The "Two-Faced" Effects of Reactive Oxygen Species and the Lipid Peroxidation Product 4-Hydroxynonenal in the Hallmarks of Cancer

Pizzimenti, Stefania; Toaldo, Cristina; Pettazzoni, Piergiorgio; Dianzani, Mario U.; Barrera, Giuseppina

doi:10.3390/cancers2020338

Cited by 84 publications

(65 citation statements)

References 180 publications

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“…It is now well known that many cancer cells possess higher cellular oxidative stress with increased levels of ROS than normal cells (23,24). We have also demonstrated that ROS levels in androgen-sensitive LNCaP prostate cancer cells or androgeninsensitive DU-145 prostate cancer cells could be further modulated by selected androgen (26,27) or polyamine analogs (28, 29), respectively, as well as polyamine oxidase inhibitors (30).…”

Section: Lnm E1 (2) Showing Potent Cytotoxicity Against Prostate Cancmentioning

confidence: 64%

“…The feasibility of exploiting 2 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145, that are known to exist under higher oxidative stress than normal tissues. Because many cancer cells are under higher cellular oxidative stress with increased levels of ROS than normal cells (23,24), our results suggest a means of exploiting ROS to target cancer cells and highlight 2 as a novel lead for the development of anticancer prodrugs activated by ROS.…”

Section: Significancementioning

confidence: 88%

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Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species

Huang

Yun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Previously, we have cloned the lnm gene cluster from S. atroolivaceus S-140 and characterized the biosynthetic machinery responsible for the 18-membered lactam backbone and the alkyl branch at C3 of LNM. We now report the isolation and characterization of leinamycin E1 (LNM E1) from S. atroolivacues SB3033, a ΔlnmE mutant strain of S. atroolivaceus S-140. Complementary to the reductive activation of LNM by cellular thiols, LNM E1 can be oxidatively activated by cellular reactive oxygen species (ROS) to generate a similar episulfonium ion intermediate, thereby alkylating DNA and leading to eventual cell death. The feasibility of exploiting LNM E1 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145. Because many cancer cells are under higher cellular oxidative stress with increased levels of ROS than normal cells, these findings support the idea of exploiting ROS as a means to target cancer cells and highlight LNM E1 as a novel lead for the development of anticancer prodrugs activated by ROS. The structure of LNM E1 also reveals critical new insights into LNM biosynthesis, setting the stage to investigate sulfur incorporation, as well as the tailoring steps that convert the nascent hybrid peptide-polyketide biosynthetic intermediate into LNM.cancer targeting | drug discovery | natural product | pathway engineering | sulfur metabolism

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Section: Lnm E1 (2) Showing Potent Cytotoxicity Against Prostate Cancmentioning

confidence: 64%

Section: Significancementioning

confidence: 88%

Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species

Huang

Yun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In the membranes of cells, ROS target polyunsaturated fatty acids and initiate lipid peroxidation. Malonaldehyde (MDA) is a major end product from the peroxidation of lipid membranes and used for the assessment of damage by ROS (Pizzimenti et al 2010;Siddique et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells

2014

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Hyperglycemia plays an important role in the development of diabetic neuropathy. In this study, we investigated the protective effects of alpha lipoic acid (ALA) against high glucose-induced neurotoxicity in PC12 cells as a suitable in vitro model for studying neuronal functions. PC12 cells were treated with high glucose (25 mg/ml for 24 h) in the absence and presence of ALA (100 μM for 24 h). The viability of PC12 cells was estimated by using MTT assay. The expression of pro- apoptotic Bax, anti- apoptotic Bcl-2 and caspase 3 protein were evaluated by western blotting. The reactive oxygen species (ROS) levels were determined with 2,7-dichlorodihydro- fluorescein diacetate (H2DCFDA). Biochemical markers of oxidative stress were assessed by using the total antioxidant power (TAP), lipid peroxidation (LPO), ADP/ATP ratio, activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Pretreatment of PC12 cells with ALA, significantly improved high glucose-induced toxicity by increasing activity of antioxidant enzymes CAT and SOD in the PC12 cell. It also increased the concentrations of TAP. An elevated level of cell death and ROS in high glucose conditions, diminished with ALA treatment. Over expression of Bax and caspase 3 protein, elevation of ADP/ATP ratio and LPO level in high glucose- treated PC12 cells, were significantly reduced by ALA. It was concluded that ALA attenuates neurotoxicity induced by high glucose in PC12 cells.

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“…Among the products of LPO, 4-hydroxy-2-alkenals represent the most biologically active alkenals and aldehydes, that, due to their prolonged half-lives and their ability to diffuse from their sites of formation, have been considered as second messengers of oxidative stress (14). The peroxidation of n-3 polyunsaturated fatty acids (α-linolenic acid and docosahexaenoic acid) generates 4-hydroxy-hexenal (HHE), which is a mediator of the mitochondrial permeability transition (99), while the peroxidation of n-6 polyunsaturated fatty acids, such as linoleic acid and arachidonic acid, generates 4-hydroxy-2-nonenal (HNE), which is the most intensively studied aldehyde (15,154), because it is highly electrophilic and easily reacts with low-molecular-weight compounds, such as glutathione (GSH), with proteins and, at higher concentrations, with DNA (57,204). The mechanism of HNE formation during peroxidation of arachidonic acid is reported in Fig.…”

Section: Introductionmentioning

confidence: 99%

Role of 4-Hydroxynonenal-Protein Adducts in Human Diseases

Barrera

Pizzimenti

Ciamporcero

et al. 2015

Antioxidants & Redox Signaling

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107

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However, in some cases, the generation of HNE-protein adducts can represent a contrast to the progression of disease or can promote adaptive cell responses, demonstrating that HNE is not only a toxic product of lipid peroxidation, but also a regulatory molecule, involved in several biochemical pathways.Future directions. In the coming years, the refinement of proteomical techniques, allowing the individuation of novel cellular targets of HNE, will lead to a better understanding the role of HNE in human diseases.

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The "Two-Faced" Effects of Reactive Oxygen Species and the Lipid Peroxidation Product 4-Hydroxynonenal in the Hallmarks of Cancer

Cited by 84 publications

References 180 publications

Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species

Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells

Role of 4-Hydroxynonenal-Protein Adducts in Human Diseases

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