Sapogenin based self-assembly structures activating a non-apoptotic cell death via multiple pathways

AbstractInduction of distinct cell death pathways is critical to deal with tumor heterogeneity and therapeutic resistance. In our previous study, we reported a promising saponin analog (AG-08) for cancer therapy inducing non-canonical necrotic cell death. Here, we describe that AG-08 forms unique supramolecular structures responsible for its biological activity. After internalization via non-canonical endocytosis pathway, these structures affect several cell signaling pathways including unfolded protein response, immune response, oxidative stress and heat stress. Moreover, we prepared 18 analogs to reveal the role of residues on the formation of supramolecular structures and biological activities. The results have demonstrated that unique structural features are required for particulate structures and unprecedented cell death mechanism. Although small molecule based supramolecular assemblies have widely been accepted as nuisance for drug discovery studies, our results indicate that they may provide a new research field for anti-cancer drug development studies.

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18β-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity

Life Sciences ◽

10.1016/j.lfs.2008.07.014 ◽

2008 ◽

Vol 83 (13-14) ◽

pp. 481-489 ◽

Cited By ~ 79

Author(s):

Chung Soo Lee ◽

Yun Jeong Kim ◽

Min Sung Lee ◽

Eun Sook Han ◽

Sun Joo Lee

Keyword(s):

Cell Death ◽

Synergistic Effect ◽

Drug Toxicity ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Glycyrrhetinic Acid ◽

Cancer Drug ◽

Siha Cells ◽

Anti Cancer

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Arsenic Trioxide-Induced Cell Death Occurs Partially Independent of the Pro-Apoptotic Bcl-2-Family Members Bax and Bak.

Blood ◽

10.1182/blood.v108.11.4585.4585 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4585-4585

Author(s):

Christian Scholz ◽

Antje Richter ◽

Anja Richter ◽

Bernd Dörken ◽

Peter T. Daniel

Keyword(s):

Cell Death ◽

Arsenic Trioxide ◽

Cell Lines ◽

Apoptotic Cell ◽

Family Members ◽

Death Receptor ◽

Hematologic Malignancies ◽

Mitochondrial Pathway ◽

Cell Death Pathways

Abstract Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed for the treatment of acute promyelocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. Investigating the mechanisms of arsenic trioxide-induced cell death, we recently demonstrated that arsenite-mediated cell demise has a partially necrotic phenotype, occurs independently of the extrinsic death receptor pathway of apoptosis, and is not hampered by the absence of functioning caspases. On the contrary, cell death proceeded entirely via an intrinsic, mitochondrial pathway and was efficiently blocked by the anti-apoptotic Bcl-2 family members Bcl-2 or Bcl-xL. Here, we address the role of the pro-apoptotic multi-domain Bcl-2 family members Bax and Bak. By employing different cell lines deficient for Bax and/or Bak, we demonstrate that Bax- or Bak-deficiency as well as the combined absence only partially blocks arsenite-induced cell death. While the detection of an additive effect of the combined Bax-/Bak-deficiency argues for a non redundant function of Bax and Bak, the persistence of a substantial percentage of arsenite-mediated cell demise in different double deficient cell lines nevertheless suggests a mode of arsenic trioxide-mediated cell death independent from these central inducers of apoptotic cell demise. The presented data add to the notion that arsenic trioxide kills tumor cells independent of the apoptotic machinery, and warrants further investigation on the efficacy of this compound in malignancies with deficiencies of the apoptotic cell death pathways.

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Regulated necrosis: the expanding network of non-apoptotic cell death pathways

Nature Reviews Molecular Cell Biology ◽

10.1038/nrm3737 ◽

2014 ◽

Vol 15 (2) ◽

pp. 135-147 ◽

Cited By ~ 843

Author(s):

Tom Vanden Berghe ◽

Andreas Linkermann ◽

Sandrine Jouan-Lanhouet ◽

Henning Walczak ◽

Peter Vandenabeele

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Cell Death Pathways ◽

Regulated Necrosis

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Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases

Molecules ◽

10.3390/molecules24091827 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1827 ◽

Cited By ~ 1

Author(s):

Khurshid Ahmad ◽

Vishal M. Balaramnavar ◽

Navaneet Chaturvedi ◽

Saif Khan ◽

Shafiul Haque ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Structural Information ◽

Apoptotic Cell ◽

Critical Role ◽

Caspase 8 ◽

Cell Death Pathways ◽

Cell Death Pathway ◽

Zinc Database ◽

Dynamics Simulations

Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.

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Identification and Characterization of the Caspase-Mediated Apoptotic Activity of Teucrium mascatense and an Isolated Compound in Human Cancer Cells

Molecules ◽

10.3390/molecules24050977 ◽

2019 ◽

Vol 24 (5) ◽

pp. 977 ◽

Cited By ~ 7

Author(s):

Neena Panicker ◽

Sameera Balhamar ◽

Shaima Akhlaq ◽

Mohammed Qureshi ◽

Tania Rizvi ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Human Cancer ◽

Annexin V ◽

Dependent Manner ◽

Human Cancer Cells ◽

Cell Death Pathways ◽

Proliferative Effect ◽

Mcf 7

Plants of the genus Teucrium (Lamiaceae or Labiatae family) are known historically for their medicinal value. Here, we identify and characterize the anticancer potential of T. mascatense and its active compound, IM60, in human cancer cells. The anti-proliferative effect of a T. mascatense methanol extract and its various fractions were analyzed in MCF-7 and HeLa cells in a dose- and time dependent manner. The dichloromethane fraction (TMDF) was observed to be the most effective with cytotoxicity against a more expanded series of cell lines, including MDA-MB-231. A time and dose-dependent toxicity profile was also observed for IM60; it could induce rapid cell death (within 3 h) in MCF-7 cells. Activation of caspases and PARP, hallmarks of apoptotic cell death pathways, following treatment with TMDF was demonstrated using western blot analysis. Inversion of the phosphatidylserine phospholipid from the inner to the outer membrane was confirmed by annexin V staining that was inhibited by the classical apoptosis inhibitor, Z-VAK-FMK. Changes in cell rounding, shrinkage, and detachment from other cells following treatment with TMDF and IM60 also supported these findings. Finally, the potential of TMDF and IM60 to induce enzymatic activity of caspases was also demonstrated in MCF-7 cells. This study, thus, not only characterizes the anticancer potential of T. mascatense, but also identifies a lead terpenoid, IM60, with the potential to activate anticancer cell death pathways in human cancer cells.

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p53: The Attractive Tumor Suppressor in the Cancer Research Field

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/603925 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 49

Author(s):

Toshinori Ozaki ◽

Akira Nakagawara

Keyword(s):

Cell Cycle ◽

Cancer Research ◽

Cell Death ◽

Tumor Suppressor ◽

Cell Cycle Arrest ◽

Apoptotic Cell ◽

Genetic Alterations ◽

Research Field ◽

Apoptotic Cell Death ◽

Cycle Arrest

p53 is one of the most studied tumor suppressors in the cancer research field. Of note, over 50% of human tumors carry loss of function mutations, and thus p53 has been considered to be a classical Knudson-type tumor suppressor. From the functional point of view, p53 is a nuclear transcription factor to transactivate a variety of its target genes implicated in the induction of cell cycle arrest, DNA repair, and apoptotic cell death. In response to cellular stresses such as DNA damage, p53 is activated and promotes cell cycle arrest followed by the replacement of DNA lesions and/or apoptotic cell death. Therefore, p53 is able to maintain the genomic integrity to prevent the accumulation of genetic alterations, and thus stands at a crossroad between cell survival and cell death. In this paper, we describe a variety of molecular mechanisms behind the regulation of p53.

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Structural Features of Galectin‐9 and Galectin‐1 that Determine Distinct T cell Death Pathways

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.808.5 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Shuguang Bi ◽

Lesley A. Earl ◽

Linsey Jacobs ◽

Linda G. Baum

Keyword(s):

Cell Death ◽

T Cell ◽

Structural Features ◽

Cell Death Pathways

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Regulated Cell Death Seen through the Lens of Islet Transplantation

Cell Transplantation ◽

10.1177/0963689718766323 ◽

2018 ◽

Vol 27 (6) ◽

pp. 890-901 ◽

Cited By ~ 9

Author(s):

Antonio Bruni ◽

Stefan Bornstein ◽

Andreas Linkermann ◽

A. M. James Shapiro

Keyword(s):

Cell Death ◽

Islet Transplantation ◽

Apoptotic Cell ◽

Glycosylated Hemoglobin ◽

Solid Organ Transplantation ◽

Apoptotic Cell Death ◽

Solid Organ ◽

Cell Death Pathways ◽

Regulated Cell Death ◽

Clinical Islet Transplantation

Clinical islet transplantation effectively restores euglycemia and corrects glycosylated hemoglobin in labile type 1 diabetes mellitus (T1DM). Despite marked improvements in islet transplantation outcomes, acute islet cell death remains a substantial obstacle that compromises long-term engraftment outcomes. Multiple organ donors are routinely required to achieve insulin independence. Therapeutic agents that ameliorate cell death and/or control injury-related inflammatory cascades offer potential to improve islet transplant success. Apoptotic cell death has been identified as a major contributor to cellular demise and therapeutic strategies that subvert initiation and consequences of apoptotic cell death have shown promise in pre-clinical models. Indeed, in numerous pathologies and diseases apoptosis has been the most extensively described form of regulated cell death. However, recent identification of novel, alternative regulated cell death pathways in other disease states and solid organ transplantation suggest that these additional pathways may also have substantial relevance in islet transplantation. These regulated, non-apoptotic cell death pathways exhibit distinct biochemical characteristics but have yet to be fully characterized within islet transplantation. We review herein the various regulated cell death pathways and highlight their relative potential contributions to islet viability, engraftment failure and islet dysfunction.

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