The phytoalexin camalexin mediates cytotoxicity towards aggressive prostate cancer cells via reactive oxygen species

Smith, Basil A.; Neal, Corey L.; Chetram, Mahandranauth A.; Vo, BaoHan T.; Mezencev, Roman; Hinton, Cimona V.; Odero-Marah, Valerie

doi:10.1007/s11418-012-0722-3

Cited by 21 publications

(13 citation statements)

References 45 publications

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“…Our laboratory has shown that camalexin induced apoptosis in prostate cancer cells (PCa) through the generation of Reactive Oxygen Species (ROS), and that the more aggressive prostate cancer cells with higher levels of endogenous ROS displayed greater sensitivity to camalexin treatments evidenced by decreased viability and increased apoptosis as compared to the less aggressive prostate cancer cells, while normal epithelial cells were unaffected [ 9 ]. The generation of intracellular ROS activates several signal transduction pathways leading to inflammation, cell cycle progression, apoptosis, migration, and invasion in cancer [ 10 ]. Thus, excessive production of ROS or inadequacy in a cell’s antioxidant defense system (or both) induces oxidative stress with consequent initiation of cellular processes associated with initiation and development of many cancers including prostate cancer [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Camalexin-Induced Apoptosis in Prostate Cancer Cells Involves Alterations of Expression and Activity of Lysosomal Protease Cathepsin D

et al. 2014

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Camalexin, the phytoalexin produced in the model plant Arabidopsis thaliana, possesses antiproliferative and cancer chemopreventive effects. We have demonstrated that the cytostatic/cytotoxic effects of camalexin on several prostate cancer (PCa) cells are due to oxidative stress. Lysosomes are vulnerable organelles to Reactive Oxygen Species (ROS)-induced injuries, with the potential to initiate and or facilitate apoptosis subsequent to release of proteases such as cathepsin D (CD) into the cytosol. We therefore hypothesized that camalexin reduces cell viability in PCa cells via alterations in expression and activity of CD. Cell viability was evaluated by MTS cell proliferation assay in LNCaP and ARCaP Epithelial (E) cells, and their respective aggressive sublines C4-2 and ARCaP Mesenchymal (M) cells, whereby the more aggressive PCa cells (C4-2 and ARCaPM) displayed greater sensitivity to camalexin treatments than the lesser aggressive cells (LNCaP and ARCaPE). Immunocytochemical analysis revealed CD relocalization from the lysosome to the cytosol subsequent to camalexin treatments, which was associated with increased protein expression of mature CD; p53, a transcriptional activator of CD; BAX, a downstream effector of CD, and cleaved PARP, a hallmark for apoptosis. Therefore, camalexin reduces cell viability via CD and may present as a novel therapeutic agent for treatment of metastatic prostate cancer cells.

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Section: Introductionmentioning

confidence: 99%

Camalexin-Induced Apoptosis in Prostate Cancer Cells Involves Alterations of Expression and Activity of Lysosomal Protease Cathepsin D

et al. 2014

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“…Multiple agents such as artesunate, NPI-0052, and plumbagin showed toxicity against leukemia cells which are relied on its ability to generate ROS [ 24 – 26 ]. According to previous studies, camalexin could induce ROS in prostate cancer and leukemia cells [ 6 , 7 ]. Interestingly, camalexin was found unable to induce ROS in erythrocytes in a recent study [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Camalexin has been extensively studied for its role in plant chemical defense mechanisms and has been shown to exert cytotoxic against human protozoan pathogen, Trypanosoma cruzi [ 5 ]. Camalexin also exhibits antitumor effects against prostate cancer and leukemia cells [ 6 , 7 ]. However, the underling mechanisms of the antitumor activities of camalexin are still elusive.…”

Section: Introductionmentioning

confidence: 99%

Camalexin Induces Apoptosis via the ROS‐ER Stress‐Mitochondrial Apoptosis Pathway in AML Cells

Yang

Wang

et al. 2018

Oxidative Medicine and Cellular Longevity

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Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. It was shown that camalexin has potent antitumor properties, but its underlying mechanisms are still elusive. In the present study, we evaluated the effects of camalexin on human leukemic cells and normal polymorph nuclear cells. CCK-8 assay was used to determine cell viability after camalexin treatment. Apoptosis, intracellular reactive oxygen species (ROS) levels, and loss of mitochondrial membrane potential (MMP) were measured by flow cytometry. The activity of SOD, catalase, and ratio of GSH/GSSG were assayed. ER stress and apoptotic signaling pathway was examined by Western blot. Xenograft mice were used to verify the effect of camalexin in vivo. Our results indicated that camalexin inhibited viability of leukemic but not normal polymorph nuclear cells. Furthermore, camalexin induces apoptosis via the mitochondrial pathway in a caspase-dependent manner. We also observed ER stress is located upstream of apoptosis induced by camalexin. Besides, ROS levels, SOD activity, CAT activity, and GSSG levels were significantly enhanced while the GSH level was decreased after treatment of camalexin. In addition, the generation of ROS is critical for the ER stress and apoptosis induced by camalexin. Finally, administration of camalexin suppresses xenograft tumor graft growth without obvious toxicity. Taken together, this study indicates that camalexin exerts antitumor effects against leukemia cells via the ROS-ER stress-mitochondrial apoptosis pathway.

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“…In addition to bacterial pathways, some eukaryotic pathways were also reconstituted in vitro . The biosynthetic pathways of dhurrin, which plays an important role in plant defense against pathogens [35] , and camalexin, which is cytotoxic against aggressive prostate cancer cell lines [36] , have been studied in cell-free synthetic enzyme system. Kahn and colleagues reconstituted the entire dhurrin biosynthetic pathway in vitro using enzymes from the natural host organism [37] .…”

Section: Cell-free Synthetic Enzyme Engineeringmentioning

confidence: 99%

Mini-review: In vitro Metabolic Engineering for Biomanufacturing of High-value Products

Guo

Sheng

Feng

2017

Computational and Structural Biotechnology Journal

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With the breakthroughs in biomolecular engineering and synthetic biology, many valuable biologically active compound and commodity chemicals have been successfully manufactured using cell-based approaches in the past decade. However, because of the high complexity of cell metabolism, the identification and optimization of rate-limiting metabolic pathways for improving the product yield is often difficult, which represents a significant and unavoidable barrier of traditional in vivo metabolic engineering. Recently, some in vitro engineering approaches were proposed as alternative strategies to solve this problem. In brief, by reconstituting a biosynthetic pathway in a cell-free environment with the supplement of cofactors and substrates, the performance of each biosynthetic pathway could be evaluated and optimized systematically. Several value-added products, including chemicals, nutraceuticals, and drug precursors, have been biosynthesized as proof-of-concept demonstrations of in vitro metabolic engineering. This mini-review summarizes the recent progresses on the emerging topic of in vitro metabolic engineering and comments on the potential application of cell-free technology to speed up the “design-build-test” cycles of biomanufacturing.

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The phytoalexin camalexin mediates cytotoxicity towards aggressive prostate cancer cells via reactive oxygen species

Cited by 21 publications

References 45 publications

Camalexin-Induced Apoptosis in Prostate Cancer Cells Involves Alterations of Expression and Activity of Lysosomal Protease Cathepsin D

Camalexin-Induced Apoptosis in Prostate Cancer Cells Involves Alterations of Expression and Activity of Lysosomal Protease Cathepsin D

Camalexin Induces Apoptosis via the ROS‐ER Stress‐Mitochondrial Apoptosis Pathway in AML Cells

Mini-review: In vitro Metabolic Engineering for Biomanufacturing of High-value Products

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