Dual-targeted nanoparticles with removing ROS inside and outside mitochondria for acute kidney injury treatment.

Mitochondrial oxidative stress and inflammation are the main pathological features of acute kidney injury (AKI). However, systemic toxicity of anti-inflammatory drugs and low bioavailability of antioxidants limit the treatment of AKI. Here, the lipid micelle nanosystem modified with l-serine was designed to improve treatment of AKI. The micelle kernels coating the antioxidant drug 4-carboxybutyl triphenylph-osphine bromide-modified curcumin (Cur-TPP) and quercetin (Que). In the cisplatin (CDDP)-induced AKI model, the nanosystem protected mitochondrial structure and improved renal function. Compared to mono-targeted group, the mitochondrial ROS content of renal tubular epithelial cells acting in the dual-target group decreased about 1.66-fold in vitro, serum creatinine (Scr) and urea nitrogen (BUN) levels were reduced by 1.5 and 1.2 mmol/L in vivo, respectively. Mechanistic studies indicated that the nanosystem inhibited the inflammatory response by interfering with the NF-κB and Nrf2 pathways. This study provides an efficient and low-toxicity strategy for AKI therapy.

Effects of Nutraceuticals on Cisplatin-Induced Cytotoxicity in HEI-OC1 Cells.

Cisplatin is a chemotherapeutic drug for the treatment of several solid tumors, whose use is limited by its nephrotoxicity, neurotoxicity, ototoxicity, and development of resistance. The toxicity is caused by DNA cross-linking, increase in reactive oxygen species and/or depletion of cell antioxidant defenses. The aim of the work was to study the effect of antioxidant compounds (Lisosan G, Taurisolo®) or hydrogen sulfide (H2S)-releasing compounds (erucin) in the auditory HEI-OC1 cell line treated with cisplatin. Cell viability was determined using the MTT assay. Caspase and sphingomyelinase activities were measured by fluorometric and colorimetric methods, respectively. Expression of transcription factors, apoptosis hallmarks and genes codifying for antioxidant response proteins were measured by Western blot and/or RT-qPCR. Lisosan G, Taurisolo® and erucin did not show protective effects. Sodium hydrosulfide (NaHS), a donor of H2S, increased the viability of cisplatin-treated cells and the transcription of heme oxygenase 1, superoxide dismutase 2, NAD(P)H quinone dehydrogenase type 1 and the catalytic subunit of glutamate-cysteine ligase and decreased reactive oxygen species (ROS), the Bax/Bcl2 ratio, caspase-3, caspase-8 and acid sphingomyelinase activity. Therefore, NaHS might counteract the cytotoxic effect of cisplatin by increasing the antioxidant response and by reducing ROS levels and caspase and acid sphingomyelinase activity.

Cannabidiol and Cannabis Sativa as a potential treatment in vitro prostate cancer cells silenced with RBBp6 and PC3 xenograft.

BACKGROUND: Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375,000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3. METHODS: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell attachment. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumour suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo. RESULTS: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumours in the mouse models were reduced following treatment with cisplatin and cannabidiol. CONCLUSION: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression.

MiR-936 Targets GPR78 and Regulates Chemotherapy Resistance in Non-Small Cell Lung Cancer by Activating the Galphaq Rho GTPase Pathway.

Objective: We aimed to explore the mechanism of microRNA-936 (miR-936) targeting G protein coupled receptor 78 (GPR78) regulating chemoresistance of non-small cell lung cancer (NSCLC) by activating the Galphaq Rho GTPase pathway. Methods: We added cisplatin to DMEM medium of HCC827/cisplatin cells and adjusted the final concentration to 1 µg/mL. Cells were divided into the control group and the miR-936 transfection group. Tissue samples were divided into the normal tissue group and the NSCLC tissue group. The mRNA expression of miR-936 in tissue samples was analyzed via reverse transcription polymerase chain reaction (RT-PCR). Cell migration and invasion were detected by wound healing assay. Cell counting kit 8 (CCK-8) was used to detect the cell viability 1, 2 and 3 days after cisplatin induction. The toxicity of cisplatin was analyzed by flow cytometry. The targeting relationship between miR-936 and GPR78 was detected by luciferase reporter gene assay. The regulation of miR-936 on GPR78/Rho GTPase was analyzed by Western blot. Results: The expression of miR-936 in NSCLC was lower than in normal tissues (P < .05). The number of cell migrations and invasions in the miR-936 transfection group was lower than in the control group (P < .05). The cell viability in the miR-936 transfection group was lower than in the control group on the 1st, 2nd and 3rd day (P < .05). With the increase in cisplatin concentration, the apoptosis rate of cells increased in a dependent manner (P < .05). Compared with GPR78 Mut, overexpression of miR-936 inhibited the luciferase activity of GPR78 WT 3'- UTR (P < .05). The expression of GPR78, RhoA, Rac1 and ABCB1 protein in the miR-936 transfection group was lower than in the control group (P < .05). The expression of GPR78 protein in the inhibitor+miR-936 transfection group was lower than in the inhibitor+control group (P < .05). Conclusion: miR-936 targets GPR78 and improves the sensitivity of NSCLC cells to cisplatin via the Galphaq Rho GTPase pathway.

Cisplatin exposure acutely disrupts mitochondrial bioenergetics in the zebrafish lateral-line organ.

Cisplatin is a commonly used chemotherapeutic agent that causes debilitating high-frequency hearing loss. No targeted therapies currently exist to treat cisplatin ototoxicity, partly because the underlying mechanisms of cisplatin-induced hair cell damage are not completely defined. Zebrafish may offer key insights to cisplatin ototoxicity because their lateral-line organ contains hair cells that are remarkably similar to those within the cochlea but are optically accessible, permitting observation of cisplatin injury in live intact hair cells. In this study, we used a combination of genetically encoded biosensors in zebrafish larvae and fluorescent indicators to characterize changes in mitochondrial bioenergetics in response to cisplatin. Following exposure to cisplatin, confocal imaging of live intact neuromasts demonstrated increased mitochondrial activity. Staining with fixable fluorescent dyes that accumulate in active mitochondria similarly showed hyperpolarized mitochondrial membrane potential. Zebrafish expressing a calcium indicator within their hair cells revealed elevated levels of mitochondrial calcium immediately following completion of cisplatin treatment. A fluorescent ROS indicator demonstrated that these changes in mitochondrial function were associated with increased oxidative stress. After a period of recovery, cisplatin-exposed zebrafish demonstrated caspase-3-mediated apoptosis. Altogether, these findings suggest that cisplatin acutely disrupts mitochondrial bioenergetics and may play a key role in initiating cisplatin ototoxicity.

Effect of cashew (Anacardium occidentale L.) nut-supplemented diet on steroidogenic enzymes, hormonal and oxidative imbalances, and sperm parameters in cisplatin-induced reproductive toxicity in male rats.

Cisplatin (CP) is a chemotherapeutic/anticancer drug culpable in sperm and testicular damage, but the use of dietary patterns has been reported to averse this effect. To date, no report on the use of roasted cashew nut-supplemented diets (RCNSD) against chemotherapy-induced testicular damage has been presented. In this study, the effect of 10% and 20% RCNSD on reproductive hormones, sperm parameters, testicular and epididymal antioxidant status, and steroidogenic enzymes activities in CP-induced rats were determined. Interestingly, these parameters were boosted, but with a decrement in radical species level in the testes/epididymis of CP-induced rats fed with RCNSD as against the untreated CP-induced rats. The modulatory effect of RCNSD on the tested reproductive parameters in studied tissues could be among the mechanism of action, by which RCNSD mitigates andrological toxicity. Hence, RCNSD could be harnessed as a functional food/nutraceutical agent for alleviating the andrological toxicity of CP-induced male reproduction. PRACTICAL APPLICATIONS: Consumption of cashew nuts has been a great benefit to human health, as a result of its richness in nutritional constituents including biologically active amino acids, tocopherols, fatty acids, polyphenols, and selenium, among others. Cashew nuts are mostly consumed fried/roasted, with yoghurt, as a paste, or used as an ingredient in confectionery products. The folkloric use of cashew nuts in the management of cardiovascular diseases, male reproductive disorders, and diabetes has been reported. In this study, the ability of roasted cashew nut-supplemented diets to modulate reproductive hormones, sperm parameters, testicular and epididymal antioxidant status, and steroidogenic enzymes activities in CP-induced reproductive toxicity in male rats was revealed, thus, indicating its possible use, clinically, in the management of reproductive toxicity induced by cancer drugs.

Design, synthesis and biological evaluation of novel arylpropionic esters for the treatment of acute kidney injury.

Acute kidney injury (AKI) is associated with a strong inflammatory response, and inhibiting the response effectively prevents or ameliorates AKI. A series of novel arylpropionic esters were designed, synthesized and evaluated their biological activity in LPS-stimulated RAW264.7 cells. Novel arylpropionic esters bearing multi-functional groups showed significant anti-inflammatory activity, in which, compound 13b exhibited the most potent activity through dose-dependent inhibiting the production of nitric oxide (NO, IC50 = 3.52 µM), TNF-α and IL-6 (84.1% and 33.6%, respectively), as well as suppressing the expression of iNOS, COX-2 and TLR4 proteins. In C57BL/6 mice with cisplatin-induced AKI, compound 13b improved kidney function, inhibited inflammatory development, and reduced pathological damage of kidney tissues. In brief, this arylpropionic ester scaffold may be developed as anti-inflammatory agents.

Metal element alteration in the lung by cisplatin and CV247 administration.

Despite significant nephrotoxicity, cisplatin is still used in the therapy of various tumors. We were interested in how metal ion composition is altered by cisplatin and whether platinum accumulates in the non-tumorous lung. We also aimed to study metal ion changes after treatment with a veterinary medicament CV247 with antioxidant property (containing Cu and Mn gluconate, ascorbic acid, Na salicylate), and whether CV247 alters pulmonary platinum accumulation in the healthy lung. Male Wistar rats were randomly selected into 4 groups (n = 10/group): control group, cisplatin-treated group, CV247-treated group, cisplatin + CV247-treated group. Inductively coupled plasma optical emission spectrometry and mass spectrometry were used for measuring Al, As, B, Ba, Ca, Cd, Co, Cu, Cr, Fe, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, Pt, S, Sb, Se, Sn, Sr, and Zn in the lung and the redox state was measured in the plasma. Cisplatin influenced the element homeostasis in the lung. Pt, Mn, Se accumulation and Ca, Mg excretion were observed after treatment with cisplatin. The antioxidant CV247 supplementation modified the Mn concentration; however, the concentration of Cu did not change despite the Cu content of the product, and CV247 did not affect other metal concentrations in the lung of the cisplatin-treated group. In conclusion, cisplatin has a systemic impact on the metal element metabolism, and this effect was demonstrated in the healthy lung, too. The results indicate the importance of supplementing some essential elements, such as Ca and Mg during cisplatin cancer therapy.

Saikosaponin b2 enhances the hepatotargeting effect of anticancer drugs through inhibition of multidrug resistance-associated drug transporters.

AIMS: Vinegar-baked Radix Bupleuri (VBRB) potentiates the activity of anticancer drugs in the liver by increasing their hepatic distribution. However, this phenomenon may be associated with drug transporters. We investigated the effect of saikosaponin b2 (SSb2; the main component of VBRB) on the activity and expression of different drug transporters in both normal cells and those that overexpress the transporter. MAIN METHODS: The activities of transporters were analyzed by concentration of their cellular substrates. Concentrations of colchicine (substrate of Pgp and MRP1) and cisplatin (substrate of OCT2 and MRP2) were determined by high-performance liquid chromatography (HPLC). The concentration of rhodamine B was determined by flow cytometry. The expression of transporter gene and protein were determined by qRT-PCR and Western blotting analysis. KEY FINDINGS: SSb2 increased colchicine efflux in HEK293 cells by primarily increasing Mrp1 activity, independent of gene and protein expression. SSb2 enhanced Mrp2 function and increased cisplatin efflux in BRL3A cells by upregulating Mrp2 gene expression, with a marginal effect on Pgp in normal cells. SSb2 increased OCT2 activity in OCT2-HEK293 cells by increasing the expression of OCT2 protein and mRNA; however, SSb2 inhibited MRP2 activity in MRP2-HEK293 cells by decreasing MRP2 protein expression, and decreased Pgp and MRP1 activity in Pgp- and MRP1-HEK293 cells. SIGNIFICANCE: SSb2 might potentially be the key active component of VBRB that enhances the hepatotargeting of anticancer drugs through the inhibition of multidrug resistance-associated drug transporters (Pgp, MRP1, and MRP2) in an environment-dependent manner.

Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver.

Cisplatin is the most commonly used chemotherapeutic drug for managing solid tumors. However, toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly the Pt-d(GpG) diadduct. We recently showed that, in mice, repair of this adduct 2 h following injection is controlled by two circadian programs. 1) The circadian clock controls transcription of 2000 genes in liver and, via transcription-directed repair, controls repair of the transcribed strand (TS) of these genes in a rhythmic fashion unique to each gene's phase of transcription. 2) The excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the nontranscribed strand (NTS) and the rest of the genome takes place. Here, we followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to better understand cisplatin DNA damage and repair. We find that transcription-driven repair is nearly complete after 2 days, whereas weeks are required for repair of the NTS and the rest of the genome. TS repair oscillates in rhythmically expressed genes up to 2 days post injection, and in all expressed genes, we see a trend in TS repair with time from the 5' to 3' end. These findings help to understand the circadian- and transcription-dependent and -independent control of repair in response to cisplatin, and should aid in designing cisplatin chemotherapy regimens with improved therapeutic indexes.

Profiling of apoptosis- and autophagy-associated molecules in human lung cancer A549 cells in response to cisplatin treatment using stable isotope labeling with amino acids in cell culture.

Cis­diammine­dichloro­platinum II­based adjuvant chemotherapy provides an alternative therapy to improve the survival of patients with lung tumors, especially those with non­small cell lung cancer (NSCLC). However, drug resistance is a large clinical problem and its underlying mechanism remains unclear. In the present study, NSCLC A549 cells were treated with a low concentration of cisplatin in order to observe and determine the development of chemoresistance, via growth curves, colony forming assays and apoptosis assays. Then the induction of autophagy was examined in the cisplatin­treated A549 cells with a fluorescence reporter. Profiled proteins in the cisplatin­treated A549 cells were also assessed using the stable isotope labeling by amino acids in cell culture (SILAC) method, and then the differentially expressed molecules were verified. The results demonstrated that A549 cells became less sensitive to cisplatin [resistant A549 cells (A549R)] following 20 passages in the medium containing a low concentration of cisplatin, with less apoptotic cells post­cisplatin treatment. A549R cells grew more efficiently in the cisplatin medium, with more colony formation and more cells migrating across the baseline. In addition, NSCLC results demonstrated that more autophagy­related proteins (ATGs) were expressed in the A549R cells. Furthermore, the western blotting results confirmed this upregulation of ATGs in A549R cells. In addition, two repeated SILAC screening experiments recognized 15 proteins [glucose­regulated protein, 78 kDa (GRP78), heat shock protein 71, pre­mRNA processing factor 19, polypyrimidine tract binding protein 1, translationally controlled tumor protein, Cathepsin D, Cytochrome c, thioredoxin domain containing 5, MutS homolog (MSH) 6, Annexin A2 (ANXA2), BRCA2 and Cyclin dependent kinase inhibitor 1A interacting protein, MSH2, protein phosphatase 2A 55 kDa regulatory subunit Bα, Rho glyceraldehyde­3­phosphate­dissociation inhibitor 1 and ANXA4] that were upregulated by >1.5­fold in heavy (H)­ and light (L)­labeled A549R cells. In addition, 16 and 14 proteins were downregulated by >1.5­fold in the H­ and L­labeled A549R cells, respectively. The majority of the downregulated proteins were associated with apoptosis. In conclusion, the present study isolated a cisplatin­resistant human lung cancer A549 cell clone, with reduced apoptosis and high levels of autophagy, in response to cisplatin treatment. In cisplatin­resistant A549R cells, SILAC proteomics recognized the high expression of GRP78 and other proteins that are associated with anti­apoptosis and/or autophagy promotion.

Phytochemicals: Current strategy to sensitize cancer cells to cisplatin.

Cisplatin-based chemotherapeutic regimens are the most frequently used adjuvant treatments for many types of cancer. However, the development of chemoresistance to cisplatin results in treatment failure. Despite the significant developments in understanding the mechanisms of cisplatin resistance, effective strategies to enhance the chemosensitivity of cisplatin are lacking. Phytochemicals are naturally occurring plant-based compounds that can augment the anti-cancer activity of cisplatin, with minimal side effects. Notably, some novel phytochemicals, such as curcumin, not only increase the efficacy of cisplatin but also decrease toxicity induced by cisplatin. However, the exact mechanisms underlying this process remain unclear. In this review, we discussed the progress made in utilizing phytochemicals to enhance the anti-cancer efficacy of cisplatin. We also presented some ideal phytochemicals as novel agents for counteracting cisplatin-induced organ damage.

Synergic highly effective photothermal-chemotherapy with platinum prodrug linked melanin-like nanoparticles.

Cisplatin is widely used in cancer treatment, but the application is limited due to toxicities and its acquired resistance. In this study, we delivered cisplatin to prostate cancer cells by linking the platinum prodrug Pt(IV) to melanin-like nanoparticles (MeNPs), a promising photothermal therapeutic agent with excellent biocompatibility. As expected, the Pt(IV)-MeNPs exhibited brilliant synergic photothermal-chemotherapy upon near-infrared reflection exposure. Compared with free cisplatin, Pt(IV)-MeNPs displayed highly effective antitumour activity both in vitro and in vivo.

Chemical Imaging of Platinum-Based Drugs and their Metabolites.

Platinum-based drugs (cisplatin, carboplatin, and oxaliplatin) are widely used therapeutic agents for cancer treatment. Even though the platinum (Pt)-drugs are routinely used clinically, a clear picture of their distribution within tumor tissues is lacking. The current methods to image the distribution of Pt drugs are limited and do not enable the discrimination of the drug from its metabolites. In this manuscript, we demonstrate a methodology that enables chemical imaging of a Pt drug and its metabolites simultaneously and specifically. Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) is combined with an on-tissue chemical derivatization using diethyldithiocarbamate (DDTC). DDTC abstracts the Pt atom to generate ionizable complexes that can be imaged by MALDI MSI. We demonstrate that Pt drugs and their metabolites can be specifically imaged. This approach was successfully applied to map the penetration and metabolism of oxaliplatin in hyperthermic intraperitoneal chemotherapy (HIPEC)-like treated 3D colorectal tumor mimics. The distribution of cisplatin and carboplatin was mapped in additional 3D tumor mimics. We demonstrate that the approach can also be used to image the distribution of copper ions in cells. This method has the potential to be used to evaluate the penetration and distribution of a wide range of compounds.

A new hexapeptide from the leader peptide of rMnSOD enters cells through the oestrogen receptor to deliver therapeutic molecules.

A 24-amino acid leader peptide of a new human recombinant manganese superoxide dismutase can enter cells and carry molecules. Here, we demonstrated that six of the 24 amino acids penetrate cells through a particular gate represented by a specific amino acid sequence of the oestrogen receptor (ER). We analysed the internalization of the synthetic hexapeptide and the cytotoxic activity of the hexapeptide conjugated to cisplatin on a cell line panel. In most cell lines, the hexapeptide delivered an amount of cisplatin that was 2 to 8 times greater than that released by cisplatin when the drug was used alone. This increased delivery increases the therapeutic index of cisplatin and reduces side effects caused by a high dosage or long-term treatment times. We may consider this hexapeptide a new molecular carrier to deliver molecules with therapeutic activity into ER(+) cells for diagnostic purposes and clinical or immune therapy.

RETRACTED: Tea polyphenols enhance cisplatin chemosensitivity in cervical cancer cells via induction of apoptosis.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Multiple figures in this article appear to be falsified/fabricated. Figure 2A and C. The representative dot plots from the EGCG (15ug/ml)+CDDP (10ug/ml) and TF (15ug/ml) groups appear to be duplicated. Figures 3, 4 and 6. Multiple Western blot bands appear to be rotated and reused throughout Figure 3 (A and B); 4 (A and B) and 6 (A, B, C). In particular, the Cytochrome-c blot in Figure 3B is duplicated and flipped in Figure 6B as p-NFKB. The p53 blot in Figure 3B is duplicated in Figure 6C as p-NFKB. The B-actin blot in Figure 3B is shown as an unmarked control lane (flipped in Figure 6B. The p53 band in Figure 3C is very similar to the Caspase 9 blot in Figure 4B and is cropped and duplicated in Figure 6A as p-NFKB by cisplatin in SiHa cells. The Caspase 3 blot in Figure 4A is rotated and flipped and appears in Figure 6B as p-IKBa.

Cloning analysis of ferritin and the cisplatin-subunit for cancer cell apoptosis in Aplysia juliana hepatopancreas.

Ferritin, an iron storage protein, plays a key role in iron metabolism in vivo. Here, we have cloned an inducible ferritin cDNA with 519 bp within the open reading frame fragment from the hepatopancreas of Aplysia juliana (AJ). The subunit sequence of the ferritin was predicted to be a polypeptide of 172 amino acids with a molecular mass of 19.8291kDa and an isoelectric point of 5.01. The cDNA sequence of hepatopancreas ferritin in AJ was constructed into a pET-32a system for expressing its relative protein efficiently in E. coli strain BL21, under isopropyl-ß-d-thiogalactoside induction. The recombinant ferritin, which was further purified on a Ni-NTA resin column and digested with enterokinase, was detected as a single subunit of approximately 20 kDa mass using both SDS-PAGE and mass spectrometry. The secondary structure and phosphorylation sites of the deduced amino acids were predicted using both ExPASy proteomic tools and the NetPhos 2.0 server, and the subunit space structure of the recombinant AJ ferritin (rAjFer) was built using a molecular operating environment software system. The result of in-gel digestion and identification using MALDI-TOF MS/MS showed that the recombinant protein was AjFer. ICP-MS results indicated that the rAjFer subunit could directly bind to cisplatin[cis-Diaminedichloroplatinum(CDDP)], giving approximately 17.6 CDDP/ferritin subunits and forming a novel CDDP-subunit. This suggests that a nanometer CDDP core-ferritin was constructed, which could be developed as a new anti-cancer drug. The flow cytometry results indicated that CDDP-rAjFer could induce Hela cell apoptosis. Results of the real-time PCR and Western blotting showed that the expression of AjFer mRNA was up-regulated in AJ under Cd(2+) stress. The recombinant AjFer protein should prove to be useful for further study of the structure and function of ferritin in Aplysia.

Reduction of cisplatin-induced nephrotoxicity in vivo by selenomethionine: the effect on cisplatin-DNA adducts.

Cisplatin is one of the most effective chemotherapeutic agents, although its clinical use is limited by severe renal toxicity. This toxicity seems to be related to the accumulation of the drug in kidney tissues, leading to renal failure. For this reason, several compounds have been evaluated to ameliorate the nephrotoxicity induced by cisplatin. In the present investigation, we report the effect of the oral administration of selenomethionine before intraperitoneal cisplatin treatment. The preadministration of this Se species has been shown to have an important effect in reducing renal damage induced by cisplatin by increasing the excreted urea and improving creatinine clearance. Quantification of the level of DNA--cisplatin adducts in kidney and liver tissues was carried out by postcolumn isotope dilution analysis using liquid chromatography-inductively coupled plasma (LC-ICP-MS) as speciation set up. The level of DNA--cisplatin adducts in rats given Se-methionine in the drinking water before cisplatin administration was considerably lower in kidney tissues with respect to the animals drinking only water. Such effects were not observed in liver tissue. Initial speciation studies of Pt and Se conducted in kidney tissues of exposed animals by HPLC-ICP-MS have revealed the presence of cisplatin as part of a complex with Se-methionine, which can be eventually excreted into urine. This Pt--Se complex could explain the observed reduction of the kidney damage in Se-methionine-treated animals.

Cisplatin-loaded gelatin-poly(acrylic acid) nanoparticles: synthesis, antitumor efficiency in vivo and penetration in tumors.

Cisplatin (CDDP)-loaded gelatin-poly(acrylic acid) (GEL-PAA) nanoparticles were successfully prepared by polymerizing acrylic acid in the presence of gelatin in aqueous solution followed by incorporating CDDP into the formed GEL-PAA nanoparticles through polymer-metal complex formation of CDDP with carboxylic groups in the nanoparticles. The obtained nanoparticles had a spherical shape, with a mean size of about 100 nm, and high drug payload as well as stability. It is found that CDDP can be released from the nanoparticles in a sustained manner with a small initial burst release. In vitro cytotoxicity revealed that CDDP-loaded nanoparticles had similar cytotoxicity to free CDDP after 48 h co-incubation with human colorectal cancer cell line LoVo. In vivo antitumor activity indicated that the nanoparticle formulation was superior in anticancer effect to free CDDP on murine hepatic H22 tumor-bearing mice model through intraperitoneal (i.p.) administration and displayed a dose-dependent antitumor efficacy. Further, the penetration examination of the nanoparticles through tumor tissue revealed that the CDDP-loaded GEL-PAA nanoparticles could only affect the cells near the tumor vasculature after they entered into the tumor tissue.

Comparison of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a murine model of peritoneal carcinomatosis.

BACKGROUND: The best method to deliver intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis from ovarian cancer is not well defined. The aim of this study was to assess the ability of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a rat model of peritoneal carcinomatosis. METHODS: Four groups of 5 BDIX rats with ovarian peritoneal carcinomatosis underwent IPC with 30 mg/l of cisplatin according to the following conditions: normothermia at 37° for 1 or 2 hours, hyperthermia at 42°C for 1 hour or normothermia at 37°C for 2 hours with 2 mg/l adrenaline. Tissue platinum content was measured by atomic absorption spectroscopy. The effect of hyperthermia, adrenaline and the duration of exposure to the drug was measured in vivo (tissue concentration of platinum in tumor, abdominal and extra abdominal tissues) and in vitro (cytotoxicity on human ovarian cancer cells). RESULTS: In vitro, hyperthermia and longer exposure enhanced the accumulation and the cytotoxic effect of cisplatin on cancer cells. In vivo, only the 2 hours treatment with adrenaline resulted in increased platinum concentrations. The rats treated with adrenaline showed significantly lower concentrations of cisplatin in extra peritoneal tissues than those treated with hyperthermia. CONCLUSION: Adrenaline is more effective than hyperthermia in order to enhance the intratumoral concentration of cisplatin in rats with peritoneal carcinomatosis from ovarian origin. It may also decrease the systemic absorption of the drug.