Cisplatin-induced Side Effects Research Articles

Cisplatin and dexamethasone separate and combined effect on nephrotoxic processes in female rats

Nephrotoxicity is one of the most severe side effects caused by cisplatin, limiting its use at high, effective concentrations. Dexamethasone, known for its strong anti-inflammatory and immunomodulating properties, is often used to alleviate cisplatin-induced side effects. However, dexamethasone also exhibits pro-oxidant properties and has been associated with morphological impairments and acute kidney injury. Although the mechanisms of cisplatin-induced nephrotoxicity are complex and involve numerous cellular processes, oxidative stress is widely accepted as the primary cause of this pathology. This study aims to investigate how dexamethasone, despite having effects similar to cisplatin, alleviates the side effects caused by this drug. Methods. The study measured lipid peroxide product malondialdehyde (MDA) levels using the thiobarbituric acid method and catalase activity using the molybdenum method. For histological examination, 5-6 μm thick tissue sections were prepared from samples processed with formalin and fixed with paraffin. These sections were stained with hematoxylin-eosin and observed under a light microscope. Results. Cisplatin and dexamethasone independently increased MDA levels to varying degrees. Cisplatin raised MDA by 75% in the homogenate and 38% in the supernatant, while dexamethasone increased these levels by 41% and 25%, respectively. The combined use of cisplatin and dexamethasone produced effects similar to those of dexamethasone alone. Catalase activity decreased following exposure to cisplatin (36% in the supernatant and 14% in the nucleus) and dexamethasone alone (33% in the supernatant and 24% in the nucleus). Combined use of the drugs led to a similar reduction in catalase activity. Histological analysis revealed tissue damage, supporting the pro-oxidant nature of both cisplatin and dexamethasone. Conclusions. The findings indicate that both cisplatin and dexamethasone exhibit pro-oxidant effects, as demonstrated by increased malondialdehyde levels, reduced catalase activity, and histological evidence of tissue damage. The ability of dexamethasone to mitigate cisplatin-induced side effects is likely attributable to a combination of its anti-inflammatory and immunomodulatory properties, as well as a "preventive or restraining" effect.

MTOR potentiates senescent phenotypes and primary cilia formation after cisplatin-induced G2 arrest in retinal pigment epithelial cells

Cisplatin, a platinum-based anticancer drug, is used to treat several types of cancer. Despite its effectiveness, cisplatin-induced side effects have often been reported. Although cisplatin-induced toxicities, such as apoptosis and/or necrosis, have been well studied, the fate of cells after exposure to sublethal doses of cisplatin needs further elucidation. Treatment with a sublethal dose of cisplatin induced cell cycle arrest at the G2 phase in retinal pigment epithelial cells. Following cisplatin withdrawal, the cells irreversibly exited the cell cycle and became senescent. Notably, the progression from the G2 to the G1 phase occurred without mitotic entry, a phenomenon referred to as mitotic bypass, resulting in the accumulation of cells containing 4N DNA content. Cisplatin-exposed cells exhibited morphological changes associated with senescence, including an enlarged size of cell and nucleus and increased granularity. In addition, the senescent cells possessed primary cilia and persistent DNA lesions. Senescence induced by transient exposure to cisplatin involves mTOR activation. Although transient co-exposure with an mTORC1 inhibitor rapamycin did not prevent mitotic bypass and entry into senescence, it delayed the progression of senescence and attenuated senescent phenotypes, resulting in shorter primary cilia formation. Conclusively, cisplatin induces senescence in retinal pigment epithelial cells by promoting mTOR activation.

Natural killer cells strengthen antitumor activity of cisplatin by immunomodulation and ameliorate cisplatin-induced side effects

PurposeCisplatin-based chemotherapy is now an important treatment for improving bladder cancer prognosis. However, challenges in clinical treatment remain due to the numerous side effects of chemotherapy. Natural killer (NK) cells regulate certain immune responses and play a significant role in tumor surveillance and control. The efficacy of NK cells combined with cisplatin for chemoimmunotherapy in bladder cancer remains poorly understood.MethodsIn this study, we established an MB49 tumor-bearing mouse model, tumor growth was measured in a control group and in groups treated with cisplatin, NK cells or both. Organ indices, biochemical indicators of blood serum, and expression of apoptotic proteins were used to assess the extent of organ damage. ELISA and immunohistochemistry were used to analyze the levels of immune cells and cytokine expression in serum, spleen, and tumor tissue.ResultsNK cells combined with cisplatin exhibited better antitumor activity. NK cells also alleviated the organ damage caused by cisplatin and improved the survival rate. Treatment with NK cells increased the expression of IL-2 and IFN-γ as well as the number of CD4 + T cells. Additionally, cisplatin increased the expression of natural killer group 2, member D (NKG2D) ligands thus activating NK cells to kill tumor cells.ConclusionNK cells could alleviate the side effects of cisplatin treatment and enhance antitumor activity. The combination of NK cells and cisplatin thus provides a promising option for chemoimmunotherapy for bladder cancer.

Selenium Status in Diet Affects Nephrotoxicity Induced by Cisplatin in Mice.

Cisplatin is one of the most active chemotherapy drugs to treat solid tumors. However, it also causes various side effects, especially nephrotoxicity, in which oxidative stress plays critical roles. Our previous studies found that cisplatin selectively inhibited selenoenzyme thioredoxin reductase1 (TrxR1) in the kidney at an early stage and, subsequently, induced the activation of Nrf2. However, the effects of selenium on cisplatin-induced nephrotoxicity are still unclear. In this study, we established mice models with different selenium intake levels to explore the effects of selenoenzyme activity changes on cisplatin-induced nephrotoxicity. Results showed that feeding with a selenium-deficient diet sensitize the mice to cisplatin-induced damage, whereas selenium supplementation increased the activities of selenoenzymes TrxR and glutathione peroxidase (GPx), changed the renal cellular redox environment to a reduced state, and exhibited protective effects. These results demonstrated the correlation of selenoenzymes with cisplatin-induced side effects and provided a basis for the potential approach to alleviate cisplatin-induced renal injury.

Tetrathiomolybdate as an old drug in a new use: As a chemotherapeutic sensitizer for non-small cell lung cancer

BackgroundCisplatin-based chemotherapy is the standard treatment for non-small cell lung cancer (NSCLC). However, cisplatin resistance is a major obstacle to successful therapeutic efficacy. Novel therapeutic strategies are urgently needed to reverse chemotherapy resistance and improve prognosis. In the present study, we aimed to investigate whether copper chelator Tetrathiomolybdate (TM) can enhance the anticancer effect of cisplatin, and elucidate the underlying mechanisms. MethodsCell viability, wounding healing, and colony formation assays were performed on H1299 and A549 cells. The combination indices (CI) were determined by the Chou-Talalay method. Flow cytometry was used to detect cell apoptosis and ROS generation. GSH levels were measured in a microplate reader. RNA-seq and bioinformatics analyses were used to analyze the differentially expressed genes (DEGs) and enriched biology processes. The concentrations of Pt and Cu were determined by ICP-MS. Animal xenograft tumor model was established to evaluate the synergistic anticancer effect of TM and cisplatin. ResultsCombination treatment with TM and cisplatin decreased cell viability and migration of H1299 and A549 cells compared with cisplatin alone. Mechanistically, combination treatment could significantly increase ROS and reduce GSH content, leading to a notable increase in DNA-bound Pt and cell apoptosis. Moreover, in animal xenograft tumor model, TM enhanced cisplatin-elicited antitumor effect, but did not increase cisplatin-induced side effects. ConclusionOur study suggests that TM may be a promising chemotherapeutic sensitizer for non-small cell lung cancer.

Understanding Pyrrolidine Dithiocarbamate’s protective effect against Cisplatin-induced toxic side effects in Rats

Through the examination of biochemical parameters (creatinine and BUN) and oxidative stress values (TBRAS, Catalase activity, and GSH), we have attempted to evaluate the protective effect of PDTC against toxic consequences of CIS treatment. In the study, animals (Rats Wistar) were randomly assigned to one of four groups of six animals each: untreated or treated with vehicle (group-1), treated with PDTC (group-2), treated with CIS (group-3), and treated with a combination of CIS and PDTC (group-4). In this study, two tissues were chosen to investigate oxidative stress (a toxic side effect), and these tissues were the kidney and the ileum. In CIS treatment, the level of serum creatinine and blood urea nitrogen (BUN) exponentially increased and simultaneous treatment of CIS and PDTC restored their levels. Similarly, treatment of CIS, considerably increases lipid peroxidation, i.e., TBRAS level in both tissue Kidney and intestine, however, treatment in the combination of PDTC, substantially retained their level similar to the vehicle-treated group. In contrast, Catalase activity and reduced glutathione (GSH) levels were compromised in the kidney after CIS treatment, but significantly increased in the intestinal tissue compared to the untreated group, and treatment with PDTC restored Catalase activity and GSH levels in both tissues to levels comparable to the untreated group. Thus, the study indicated that oxidative stress is caused by an increase in reactive oxygen species (ROS) or a depleted antioxidant system, or both, which ultimately result in side toxic effects toward the different organs.

Red ginseng protects against cisplatin-induced intestinal toxicity by inhibiting apoptosis and autophagy via the PI3K/AKT and MAPK signaling pathways.

Although growing evidence has shown that ginseng (Panax ginseng C.A. Meyer.) exerts strong protective and preventive effects on cisplatin-induced side effects, including nephrotoxicity, ototoxicity and cardiotoxicity, the ameliorative effects of ginseng on intestinal damage caused by cisplatin are unknown to date. Red ginseng (RG), a major processed product of the roots of Panax ginseng C.A. Meyer, can be used to control chemotherapy drug-induced multiple toxicity. In the present work, an animal model of cisplatin-induced intestinal injury was established to evaluate the ameliorative effects of RG and their underlying molecular mechanism for the first time. The results showed that a single cisplatin injection (20 mg kg-1) leads to loss of body weight, shrinkage of the small intestine, and sharp increase of the intestinal function index of diamine oxidase (DAO). These symptoms were remarkably relieved after the administration of RG at 300 and 600 mg kg-1 for 10 continuous days, respectively. In addition, RG markedly reduced the increase in malondialdehyde (MDA) levels and the consumption of superoxide dismutase (SOD) and catalase (CAT) caused by cisplatin-induced oxidative stress. Furthermore, RG pretreatment dramatically improved the cisplatin-induced apoptosis of intestinal villous cells, irregular nuclear arrangement, ablation of crypt cells, and damage to the mechanical barrier. In this study, pharmacological methods have been used to prove that RG can inhibit cisplatin intestinal toxicity by activating the PI3K/AKT signaling pathway to inhibit apoptosis and by antagonizing the MAPK-mediated autophagy pathway.

시스플라틴 유도 신장 독성에 대한 반하사심탕 추출물의 방어효과

In this study, Banhasasim-tang extracts (BSTE) have an inhibitory effects on cisplatin-induced nephrotoxicity in mouse model. Cisplatin is the most widely used anticancer drug for treatment of various cancer. However, cisplatin treatment to cancer patients leads to many side effects such as nephrotoxicity and body weight decrease. We hypothesize that BSTE improve the cisplatin-induced side effects in mouse model. We found that BSTE administration protected tubular injury by cisplatin in mouse model. BSTE also inhibited increase of creatinine and BUN induced by cisplatin injection in serum. Collectively, our data suggest that BSTE could be a therapeutic agent for reducing kidney injury induced by cisplatin treatment in cancer patients.

Evaluating protective and therapeutic effects of alpha-lipoic acid on cisplatin-induced ototoxicity

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction

Cisplatin is an alkylating agent that interferes with DNA replication and kills proliferating carcinogenic cells. Several studies have been conducted to attenuate the side effects of cisplatin; one such side effect in cancer patients undergoing cisplatin chemotherapy is ototoxicity. However, owing to a lack of understanding of the precise mechanism underlying cisplatin-induced side effects, management of cisplatin-induced ototoxicity remains unsolved. We investigated the protective effects of fenofibrate, a PPAR-α activator, on cisplatin-induced ototoxicity. Fenofibrate prevented cisplatin-induced loss of hair cells and improved cell viability; moreover, fenofibrate significantly attenuated the threshold of auditory brainstem responses (ABR) in cisplatin-injected mice. Fenofibrate significantly increased PPAR-α, PPAR-γ, and PGC-1α expression, which consequently resulted in increased number and functional enzyme levels of peroxisomes and mitochondria, and markedly decreased phospho-p53 (S15), activated caspase-3, cleaved-PARP, and NF-κB p65 nuclear translocation, which reduced NADPH oxidase isoform (NOX3 and NOX4) expression, thereby decreasing reactive oxygen species (ROS) production in cisplatin-treated tissues ex vivo. Taken together, these results indicate that fenofibrate rescues cisplatin-induced ototoxicity by maintaining peroxisome and mitochondria number and function, reducing inflammation, and decreasing ROS levels. Our findings suggest that fenofibrate administration might serve as an effective therapeutic agent against cisplatin-induced ototoxicity.

Effect of orexin-A in the arcuate nucleus on cisplatin-induced gastric side effects in rats

The most common side effects of the cancer chemotherapy drug cisplatin are nausea and vomiting. These effects are heavily influenced by orexigenic and anorexigenic peptides. We explored the effects of orexin-A on the cisplatin-treated rats and a possible mechanism for its effects on cisplatin-induced side effects. Quantitative real-time PCR was used to measure the change of prepro-orexin mRNA in the hypothalamus following cisplatin treatment. The effect of orexin-A and cisplatin on the firing rate of arcuate nucleus neurons was recorded. The effect of administration of orexin-A and a neuropeptide Y1 receptor antagonist to the arcuate nucleus on food intake, pica, and gastric motility on cisplatin treated rats were also measured. The relative expression of prepro-orexin mRNA in the hypothalamus was reduced by cisplatin. Exogenous orexin-A altered cisplatin-induced changes to the neuronal firing of gastric distension-responsive neurons, alleviated the cisplatin-induced anorexia, pica and improves the weakened gastric motility in the arcuate nucleus of rats. These effects could be partially blocked by intracerebroventricular injection (i.c.v.) of a neuropeptide Y1 receptor antagonist. These results suggest that orexin-A signaling ameliorates the gastric disorder induced by cisplatin in rats, and may act through neuropeptide Y neurons in the arcuate nucleus.

Flavored Guilu Erxian decoction inhibits the injury of human bone marrow mesenchymal stem cells induced by cisplatin

To examine the exact role of flavored Guilu Erxian decoction, a Traditional Chinese Medicine (TCM) in the treatment of cisplatin-induced side-effects in bone marrow mesenchymal stem cells (BM-MSCs). BM-MSCs were isolated from bone marrow collected from SD rats and identified by flow cytometry. Cells were cultivated in MEM alpha medium containing 5% (TCM-L), 10% (TCM-M) and 20% (TCM-H) dosages of flavored Guilu Erxian decoction with or without cisplatin. Cell viability was determined through CCK-8 and thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) staining assay. Flow cytometry was used to determine cell cycle and apoptosis. The expression of p21 and cleaved-caspase-3 were examined using Western blot assay. ThePI3K-AKT-mTOR pathway associated proteins, including p-PI3K, p-AKT and p-mTOR, were also examined by Western blot assay. CCK-8 and EdU staining assay demonstrated that cisplatin could inhibit cell proliferation in BM-MSCs in a dose and time dependent manner. Further, cisplatin could induce apoptosis through increasing G0/G1 cell cycle arrest, p21 and cleaved-caspase-3 expression. However, these phenomena would be significantly alleviated when adding the serum containing flavored Guilu Erxian decoction. Furthermore, thePI3K-AKT-mTOR pathway activation could be inhibited by cisplatin in BM-MSCs, while flavored Guilu Erxian decoction treatment successfully abrogated this effect. Combination of flavored Guilu Erxian decoction and cisplatin could reduce the damage to BM-MSCs. This indicates that the flavored Guilu Erxian decoction can enhance the possibility of BM-MSCs repairing and rehabilitating the normal function of injured tissues induced by cisplatin, which could provide a new direction for therapeutic applications.

Liu Jun Zi Tang-A Potential, Multi-Herbal Complementary Therapy for Chemotherapy-Induced Neurotoxicity.

Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity.

Beneficial Effects of Cynaroside on Cisplatin-Induced Kidney Injury In Vitro and In Vivo

Anti-cancer drugs such as cisplatin and doxorubicin are effectively used more than radiotherapy. Cisplatin is a chemotherapeutic drug, used for treatment of various forms of cancer. However, it has side effects such as ototoxicity and nephrotoxicity. Cisplatin-induced nephrotoxicity increases tubular damage and renal dysfunction. Consequently, we investigated the beneficial effect of cynaroside on cisplatin-induced kidney injury using HK-2 cell (human proximal tubule cell line) and an animal model. Results indicated that 10 µM cynaroside diminished cisplatin-induced apoptosis, mitochondrial dysfunction and caspase-3 activation, cisplatin-induced upregulation of caspase-3/MST-1 pathway decreased by treatment of cynaroside in HK-2 cells. To confirm the effect of cynaroside on cisplatin-induced kidney injury in vivo, we used cisplatin exposure animal model (20 mg/kg, balb/c mice, i.p., once a day for 3 days). Renal dysfunction, tubular damage and neutrophilia induced by cisplatin injection were decreased by cynaroside (10 mg/kg, i.p., once a day for 3 days). Results indicated that cynaroside decreased cisplatin-induced kidney injury in vitro and in vivo, and it could be used for improving cisplatin-induced side effects. However, further experiments are required regarding toxicity by high dose cynaroside and caspase-3/ MST-1-linked signal transduction in the animal model.

Pretreatment with taurine prevented brain injury and exploratory behaviour associated with administration of anticancer drug cisplatin in rats

The neurotoxicity associated with cisplatin treatment is one of the major side effects compromising the efficacy of the anti-cancer treatment. The present study investigated the possible protective effects of taurine, an intracellular amino acid, on cisplatin-induced brain injury and exploratory behaviour using five groups of ten female rats each. Group I received drinking water only. Group II orally received taurine alone at 200 mg/kg whereas Group III received cisplatin alone intraperitoneally at 10 mg/kg. Groups IV and V were treated with taurine at 100 and 200 mg/kg respectively for sixteen consecutive days and a single intraperitoneal injection of cisplatin on day 13 to induce neurotoxicity. Endpoint analyses using video-tracking software revealed that cisplatin administration alone caused neurobehavioral deficits evinced by marked decrease in the total distance travelled, average speed, total time mobile, total mobile episode, number of crossing and absolute turn angle. Furthermore, cisplatin alone significantly suppressed brain antioxidant defense mechanisms, elevated nitric oxide and lipid peroxidation levels whereas it increased acetylcholinesterase activity in the treated rats. However, rats pretreated with taurine exhibited significant improvement in behavioural performance and brain antioxidant status with concomitant decrease in acetylcholinesterase activity and oxidative stress indices when compared with cisplatin alone group. Histologically, taurine pretreatment prevented cisplatin-induced neuronal death in the cerebral and cerebellar cortices, caudo-putamen and hippocampus as well as abrogated cisplatin-mediated decrease in the dendritic arborization and mean diameter of the somata of pyramidal neurons in the treated rats. In conclusion, taurine may be a possible protective supplement to reduce cisplatin-induced side-effects including neurotoxicity in patients undergoing cisplatin treatment.

Potential protective role of hydrogen against cisplatininduced side effects during chemotherapy: A mini-review of a novel hypothesis for antagonism of hydrogen

Purpose: To review the potential protective role of hydrogen against cisplatin-induced side effects during chemotherapy.Methods: We searched PubMed and SCOPUS using the following keywords and combinations in titles, keywords, abstracts and full texts: cisplatin; side effects; chemotherapy; tumor; toxicity; hydrogen; reactive oxidative species; and ischemic reperfusion.Results: The pathogenesis of cisplatin-induced side effects is suggested based on the increased level of reactive oxidative species (ROS). Cisplatin induces ROS-dependent platelet apoptosis via the extracellular signal-regulated kinase (ERK) signaling pathway, which might have contributed to cisplatininduced hematotoxicity, and in particular, thrombocytopenia. Molecular hydrogen has been shown to have therapeutic effects against damage to various organs (especially kidney, brain and liver) caused by ischemic reperfusion (IR) through selective elimination of the most cytotoxic ROS hydrogen radicals without affecting other types of ROS involved in signal transduction in vitro and in vivo.Conclusion: Hydrogen may not only alleviate hematotoxicity in patients with hemorrhagic tendencies during cisplatin-based chemotherapy, but also has a potential protective effect against other side effects induced by cisplatin.Keywords: Reactive oxygen species, Hydrogen radicals, Cisplatin, Hepatotoxicity, Chemotherapy, Side effects, Antagonism

시스플라틴 유도 체중감소에 대한 반하사심탕 추출물의 방어효과

In this study, Banhasasim-tang extracts (BSTE) have an inhibitory effects on cisplatin-induced decrease of body weights in two mouse model. Cisplatin is the most widely used anticancer drug for treatment of various cancer. However, cisplatin treatment to cancer patients leads to many side effects such as nausea, vomiting and body weight decrease. BSTE has been used to decrease digestive disorders in South Korea. We hypothesize that BSTE improve the cisplatin-induced side effects in mouse models. We found that pre- and co-administration of BSTE inhibited decreases of body weights and food intake by cisplatin in mouse models. But BSTE had no synergistic effects for tumor shrinkage by cisplatin in xenograft model. Collectively, our data suggest that BSTE have great potential as a agent for having decrease effects on side effects by cisplatin in cancer patients.

Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation

UTL-5g is a novel small-molecule TNF-alpha modulator. It reduces cisplatin-induced side effects by protecting kidney, liver, and platelets, thereby increasing tolerance for cisplatin. UTL-5g also reduces radiation-induced acute liver toxicity. The mechanism of action for UTL-5g is not clear at the present time. A phosphoproteomic analysis to a depth of 4943 phosphopeptides and a luminescence-based transcription factor activity assay were used to provide complementary analyses of signaling events that were disrupted by UTL-5g in RAW 264.7 cells. Transcriptional activity downstream of the interferon gamma, IL-6, type 1 Interferon, TGF-β, PKC/Ca2+ and the glucocorticoid receptor pathways were disrupted by UTL-5g. Phosphoproteomic analysis indicated that hyperphosphorylation of proteins involved in actin remodeling was suppressed by UTL-5g (gene set analysis, FDR < 1%) as was phosphorylation of Stat3, consistent with the IL-6 results in the transcription factor assay. Neither analysis indicated that LPS-induced activation of the NF-kB, cAMP/PKA and JNK signaling pathways were affected by UTL-5g. This global characterization of UTL-5g activity in a macrophage cell line discovered that it disrupts selected aspects of LPS signaling including Stat3 activation and actin remodeling providing new insight on how UTL-5g acts to reduce cisplatin-induced side effects.

Cytoprotective Effects of Cell‐Permeable Bifunctional Antioxidant Enzyme, GST‐TAT‐SOD, against Cisplatin‐Induced Cell Damage

GST-TAT-SOD, a cell-permeable bifunctional antioxidant enzyme, is a potential selective radioprotector. This study aimed to investigate the cytoprotective activity of GST-TAT-SOD against cisplatin-induced damage. The current study showed that cisplatin induced the formation of reactive oxygen species in normal L-02 cells. GST-TAT-SOD (2000 U/mL) executed its antioxidant role by directly scavenging excess intracellular free radicals and augmenting cellular antioxidant defense such as reducing MDA level, enhancing the SOD activity, GST activity, and T-AOC. Thus, it suppressed the growth inhibition and apoptosis of cisplatin-treated normal cells. Meanwhile, the growth inhibition of tumor cells (SMMC-7721) caused by cisplatin was unaffected by GST-TAT-SOD pretreatment. GST-SOD, as a comparison, seemed to be powerless for related indicators as it could not enter into cells without cell-permeating peptide. These results suggest that GST-TAT-SOD might be a potential cytoprotective agent for cisplatin-induced side effects.

Chemoprotection byd-methionine against cisplatin-induced side-effects: insight from in vitro studies using human plasma

Animal studies have shown that the nephrotoxicity and ototoxicity of the anti-cancer drug cisplatin (CP) can be ameliorated by the co-administration with D-methionine. The molecular mechanisms of this activity, however, are not well understood. Since CP is intravenously administered, the underlying chemistry may involve the interaction of CP-derived Pt-species with D-methionine in the bloodstream. Our previous studies have shown that the chemoprotective agents N-acetyl-l-cysteine and sodium thiosulfate modulate the metabolism of CP in human plasma in vitro, albeit in a different manner. Using a metallomics approach, we show that the incubation of human plasma with D-methionine and CP (molar ratio of 20 : 1) leads to the formation of a Pt-D-methionine complex independent of the order of addition. These results were corroborated by analogous experiments that were carried out using PBS-buffer instead of plasma. In addition, CP and D-methionine were added simultaneously to PBS-buffer and samples were analyzed at certain time intervals by the same metallomics method and LC-ESI-MS over a ∼21 h time period. Whereas the intermediate [Pt(NH3)Cl(D-methionine)](+) species was detected between 1-4 h, only the terminal [Pt(D-methionine)2](+) complex was present 21 h later. Combined, these studies demonstrate that in plasma and at the 20 : 1 D-methionine : CP molar ratio, an early CP hydrolysis product reacts with D-methionine to form a 1 : 1 complex that is followed by the formation of a 2 : 1 compound at a later time point. The formation of these Pt-D-methionine species may therefore play an important role in the processes by which D-methionine protects mammalian organisms against CP-induced toxicities.