitize tumors to the chemotherapeutics. In this review, we discuss that the use of resveratrol can sensitize tumor cells to chemotherapeutic agents. The tumors shown to be sensitized by resveratrol include lung carcinoma, acute myeloid leukemia, promyelocytic leukemia, multiple myeloma, prostate cancer, oral epidermoid carcinoma, and pancreatic cancer. The chemotherapeutic agents include vincristine, adriamycin, paclitaxel, doxorubicin, cisplatin, gefitinib, 5-fluorouracil, velcade, and gemcitabine. The chemosensitization of tumor cells by resveratrol appears to be mediated through its ability to modulate multiple cell-signaling molecules, including drug transporters, cell survival proteins, cell proliferative proteins, and members of the NF-κB and STAT3 signaling pathways. Interestingly, this nutraceutical has also been reported to suppress apoptosis induced by paclitaxel, vincristine, and daunorubicin in some tumor cells. The potential mechanisms underlying this dual effect are discussed. Overall, studies suggest that resveratrol can be used to sensitize tumors to standard cancer chemotherapeutics. [ABSTRACT FROM AUTHOR]

Reverse pharmacology, also called the "bedside to bench" approach, that deals with new uses for a well known molecular entity has been used extensively in cancer drug development to identify novel compounds and delineate their mechanisms of action. Here, we show that nimbolide, a triterpenoid isolated from Azadirachta indica, enhanced the apoptosis induced by inflammatory cytokines and chemotherapeutic agents in tumor cells. This limonoid abrogated the expression of proteins associated with cell survival (Bcl-2, Bcl-xL, IAP-1, and IAP-2), proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF), all regulated by nuclear factor (NF)-κB. Nimbolide inhibited the activation of NF-κB induced by carcinogens and inflammatory stimuli. Constitutively active NF-κB found in most tumor cells was also inhibited. We found that suppression of NF-κB activation by nimbolide was caused by inhibition of IκB kinase (IKK), which led to suppression of I?Ba phosphorylation and degradation, nuclear translocation, DNA binding, and gene transcription. Reducing agent reversed the action of the limonoid, suggesting the involvement of a cysteine residue. Replacement of Cys179 of IKK-β with alanine abolished the effect of nimbolide, suggesting that Cys179 plays a critical role in inhibiting the NF-κB activation. Overall, our results indicate that nimbolide can sensitize tumor cells to chemotherapeutic agents through interaction with IKK, leading to inhibition of NF-κB-regulated proteins. [ABSTRACT FROM AUTHOR]

The sesquiterpene lactones, Isodeoxyelephantopin (IDET) and Deoxyelephantopin (DET) are known to exhibit activities against some cancer types. The activities of these lactones against breast cancer and the molecular bases is not known. We examined the efficacy of lactones in breast cancer preclinical model. Although both lactones exhibited drug like properties, IDET was relatively effective in comparison to DET. IDET suppressed the proliferation of both invasive and non-invasive breast cancer cell lines. IDET also suppressed the colony formation and migration of breast cancer cells. The assays for Acridine Orange (AO)/Propidium Iodide (PI) staining, cell cycle distribution, phosphatidylserine externalization and DNA laddering suggested the apoptosis inducing potential of IDET. The treatment with IDET also induced an accumulation of cells in the sub-G1 and G2/M phases. The exposure of breast cancer cells to the lactone was associated with a depolarization in mitochondrial membrane potential, and cleavage of caspase and PARP. The lactone induced reactive oxygen species (ROS) generation in breast cancer cells. Further, the use of N-acetyl cysteine (NAC) suppressed IDET induced ROS generation and apoptosis. The NF-κB-p65 nuclear translocation induced by okadaic acid (OA) was suppressed by the sesquiterpene. IDET also suppressed the expression of NF-κB regulated tumorigenic proteins, and induced the expression of proapoptotic gene (Bax) in cancer cells. While the expression of oncogenic lncRNAs was suppressed, the tumor suppressor lncRNAs were induced by the sesquiterpene. Collectively, the modulation of multiple cell signaling molecules by IDET may contribute to its activities in breast cancer cells. [ABSTRACT FROM AUTHOR]

Selective killing of cancer cells is one of the major goals of cancer therapy. Although chemotherapeutic agents are being used for cancer treatment, they lack selectivity toward tumor cells. Among the six different death receptors (DRs) identified to date, DR4 and DR5 are selectively expressed on cancer cells. Therefore, unlike chemotherapeutic agents, these receptors can potentially mediate selective killing of tumor cells. In this review we outline various nutraceuticals derived from ‘Mother Nature’ that can upregulate DRs and thus potentiate apoptosis. These nutraceuticals increase tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of cancer cells through different mechanisms. First, nutraceuticals have been found to induce DRs through the upregulation of various signaling molecules. Second, nutraceuticals can downregulate tumor cell-survival pathways. Third, nutraceuticals alone have been found to activate cell-death pathways. Although both TRAIL and agonistic antibodies against DR4 and DR5 are in clinical trials, combination with nutraceuticals is likely to boost their anticancer potential. [ABSTRACT FROM AUTHOR]