Cisplatin-induced Tissue Damage Research Articles

The therapeutical effects of damage-specific stress induced exosomes on the cisplatin nephrotoxicity IN VIVO

Cisplatin is one of the metal containing drugs for the solid cancer treatments. However, its side-effects limit its application in the cancer treatment. Stem cell therapy is a promising treatment for the tissue damage caused by the chemotherapeutic agents, like cisplatin. Exosomes secreted by mesenchymal stem cells (MSCs) could be used for cell-free regenerative treatment, but their potency and reproducibility are questionable. In this study, the microenvironment of the renal tubular epithelial cells was mimicked by coculture of endothelial-, renal proximal tubule epithelial- and fibroblast cells. Cisplatin was applied to this tricell culture model, and the secreted rescue signals were collected and used to induce MSCs. From these stress-induced MSCs, the (stress-induced) exosomes were collected and used for the cell-free therapeutic treatment of cisplatin-treated rats with acute kidney injury. The composition of the stress-induces exosomes was compared with the non-induced exosomes and found that the expression of some critical factors for cell proliferation, repair mechanism and oxidative stress was improved. The cisplatin-damaged renal tissue showed substantial recovery after the treatment with stress-induced exosomes compared to the treatment with non-induced exosomes. Although, the non-induced exosomes showed their activity mostly as cytoprotective, the induced exosomes further involved actively in the tissue regeneration, like MSCs.It was shown that the exosomes could be reprogrammed to improve their therapeutic effect to be used in cell-free regenerative medicine. Further, cisplatin-induced tissue damage in the kidney might be effectively prevented and used for tissue regeneration by use of induced exosomes generated for a particular damage.

Raman spectroscopy: A novel experimental approach to evaluating cisplatin induced tissue damage

The aim of this work is to clarify the effect of curcumin and beta-carotene on cisplatin-induced tissue damage and to demonstrate the potential of Raman spectroscopy to detect tissue changes consistent with liver and kidney histopathology as a potential diagnostic adjunct. İn the study, 56 Wistar albino female rats were used and randomly divided into 7 groups (n:8). Sham group received only sesame oil; Cisplatin group, received a single dose injection of cisplatin; Beta-carotene group, treated with beta-carotene orally; Cisplatin + Beta-carotene group, pretreated with beta-carotene 30 min prior to the cisplatin injection, then received cisplatin; Curcumin group, orally treated with curcumin; Cisplatin + Curcumin group, pretreated with curcumin 30min prior to the cisplatin injection, then received cisplatin. The second application was performed 1 week after the first application. One of the liver and kidney tissues was taken to 10% form for histopathological examinations and the others were taken to −80 °C for raman spectroscopy. Received sections were hematoxylin-eosin stained. The avidin-biotin peroxidase method was used for to investigate anti-TNF-α and IL1-β activities. TUNEL method was applied to determine apoptotic cells.According to our histopathological findings, beta-carotene and especially curcumin have been found to possess hepatorenal protective activities. These datas were supported by the microscopic damage scores. Although some of these findings were observed in both the cisplatin + curcumin and cisplatin + beta-carotene groups, the incidence and severity of histopathological lesions were less than the cisplatin group. Both immunohistochemical studies and Raman spectroscopy results consistent with histopathological examination of hematoxylen-eosin stained sections. Raman spectroscopy represents a suitable tool to provide insights into structural factors involved in the mechanisms underlying antitumor effects of platinum drug.

Kolaviron protects against cisplatin-induced hepatic and renal oxidative damage in rats

Kolaviron is an important bi-flavonoid complex isolated from Garcinia kola seeds which has been reported to possess significant bioactivities. Cisplatin is an antineoplastic drug but tissue damage is a limiting factor to its chemotherapy. The effect of kolaviron on cisplatin-induced alterations of some biochemical parameters in rats was investigated. The study included a control group (group I) that received neither cisplatin nor kolaviron while group II received only kolaviron (100 mg/kg/day) orally for the duration of the experiment. Rats in group III were given cisplatin (10 mg/kg/day) for three consecutive days intraperitoneally. In addition to the injection of cisplatin, rats in group IV were orally given kolaviron at 100 mg/kg/day for six consecutive days prior to the treatment with cisplatin, and for three days simultaneously with cisplatin. However animals in group V were given kolaviron at 200 mg/kg/day for six consecutive days prior to the treatment with cisplatin, and for three days simultaneously with cisplatin. Thereafter, rats were anaesthesized, dissected, serum and tissues were collected and analyzed. The intrapetitoneal-adminstration of cisplatin (10 mg/kg) caused a significant increase in the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (ASP), alkaline phosphatase (ALP), blood urea nitrogen (Urea) and creatinine indicative of liver and kidney damage. Cisplatin also increased the levels of thiobarbituric acid reactive species (TBARS), tumour necrosis factor-alpha (TNF-AE’A‘), interleukin-6 (IL-6) while significantly reducing the expression of superoxide dismutase (SOD) and catalase (CAT) in both liver and kidney. However, oral administration of kolaviron (100 mg/kg and 200 mg/kg) for six days prior and three days co-treatment with cisplatin significantly reversed the cisplatin-induced alterations close to control levels. Apart from the expression of SOD and CAT in liver, the effect of kolaviron was dose-dependent (p < 0.05). Treating the rats with kolaviron (100 mg/kg) alone only significantly enhanced the expression of SOD and CAT in liver over control (p < 0.05). The results reveal kolaviron as an effective chemoprotective agent against cisplatin-induced tissue damage in rats which can be exploited pharmacologically.

Cisplatin-Impaired Adipogenic Differentiation of Adipose Mesenchymal Stem Cells 1

Adipose tissue-derived mesenchymal stem cells (ADSCs) are derived from adipose tissue and can be induced in vitro to differentiate into osteoblasts, chondroblasts, myocytes, neurons, and other cell types. Cisplatin is a commonly used chemotherapy drug for cancer patients. However, the effects of cisplatin on ADSCs remain elusive. This study found that a high concentration of cisplatin affects the viability of ADSCs. First, the IC50 concentration of cisplatin was evaluated. Proliferation of ADSCs, as assessed by the XTT method, decreased immediately after treatment with various concentrations of cisplatin. ADSCs maintained mesenchymal stem cell surface markers after cisplatin treatment, as determined by flow cytometry. Upon differentiation by adding specific reagents, a significant decrease in adipogenic differentiation (by Oil red O staining) and osteogenic differentiation (by Alizarin red staining), and significant chondrogenic differentiation (by Alcian blue staining) were found after cisplatin treatment. Quantitative RT-PCR was also used in evaluating expression of specific genes to confirm differentiation. Finally, ADSCs from one donor who had received cisplatin showed significantly decreased adipogenic differentiation but increased osteogenic differentiation compared with ADSCs derived from one healthy donor. In conclusion, cisplatin affects the viability, proliferation, and differentiation of ADSCs both in vitro and in vivo via certain signaling pathways, such as p53 and Fas/FasL. The differentiation abilities of ADSCs should be evaluated before their transplantation for repairing cisplatin-induced tissue damage.

Mesenchymal stem cells maintain their defining stem cell characteristics after treatment with cisplatin.

Mesenchymal stem cells (MSCs) aid the regeneration of tissues damaged by treatment with cisplatin. However, the effects of this cytotoxic drug on the stem cells have been largely unknown. Here we demonstrate that human bone marrow-derived MSCs are relatively resistant to cisplatin treatment and show resistance levels comparable to these of differentiated fibroblasts. Cisplatin did not affect cellular morphology, adhesion or induction of apoptosis in MSCs. The potential for differentiation was preserved after exposure to cisplatin, and established MSC surface markers were observed to be stably expressed irrespective of cisplatin treatment. Cytoskeletal rearrangements and high expression levels of individual heat shock proteins were detected in MSCs and may be partly responsible for the observed cisplatin resistance. The cisplatin-resistant phenotype of human MSCs supports the concept of further investigating these stem cells as a potential treatment option for cisplatin-induced tissue damage.

AMP-activated protein kinase regulates autophagic protection against cisplatin-induced tissue injury in the kidney.

Although the nephrotoxicity of cisplatin has been well documented as a major side effect of chemotherapy, the exact mechanism by which prosurvival and apoptotic pathways interplay to determine renal pathology remains elusive. Recent studies suggested that autophagy might serve as an adaptive mechanism to promote cell survival during acute kidney injury (AKI). We have used AKI as a disease model to investigate the mechanism regulating the cytoprotective role of autophagy in cisplatin-induced tissue damage. Pharmacological inhibitors such as chloroquine were used to manipulate autophagy during AKI, and DNA damage was evaluated by using the cellular marker γH2AX. Cisplatin induced extensive DNA damage during AKI. Autophagy activation served as a survival strategy to suppress cisplatin-induced DNA damage in the pathology of AKI both in vitro and in vivo. Interestingly, in the kidney, cisplatin treatment can activate AMP-activated protein kinase (AMPK), a signaling molecule that is also critical for p53-mediated inactivation of mammalian target of rapamycin (mTOR) pathways. As a result, inhibition or knockdown of AMPK can lead to repressed autophagy in cisplatin-induced AKI, resulting in more DNA damage. Activation of AMPK regulates autophagy during cisplatin-induced AKI. Given the fact that p53 can regulate autophagy by inactivating mTOR via AMPK, our results suggest that the p53 pathway may also play a critical role in the pathogenesis of cisplatin-induced renal damage. This study may further our understanding of the physiological roles of autophagy in the pathogenesis of renal injuries, and thus may have pathological implications in the clinical setting.

Protective efficacy of antioxidants on cisplatin-induced tissue damage caused in Leishmania donovani infected BALB/c mice against murine visceral leishmaniasis

Objective: Therapeutic interventions against visceral leishmaniasis (VL) are limited and facing serious concerns of toxicity, high cost and emerging resistance, there is a greater interest in new drug developments which are cost effective, efficient and easily available to people suffering from leishmaniasis. Cisplatin (cis-diamminedichloroplatinum II; CDDP) has been found to have antileishmanial activity in vitro and in vivo which lead towards an apoptosis like cell death of both promastigotes and amastigotes and a significant reduction in parasite load and enhanced DTH responses which suggested the generation of protective cell-mediated immune responses. But, at higher doses it causes nephrotoxicity-a major side effect. The present study was designed to evaluate the protective efficacy of antioxidants on cisplatin induced tissue damage in Leishmania donovani infected BALB/c mice. Materials and methods: L. donovani infected and uninfected animals were treated with higher doses (5 and 2.5 mg/kg body weight) of cisplatin alone and in combination with antioxidants (vitamin C, vitamin E and silibinin) for 5 days. Mice were examined for the protective effects of antioxidants on cisplatin indiced tissue damage by DNA fragmentation and histological studies of kidneys, liver and spleen. Results: The damage caused by cisplatin was ameliorated after the supplementation of antioxidants showing a marked reduction in the extent of tubular damage, the focal reaction changes in liver were reversed and no signs of toxicity in the spleen were reported. Moreover, no DNA damage was observed in animals treated with cisplatin along with various antioxidants. Conclusion: The present results showed that antioxidants helped in the amelioration of drug induced toxic effects against murine visceral leishmaniasis, making the combination a potential anti-leishmanial therapy.

The effect of &lt;i&gt;Hibiscus sabdarriffa&lt;/i&gt; calyx extraction cisplatin-induced tissue damage in rats

No Abstract. International Journal of Natural and Applied Sciences Vol. 4 (1) 2008: pp. 63-67

Protective Effects of Increasing Vitamin E and A Doses on Cisplatin-Induced Oxidative Damage to Kidney Tissue in Rats

Objective: Cisplatin (DDP, cis-diamminedichloroplatinium II) is one of the most potent chemotherapeutic antitumor drugs, but is able to generate reactive oxygen species (ROS) and it also inhibits the activity of antioxidant enzymes in renal tissue. In the present study, we investigated the preventive effect of 100, 200 and 400 mg/kg b.w. doses of vitamin E (VE), and 25, 50, and 100 mg/kg b.w. doses of vitamin A (VA) combination on malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels and superoxide dismutase (SOD) activity in cisplatin-induced toxicity in rat kidneys. Our literature survey indicated a lack of any experimental study showing the beneficial effect of VA on cisplatin-induced MDA, NO, GSH and SOD changes. For this reason, we hoped that this study would provide a unique contribution in that respect. Materials and Methods: 59 Wistar rats (11 to replace prematurely lost animals) were used. 48 evaluable rats were divided into 8 groups (n = 6 in each group): control group, DDP alone (5 mg/kg b.w.) group, 3 VE combination treatment groups of VE100+DDP, VE200+DDP, and VE400+DDP, and 3 VA combination treatment groups of VA25+DDP, VA50+DDP, and VA100+DDP. Kidney MDA, GSH, NO levels and SOD activities were determined for the assessment of oxidant-antioxidant balance. Results: While in the DDP group the tissue levels of MDA and NO were found to be significantly higher than in the control group, GSH levels and SOD activities were significantly lower. MDA and NO levels were found to be significantly lower and GSH levels and SOD activities significantly higher in the VE200+DDP and VE400+ DDP groups when compared with the DDP alone group. MDA and NO levels were found to be significantly lower in the VA50+DDP and VA100+DDP groups when compared with the DDP alone group. However, identical comparisons with the DDP alone group showed significantly higher GSH levels and SOD activities in the VA25+DDP, VA50+DDP, and VA100+DDP groups. Among the VE100+ DDP, VE200+DDP, and VE400+DDP groups, and VA25+ DDP, VA50+DDP, and VA100+DDP groups, MDA and NO levels decreased and GSH levels and SOD activities increased steadily and significantly as the doses of VE and VA increased. Conclusion: These vitamins would be effective in protecting against cisplatin-induced tissue damage in rat kidneys. It is possible that the toxic effect of cisplatin is somehow minimized by a compensatory mechanism involving VE and VA via induction of antioxidant enzyme activities following intraperitoneal injection of DDP.

Effects of GR203040, an NK 1 Antagonist, on Radiation- and Cisplatin-Induced Tissue Damage in the Ferret

1. The effects of GR203040, a tachykinin neurokinin 1 receptor antagonist, on tissue damage induced by X-irradiation (Rad) or cisplatin (Cisp) were investigated in ferrets. 2. GR203040 (0.3 mg/kg SC) reduced the Rad-induced plasma protein extravasation (PPE) in the duodenum and kidney by 25% in each tissue. 3. GR203040 (3 mg/kg SC, 5-min pretreatment and every 8 hr for 48 hr after Cisp) reduced the Cisp-induced PPE in the duodenum, jejunum and lung by 59, 52 and 60%, respectively. 4. Histological examination showed that GR203040 also ameliorated the Rad- and Cisp-induced tissue damage.