The terms 'antioxidant', 'oxidative stress' and 'oxidative damage' are widely used but rarely defined. This brief review attempts to define them and to examine the ways in which oxidative stress and oxidative damage can affect cell behaviour both in vivo and in cell culture, using cancer as an example.

Biochemistry of oxidative stress

Silymarin (SM), an extract from the Silybum marianum (milk thistle) plant containing various flavonolignans (with silybin being the major one), has received a tremendous amount of attention over the last decade as a herbal remedy for liver treatment. In many cases, the antioxidant properties of SM are considered to be responsible for its protective actions. Possible antioxidant mechanisms of SM are evaluated in this review. (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut. (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance. (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation is probably the main driving force of antioxidant (AO) action of SM. (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases. (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins and providing additional protection in stress conditions deserves more attention. (6) Affecting the microenvironment of the gut, including SM-bacteria interactions, awaits future investigations. (7) In animal nutrition and disease prevention strategy, SM alone, or in combination with other hepatho-active compounds (carnitine, betaine, vitamin B12, etc.), might have similar hepatoprotective effects as described in human nutrition.

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Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

The present work reports a simple, cost-effective, and ecofriendly method for the synthesis of silver nanoparticles (AgNPs) using Chrysanthemum indicum and its antibacterial and cytotoxic effects. The formation of AgNPs was confirmed by color change, and it was further characterized by ultraviolet-visible spectroscopy (435 nm). The phytochemical screening of C. indicum revealed the presence of flavonoids, terpenoids, and glycosides, suggesting that these compounds act as reducing and stabilizing agents. The crystalline nature of the synthesized particles was confirmed by X-ray diffraction, as they exhibited face-centered cubic symmetry. The size and morphology of the particles were characterized by transmission electron microscopy, which showed spherical shapes and sizes that ranged between 37.71-71.99 nm. Energy-dispersive X-ray spectroscopy documented the presence of silver. The antimicrobial effect of the synthesized AgNPs revealed a significant effect against the bacteria Klebsiella pneumonia, Escherichia coli, and Pseudomonas aeruginosa. Additionally, cytotoxic assays showed no toxicity of AgNPs toward 3T3 mouse embryo fibroblast cells (25 μg/mL); hence, these particles were safe to use.

https://www.dovepress.com/getfile.php?fileID=18621

Rapid green synthesis of silver nanoparticles from Chrysanthemum indicum L and its antibacterial and cytotoxic effects: an in vitro study.

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%-35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

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Natural products: potential treatments for cisplatin-induced nephrotoxicity.

Drug-induced nephrotoxicity (DIN) accounts for up to sixty percent of hospital acquired acute kidney injury. Several efforts have been made to reduce drug-induced renal damage; however, DIN remains a matter of concern, with substantial impact on patients and the health system. Silymarin is a drug that has been used for many years in alternate and modern medicine for treating hepatic diseases. Its antioxidant, anti-inflammatory and anti-apoptotic effects make it an interesting herbal medicine, and these properties have implicated this compound as a potential renoprotective agent. Based on the findings from animal studies, this review concluded that silymarin might exert significant protective or ameliorative effects against drug-induced kidney disease, especially against cisplatin-induced renal damage. Whether the protective administration of silymarin could be an effective clinical pharmacological strategy to prevent DIN is a question that remains to be answered in clinical trials.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Potential renoprotective effects of silymarin against nephrotoxic drugs: a review of literature.

Context: Cisplatin-induced nephrotoxicity has been accepted as an important obstacle for efficient cisplatin-based chemotherapy. Silymarin from seeds of milk thistle [Silybum marianum L. (Asteraceae)] has been shown to possess various potential pharmacological properties; however, whether or not this agent selectively protects renal cells from cisplatin-induced cell death with no interfering effect on cancer cells is not clear.Objective: Potential of silymarin in protection of cisplatin-induced renal cell death without compromising effect on anticancer activity of cisplatin was demonstrated in this study.Materials and methods: Cisplatin-induced cell death was evaluated in human proximal tubular HK-2, lung carcinoma H460, and melanoma G361 cells using MTT, Hoechst 33342, and propidium iodide assays.Results: Cisplatin induced both apoptosis and necrosis in HK-2 cells and caused a decrease in cell viability by ~40% and 60% at the doses of 25 and 100 µM, respectively. Pretreatment with 25–200 µM of silymarin ...

https://www.tandfonline.com/doi/pdf/10.3109/13880209.2011.568506

Silymarin selectively protects human renal cells from cisplatin-induced cell death.

Although cisplatin is one of the most efficient chemotherapeutic agents for the treatment of solid tumors, frequently observed nephrotoxicity has limited its use in several patients. Materials and methods: The protective effect of Glycine max (GM) and Chrysanthemum indicum (CM) extracts on cisplatin-induced apoptosis in human proximal tubular HK-2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Hoechst 33342, and propidium iodide assays. Reactive oxygen species (ROS) were determined by flow cytometry with 2,7-dichlorofluorescein diacetate (DCFH2-DA). Results: Cisplatin-induced renal cell toxicity through the induction of hydrogen peroxide (H2O2•−) and hydroxyl radical (OH). CM extract protected cisplatin-induced apoptosis by its anti-oxidant activity against H2O2 and OH•−, while GM extract scavenged only H2O2. Furthermore, GM and CM extracts protect renal cells without significant interfering effect on cisplatin toxicity in lung cancer H460 and melanoma G361 cell...

Protective effect of Glycine max and Chrysanthemum indicum extracts against cisplatin-induced renal epithelial cell death:

Caveolin-1 (Cav-1) expression frequently found in lung cancer was linked with disease prognosis and progression. This study reveals for the first time that Cav-1 sensitizes cisplatin-induced lung carcinoma cell death by the mechanism involving oxidative stress modulation. We established stable Cav-1 overexpressed (H460/Cav-1) cells and investigated their cisplatin susceptibility in comparison with control-transfected cells and found that Cav-1 expression significantly enhanced cisplatin-mediated cell death. Results indicated that the different response to cisplatin between these cells was resulted from different level of superoxide anion induced by cisplatin. Inhibitory study revealed that superoxide anion inhibitor MnTBAP could inhibit cisplatin-mediated toxicity only in H460/Cav-1 cells while had no effect on H460 cells. Further, superoxide anion detected by DHE probe indicated that H460/Cav-1 cells generated significantly higher superoxide anion level in response to cisplatin than that of control cells. The role of Cav-1 in regulating cisplatin sensitivity was confirmed in shRNA-mediated Cav-1 down-regulated (H460/shCav-1) cells and the cells exhibited decreased cisplatin susceptibility and superoxide generation. In summary, these findings reveal novel aspects regarding role of Cav-1 in modulating oxidative stress induced by cisplatin, possibly providing new insights for cancer biology and cisplatin-based chemotherapy.

Caveolin-1 sensitizes cisplatin-induced lung cancer cell apoptosis via superoxide anion-dependent mechanism

Cisplatin mediated nephrotoxicity has been continuously reported and recognized as a major obstacle for cisplatinbased chemotherapy. The present study aimed to demonstrate the potential use of silymarin, an extract from the seed of Silybum marianum L., as a combination therapy with cisplatin. Previous studies indicated that cisplatin-mediated toxicity was primarily caused by cellular oxidative stress. This study found that pretreatment with silymarin significantly attenuated oxidative stress induced by cisplatin in human renal epithelial cells (HK2-cells) and protected against cisplatin-mediated apoptosis. Moreover, the present study demonstrated that silymarin could attenuate hydrogen peroxide and hydroxyl radical generated by cisplatin while having minimal effect on superoxide anion level. In summary, these observation showed significant impact of silymarin in the inhibition of cisplatin-mediated renal cell death in vitro and could be beneficial for the development of this compound as a combination therapy in patients before receiving cisplatin.

Kanittha Pongjit

Papers

Silymarin selectively protects human renal cells from cisplatin-induced cell death.

Protective effect of Glycine max and Chrysanthemum indicum extracts against cisplatin-induced renal epithelial cell death:

Caveolin-1 sensitizes cisplatin-induced lung cancer cell apoptosis via superoxide anion-dependent mechanism

Silymarin inhibits cisplatin-mediated apoptosis via inhibition of hydrogen peroxide and hydroxyl radical generation