Administration Of CDDP Research Articles

Linagliptin mitigates cisplatin-induced kidney impairment via mitophagy regulation in rats, with emphasis on SIRT-3/PGC-1α, PINK-1 and Parkin-2

Cisplatin (CDDP) often leads to kidney impairment, limiting its effectiveness in cancer treatment. The lack of mitophagy in proximal tubules exacerbates this issue. Hence, targeting SIRT-3 and PGC1-α shows promise in mitigating CDDP-induced kidney damage. The potential renoprotective effects of linagliptin, however, remain poorly understood. This study represents the first exploration of linagliptin's impact on CDDP-induced kidney impairment in rats, emphasizing its potential role in mitophagic pathways. The experiment involved four rat groups: Group (I) received saline only, Group (II) received a single intraperitoneal injection of CDDP at 6 mg/kg. Groups (III) and (IV) received linagliptin at 6 and 10 mg/kg p.o., respectively, seven days before CDDP administration, continuing for an additional four days. Various parameters, including renal function tests, oxidative stress, TNF-α, IL-1β, IL-6, PGC-1α, FOXO-3a, p-ERK1, and the gene expression of SIRT-3 and P62 in renal tissue, were assessed. Linagliptin improved renal function, increased antioxidant enzyme activity, and decreased IL-1β, TNF-α, and IL-6 expression. Additionally, linagliptin significantly upregulated PGC-1α and PINK-1/Parkin-2 expression while downregulating P62 expression. Moreover, linagliptin activated FOXO-3a and SIRT-3, suggesting a potential enhancement of mitophagy. Linagliptin demonstrated a positive impact on various factors related to kidney health in the context of CDDP-induced impairment. These findings suggest a potential role for linagliptin in improving cancer treatment outcomes. Clinical trials are warranted to further investigate and validate its efficacy in a clinical setting.

Effect of Hydration with Bicarbonate Ringer's Solution on Cisplatin-induced Acute Kidney Injury in Patients with Esophageal Cancer: A Retrospective Cohort Study.

Cisplatin (CDDP) often causes acute kidney injury (AKI), and magnesium supplementation has been suggested to be important in preventing CDDP-induced AKI. Sodium bicarbonate Ringer's solution (BRS) is a crystalloid solution composed of various electrolytes, including Mg2+, and can be generally used to supplement missing extracellular fluid and correct metabolic acidosis; however, the clinical outcomes of hydration with BRS for CDDP-induced AKI remain unclear. In this study, we retrospectively compared the effects of BRS and normal saline for hydration in patients undergoing CDDP treatment. We analyzed the incidence rate of AKI (grade ≥ 1), the severity of AKI, the serum magnesium level, and the incidence rate of grade ≥ 3 hematological toxicities (leukopenia, neutropenia, anemia, or thrombocytopenia) following CDDP and fluorouracil (5-FU) administration in 131 in-patients who received CDDP and 5-FU for the first time to treat esophageal cancer. Fifty-six patients (43%) received saline alone, while 75 patients (57%) received BRS for hydration. The incidence rate of AKI (grade ≥ 1) was significantly lower in the BRS group (11%) than that in the saline group (39%, p < 0.001). Moreover, severe AKI (grade ≥ 2) was significantly less common in the BRS group than in the saline group. Although the serum magnesium levels before CDDP administration were not significantly different between the two groups (p = 0.939), the serum magnesium levels on days 2-3 after CDDP administration in the BRS group were significantly higher than those in the saline group (p < 0.001). In contrast, there were no significant differences in the incidence rates of hematological toxicity between the two groups. Multivariate analysis revealed that BRS use was an independent factor that significantly contributed to AKI prevention (odds ratio = 0.061, p < 0.001). Hydration with BRS could prevent CDDP-induced AKI in patients with esophageal cancer.

Analysis of the effectiveness of different schemes of supportive therapy in the prophylaxis of cisplatin-induced nephrotoxicity

Objective: To evaluate, in the scenario of rapid infusion, the effectiveness of the different regimens of supportive therapy employed in the prevention of nephrotoxicity and electrolyte depletion induced by cisplatin (CDDP). Methods: Data from patients who used CDDP weekly (30 to 40mg/m2) with an infusion time of 60-120 minutes were analyzed. The regimens evaluated were: saline solution (A), saline solution and mannitol (B), saline solution and magnesium (C) and saline solution with mannitol and magnesium (D). The following laboratory parameters were evaluated: creatinine (Cr), magnesium (Mg) sodium (Na) and potassium (K), and glomerular filtration rate (GFR). They were subsequently compiled in Microsoft Office Excel® and analyzed in Software R, using with analysis by means of descriptive statistics, developed in accordance with the recommendations of Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement. Results: The study population evaluated were 46 patients, who received 218 infusions of CDDP. It was observed that schemes A and B had a progressive decrease in Mg. Scheme B had decreased levels of K, Cr and increased Na. In the individual analysis of each cycle, the different schemes of supportive therapy in rapid infusion were equally effective in preventing nephrotoxicity and electrolyte depletion. The schemes used were evaluated for throughout CDDP administrations, the regimen C and D demonstrated efficacy in maintaining renal function throughout multiple administration of CDDP. Conclusion: In the analysis of cumulative doses, regimen C proved to be effective in preserving renal function throughout CDDP administrations. In the individual analysis of each cycle, regardless of the number of times CDDP was administered, protocols C and D, which contained Mg supplementation associated or not with mannitol, were equally effective in preventing nephrotoxicity.

Integration of Network Pharmacology and Experimental Validation to Explore Jixueteng - Yinyanghuo Herb Pair Alleviate Cisplatin-Induced Myelosuppression.

Jixueteng, the vine of the bush Spatholobus suberectus Dunn., is widely used to treat irregular menstruation and arthralgia. Yinyanghuo, the aboveground part of the plant Epimedium brevicornum Maxim., has the function of warming the kidney to invigorate yang. This research aimed to investigate the effects and mechanisms of the Jixueteng and Yinyanghuo herbal pair (JYHP) on cisplatin-induced myelosuppression in a mice model. Firstly, ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) screened 15 effective compounds of JYHP decoction. Network pharmacology enriched 10 genes which may play a role by inhibiting the apoptosis of bone marrow (BM) cells. Then, a myelosuppression C57BL/6 mice model was induced by intraperitoneal (i.p.) injection of cis-Diaminodichloroplatinum (cisplatin, CDDP) and followed by the intragastric (i.g.) administration of JYHP decoction. The efficacy was evaluated by blood cell count, reticulocyte count, and histopathological analysis of bone marrow and spleen. Through the vivo experiments, we found the timing of JYHP administration affected the effect of drug administration, JYHP had a better therapeutical effect rather than a preventive effect. JYHP obviously recovered the hematopoietic function of bone marrow from the peripheral blood cell test and pathological staining. Flow cytometry data showed JYHP decreased the apoptosis rate of BM cells and the western blotting showed JYHP downregulated the cleaved Caspase-3/Caspase-3 ratios through RAS/MEK/ERK pathway. In conclusion, JYHP alleviated CDDP-induced myelosuppression by inhibiting the apoptosis of BM cells through RAS/MEK/ERK pathway and the optimal timing of JYHP administration was after CDDP administration.

Exploring the chondroitin sulfate nanogel's potential in combating nephrotoxicity induced by cisplatin and doxorubicin—An in-vivo study on rats

In this study, we aim to unveil the potential of itaconyl chondroitin sulfate nanogel (ICSNG) in tackling chronic kidney diseases triggered by the administration of CDDP and doxorubicin (Adriamycin, ADR). To that end, the new drug delivery system (ICSNG) was initially prepared, characterized, and loaded with the target drugs. Thereafter, the in-vivo studies were performed using five equally divided groups of 100 male Sprague-Dawley (SD) rats. Biochemical evaluation and immunohistochemistry studies have revealed the renal toxicity and the ameliorative effects of ICSNG on renal function. When ICSNG-based treatments were contrasted with the CDDP and ADR infected groups, they significantly increased paraoxonase-1 (PON-1), superoxide dismutase (SOD), catalase (CAT) and albumin activity and significantly decreased nitric oxide (NO), tumor necrosis factor alpha (TNF-α), creatinine, urea, and cyclooxygenase-2 (COX-2) activity (p < 0.001). The findings of the current study imply that ICSNG may be able to lessen renal inflammation and damage in chronic kidney disorders brought on by the administration of CDDP and ADR. Interestingly, according to the estimated selectivity indices, the ICSNG-encapsulated drugs have demonstrated superior selectivity for cancer MCF-7 cells, over healthy HSF cells, in comparison to the bare drugs.

Comparison of the ameliorative roles of crab chitosan nanoparticles and mesenchymal stem cells against cisplatin-triggered nephrotoxicity

AimIn the present investigation, we compared the effects of mesenchymal stem cells extracted from bone marrow (BMSCs) and crab chitosan nanoparticles (CCNPs) on renal fibrosis in cisplatin (CDDP)-induced kidney injury rats. Material and methods90 male Sprague-Dawley (SD) rats were divided into two equal groups and alienated. Group I was set into three subgroups: the control subgroup, the CDDP-infected subgroup (acute kidney injury), and the CCNPs-treated subgroup. Group II was also divided into three subgroups: the control subgroup, the CDDP-infected subgroup (chronic kidney disease), and the BMSCs-treated subgroup. Through biochemical analysis and immunohistochemical research, the protective effects of CCNPs and BMSCs on renal function have been identified. ResultsCCNPs and BMSC treatment resulted in a substantial rise in GSH and albumin and a decrease in KIM-1, MDA, creatinine, urea, and caspase-3 when compared to the infected groups (p < 0.05). ConclusionAccording to the current research, chitosan nanoparticles and BMSCs may be able to reduce renal fibrosis in acute and chronic kidney diseases caused by CDDP administration, with more improvement of kidney damage resembling normal cells after CCNPs administration.

Therapeutic potential and protection enhancement of mesenchymal stem cell against cisplatin-induced nephrotoxicity using hyaluronic acid-chitosan nanoparticles as an adjuvant

A newly synthesized nanoplatform of hyaluronic acid and chitosan nanoparticles (HA/CNPs) was applied to improve the therapeutic efficacy and protection of bone marrow mesenchymal stem cells (BM-MSCs) against cisplatin (CDDP)-induced nephrotoxicity in rats. CDDP administration causes significant increases in levels of serum creatinine (SCr), urea, and KIM-1 coupled with significant albumin level falls, as indicative of acute renal dysfunction. Moreover, the level of the antioxidant enzyme (GSH) was significantly decreased, while the levels of lipid peroxidation (MDA) and inflammatory (IL-6) and apoptotic (caspase-3) markers were significantly increased, indicating a decline in the kidney's antioxidant defense and increased inflammation. In contrast, when rats were pre-treated with either MSCs or MSCs-HA/CNPs before receiving CDDP, the levels of SCr, urea, KIM-1, MDA, IL-6, and caspase-3 were significantly decreased with simultaneous significant rises in GSH and albumin, impelling a great improvement in the antioxidant and anti-inflammatory defenses of the kidney as well as its functions. Intriguingly, MSCs-HA/CNPs were more effective against caspase-3 than MSCs alone, revealing the high anti-apoptotic capability of HA/CNPs. This finding suggests that HA/CNPs could effectively protect MSCs from oxidative stress and apoptosis and thus increase their stability and longevity.

Chlorogenic acid attenuates cisplatin-induced ovarian injury in rats

The aim of this study was to determine the possible therapeutic effect of chlorogenic acid (CGA) on cisplatin (CDDP)-induced ovarian damage in rats. Rats were first exposed to CDDP (5 mg/kg) and then treated CGA (1.5 and 3 mg/kg) for three days. Oxidative stress (OS), inflammation and apoptosis markers were determined using spectrophotometric methods. Ovarian tissues were also evaluated histologically. The levels of OS, inflammation and apoptosis biomarkers increased by CDDP administration (p < 0.05). Treatments with CGA significantly alleviated these markers dose-dependently (p < 0.05). These data reveal that CGA may exert an ovoprotective effect by reducing pro-inflammatory mediators and enhancing antioxidant status in ovarian tissue.

Cisplatin causes erectile dysfunction by decreasing endothelial and smooth muscle content and inducing cavernosal nerve senescence in rats.

Cisplatin (cis-diamminedichloroplatinum II, CDDP), a drug widely used for cancer worldwide, may affect erectile function, but its side effects have not received enough attention. To investigate the effect of CDDP on erectile function and its possible mechanism. Sprague-Dawley rats were intraperitoneally administered CDDP (CDDP group) or the same volume of normal saline (control group). Erectile function was evaluated after a one-week washout. Then, histologic changes in the corpus cavernosum and cavernous nerve (CN) were measured. Other Sprague-Dawley rats were used to isolate the major pelvic ganglion and cavernous nerve (MPG/CN). RSC96 cells were then treated with CDDP. SA-β-gal staining was used to identify senescent cells, and qPCR was used to detect the senescence-associated secretory phenotype (SASP). Finally, the supernatant of RSC96 cells was used to culture MPG/CN. Erectile function was measured after administration of CDDP. The cavernosum levels of α-SMA, CD31, eNOS, and γ-H2AX, the apoptosis rate and the expression of p16, p21 and p53 in CN were also assayed. The senescent phenotype of RSC96 cells treated with CDDP was identified, and neurite growth from the MPG/CN was photographed and measured. The CDDP group had a significantly lower ICP/MAP ratio than the control group. Compared to the control group, the CDDP group exhibited significantly lower α-SMA, CD31 and eNOS levels and significantly higher γ-H2AX and apoptosis rates in corpus cavernosum. In addition, CDDP increased some senescence markers p16, p21 and p53 in CN. In vitro, CDDP induced RSC96 senescence and SASP, and the supernatant of senescent cells slowed neurite outgrowth of MPG/CN. CDDP treatment could induce erectile dysfunction, by affecting the content of endothelial and smooth muscle and causing SASP in CN. The results indicate that CDDP treatment should be considered as a risk factor for ED. Clinicians should pay more attention to the erectile function of cancer patients who receive CDDP treatment.

Changes in zinc and manganese concentrations in cisplatin-induced acute kidney injury

Cisplatin (CDDP) is a widely used anticancer drug, but acute kidney injury (AKI) is one of the most important dose-limiting factors. Trace metal elements are present in various concentrations in the body and play an important role in maintaining normal vital functions. However, the relationship between CDDP-induced AKI and trace metal elements is unknown. In this study, we cultured human renal proximal tubular epithelial cells in the presence of CDDP (0, 12.5, 25, 50 μM) and analyzed the concentration of trace elements in medium after 24 h. We found that CDDP significantly increased the concentrations of zinc (Zn) and manganese (Mn) in medium and significantly decreased them in lysate. Therefore, we examined the effects of CDDP (3 mg/kg, i.p.) administration on serum and urinary Zn and Mn concentrations in rats. The results showed that urinary excretion of Zn and Mn increased in CDDP-treated rats 5 days after administration. Also, 5 days after administration, pyknosis, nuclear loss, loss of the brush border membrane, and DNA fragmentation were observed, and serum creatinine and blood urea nitrogen levels were found to be significantly increased. These data suggested that 24-h excretion of Zn and Mn might reflect on CDDP induced nephropathy. Monitoring urinary Zn and Mn excretion may be beneficial in detecting AKI, but further studies are needed for clinical application.

Toll-like Receptor Agonist CBLB502 Protects Against Cisplatin-induced Liver and Kidney Damage in Mice.

CBLB502, a Toll-like receptor-5 agonist derived from Salmonella flagellin, exerts protective roles against irradiation and chemical drugs in mammalian tissues and stimulates tissue regeneration. This study aimed to investigate whether CBLB502 can protect against liver and kidney damage induced by the chemotherapeutic drug cisplatin (CDDP) and the underlying mechanism of the protective effect. Mice were pretreated with CBLB502 [0.2 mg/kg, intraperitoneal (i.p.) injection] 0.5 h prior to administration of CDDP (20 mg/kg, i.p. injection), and analyses of the liver and kidney indices, blood biochemistry, and histopathology were performed. Pretreatment with CBLB502 alleviated CDDP-induced liver and kidney damage. RNA sequencing and bioinformatic analysis indicated that CDDP induced a similar damage-promoting gene regulation pattern in the liver and kidney. CBLB502 protected against liver and kidney damage only after CDDP treatment primarily via different pathways. However, some CBLB502-regulated genes were common between the liver and kidney, including those involved in blood coagulation, fibrinolysis, hemostasis, apoptotic regulation, NF-kappaB signaling, and response to lipopolysaccharide, suggesting a general protective effect by CBLB502. Our data provide insights into the protective mechanism of CBLB502 against CDDP-induced tissue damage in the liver and kidney and might provide a basis for future studies on functional genes and regulatory mechanisms that mediate protection against chemoradiotherapy-induced damage.

Inhibition of JNK/c-Jun-ATF2 Overcomes Cisplatin Resistance in Liver Cancer through down-Regulating Galectin-1.

Due to drug resistance, the clinical response to cisplatin (CDDP) from patients with liver cancer is unsatisfactory. The alleviation or overcoming of CDDP resistance is an urgent problem to be solved in clinics. Tumor cells rapidly change signal pathways to mediate drug resistance under drug exposure. Here, multiple phosphor-kinase assays were performed and c-Jun N-terminal kinase (JNK) was activated in liver cancer cells treated with CDDP. The high activity of the JNK promotes poor progression and mediates cisplatin resistance in liver cancer, leading to a poor prognosis of liver cancer. Mechanistically, the highly activated JNK phosphorylated c-Jun and ATF2 formed a heterodimer to upregulate the expression of Galectin-1, leading to promoting cisplatin resistance in liver cancer. Importantly, we simulated the clinical evolution of drug resistance in liver cancer by continuous CDDP administration in vivo. In vivo bioluminescence imaging showed the activity of JNK gradually increased during this process. Moreover, the inhibition of JNK activity by small molecular or genetic inhibitors enhanced DNA damage and overcame CDDP resistance in vitro and in vivo. Collectively, our results underline that the high activity of JNK/c-Jun-ATF2/Galectin-1 mediates cisplatin resistance in liver cancer and provides an optional scheme for dynamic monitoring of molecular activity in vivo.

Concomitant palonosetron ameliorates cisplatin-induced nephrotoxicity, nausea, and vomiting: a retrospective cohort study and pharmacovigilance analysis

BackgroundCisplatin (CDDP)-induced nephrotoxicity is the most important complication of CDDP treatment. 5-Hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are widely used to prevent chemotherapy-induced nausea and vomiting (CINV). However, in patients with the triple antiemetic (neurokinin-1 receptor antagonist, 5-HT3RA, and dexamethasone) therapy, the advantage of palonosetron in comparison with other 5-HT3RAs on CDDP-induced nephrotoxicity and CINV remains unclear. In the present study, we investigated the effect of palonosetron on CDDP-induced nephrotoxicity and CINV in patients with the triple antiemetic therapy by a retrospective cohort study and a pharmacovigilance analysis.MethodsWe retrospectively analyzed the effect of 5-HT3RAs on the development of nephrotoxicity and CINV in 110 patients who received CDDP, fluorouracil, and triple antiemetic therapy for the treatment of esophageal cancer. Moreover, the effect of 5-HT3RAs on CDDP-induced nephrotoxicity was validated in patients with the triple antiemetic therapy using the Japanese Adverse Drug Event Report (JADER) database.ResultsIn a retrospective study, the incidence of nephrotoxicity (≥ grade 1) in patients receiving palonosetron (18%) was significantly lower than that in patients receiving ramosetron (another 5-HT3RA) (36%, p = 0.044). Moreover, severe nephrotoxicity ≥ grade 3 was observed in one patient treated with ramosetron, whereas hematological toxicity was comparable between the two groups (p = 0.553). Furthermore, the incidence rate of CINV within 120 h following CDDP administration in patients treated with palonosetron (18%) was significantly lower than that in patients receiving ramosetron (39%, p = 0.026). JADER database analyses revealed that the reporting odds ratio of palonosetron for CDDP-induced acute kidney injury was 0.282 (95% confidence interval: 0.169–0.472).ConclusionsThe findings of the present study suggested a greater potential of palonosetron against CDDP-induced nephrotoxicity and CINV than other 5-HT3RAs in patients with the triple antiemetic therapy.

Biocompatibility study of P (N-isopropylacrylamide)-based nanocomposite and its cytotoxic effect on HeLa cells as a drug delivery system for Cisplatin

Cisplatin (CDDP) is widely used as an effective drug in the treatment of various cancers. In spite of its therapeutic effects, there are disadvantages in using CDDP, including causing toxicity in healthy cells, also tumor cells become resistant in prolonged use. The use of magnetic nanogels (nanocomposite), as a drug delivery system, can be a potential strategy to overcome these disadvantages. In this study, the biocompatibility (hemocompatibility and cytocompatibility) of the magnetic, pH, and thermo-responsive poly (N-isopropylacrylamide-co-N, N-dimethylaminoethyl methacrylate-co-4-acrylamidofluorescein)-Fe3O4 nanocomposite was assessed in normal cells. Moreover, we evaluated the cytotoxicity, apoptosis, and drug-resistant genes expression of CDDP-loaded nanocomposite against free CDDP in the cervical cancer cell line (HeLa cells) to investigate its potentials as a vector for drug delivery. The results exhibited that the prepared nanocomposite had an appropriate hemocompatibility. Also, the nanocomposite displayed a good cytocompatibility using LDH test. In addition, the MTT assay of the blank nanocomposite, free CDDP, and CDDP-loaded nanocomposite in the HeLa cells indicated that the blank nanocomposite, had no cytotoxic effects on the cells. However, the Free CDDP and CDDP-loaded nanocomposites demonstrated considerable amount of cytotoxicity effect on the HeLa cells (p < 0.05). The results from the Real Time PCR illustrated that the CDDP-loaded nanocomposite could increase the expression of apoptosis genes and reduce the expression of drug resistance genes in the cancer cells. Our data suggested that the synthetized nanocomposite could be used as an effective and biocompatible drug delivery system for smart delivery and intravenous administration of CDDP. Literature mining-based network discovery proposed candidates for tumor sensitivity/resistance to Cisplatin, viz NR4A1, NR1I2, TP73, and TP53 transcription factors as well as EDN1, CD40LG, INS, and TNFSF11 secreted ligands.

Protective effects of tadalafil against cisplatin-induced spermatogenic dysfunction

BackgroundCisplatin (CDDP) is an effective anticancer drug for the treatment of malignant tumors, such as lung cancer, bladder cancer, and testicular cancer. However, oligozoospermia and azoospermia after administration of CDDP are clinical problems. One of the testicular toxicities of CDDP is known to cause oxidative stress. Tadalafil has been reported to exhibit antioxidant effects and is widely used in clinical practice to treat benign prostatic hyperplasia and erectile dysfunction. Rho-kinase α (ROCK2) regulates cell migration and apoptosis and has been reported to be involved in CDDP-induced nephrotoxicity. The excessive expression of ROCK2 is known to cause oxidative stress. ObjectiveThe objective of the current study was to test the effect of tadalafil on the testicular toxicity of CDDP. Material and methodsThirty-two rats were used and divided into the following four groups. (1) The control group (CONT), treated with saline on day 1 and saline and dimethyl sulfoxide (DMSO) on days 1–10 intraperitoneally (i.p.) (2) The Tadalafil Group (TAD), treated with saline on day 1, and 0.4 mg/kg tadalafil on days 1–10 i.p. (3) The CDDP group (CD), treated with 7 mg/kg CDDP, saline, and DMSO on days 1–10 i.p. and (4) The CDDP + TAD group (CDT) was treated with 7 mg/kg CDDP on day 1, and 0.4 mg/kg tadalafil on days 1–10 i.p. Testes and epididymides samples were collected on day 11. Biochemical and pathological analyses and quantitative polymerase chain reaction were performed on the excised specimens. ResultsCDDP treatment resulted in testicular atrophy, decreased sperm concentration, and atrophy of seminiferous tubules as observed from the testicular histology. Increased apoptosis of seminiferous tubules, oxidative stress, and ROCK2 mRNA expression were observed after CDDP treatment. Treatment with tadalafil improved these adverse effects. ConclusionTadalafil is a potential drug for reducing CDDP-induced spermatogenic dysfunction. The antioxidant effect of tadalafil may be partly responsible for this phenomenon. ROCK2 and oxidative stress markers may be involved in the possible antioxidant effects of tadalafil. Tadalafil may be considered as one of a treatment option for reducing spermatogenic dysfunction after administration of CDDP.

Potential for reversing miR-634-mediated cytoprotective processes to improve efficacy of chemotherapy against oral squamous cell carcinoma

For advanced oral squamous cell carcinoma (OSCC), increasing sensitivity to chemotherapy is a major challenge in improving treatment outcomes, and targeting cytoprotective processes that lead to the chemotherapy resistance of cancer cells may be therapeutically promising. Tumor-suppressive microRNAs (miRNAs) can target multiple cancer-promoting genes concurrently and are thus expected to be useful seeds for cancer therapeutics. We revealed that miR-634-mediated targeting of multiple cytoprotective process-related genes, including cellular inhibitor of apoptosis protein 1 (cIAP1), can effectively increase cisplatin (CDDP)-induced cytotoxicity and overcome CDDP resistance in OSCC cells. The combination of topical treatment with miR-634 ointment and administration of CDDP was synergistically effective against OSCC tumor growth in a xenograft mouse model. Furthermore, the expression of miR-634 target genes is frequently upregulated in primary OSCC tumors. Our study suggests that reversing miR-634-mediated cytoprotective processes activated in cancer cells is a potentially useful strategy to improve CDDP efficacy against advanced OSCC.

Protective effects of tanshinone Ⅰ against cisplatin-induced nephrotoxicity in mice.

Objective(s):Cisplatin (CDDP) is a highly effective chemotherapeutic agent, but its clinical application has been limited by nephrotoxicity. Tanshinone Ⅰ (T-I), a phenanthrenequinone compound extracted from the Chinese herb Danshen, has been used to improve circulation and treat cardiovascular diseases. The aim of this study was to investigate the protective effect of T-I on CDDP-induced nephrotoxicity in mice.Materials and Methods:The BALB/c mouse models of nephrotoxicity were established by a single intraperitoneal injection of 20 mg/kg CDDP on the first day of the experiment. Three hours prior to CDDP administration, the mice were dosed with 10 mg/kg and 30 mg/kg T-I for 3 consecutive days intraperitoneally to explore nephroprotection of T-I.Results:Treatment with T-I significantly reduced blood urea nitrogen and creatinine levels in serum observed in CDDP-administered mice, especially at a dose of 30 mg/kg. T-I at 30 mg/kg significantly decreased malondialdehyde levels and increased glutathione levels and the enzymatic activity of catalase in kidney tissue compared to CDDP. Additionally, T-I (30 mg/kg) significantly reversed the CDDP-decreased expression level of superoxide dismutase 2 protein in renal tissue. Histopathological evaluation of the kidneys further confirmed the protective effect of T-I. Conclusion:The findings of this study demonstrate that T-I can protect against CDDP-induced nephrotoxicity through suppression of oxidative stress.

Renin-angiotensin system inhibitors combined with cisplatin exacerbate cisplatin-induced nephrotoxicity in mice

IntroductionWe previously reported that the concomitant use of enalapril and telmisartan exacerbates the risk of cisplatin (CDDP)-induced acute renal dysfunction compared to other antihypertensive drugs in mice. Thus, in the current study, we investigated the risk of developing chronic kidney disease following repeated concomitant use of CDDP and antihypertensive drugs. Materials and MethodsMale BALB/c mice were divided into 12 groups: (1) Control group (untreated), (2) CDDP group (7 mg/kg, CDDP), (3) AML group (5 mg/kg, amlodipine), (4) ENA group (2.5 mg/kg, enalapril), (5) TEL group (10 mg/kg, telmisartan), (6) LOS group (10 mg/kg, losartan), (7) CDDP+AML group (5 mg/mL, AML), (8) CDDP+ENA group (2.5 mg/kg, ENA), (9) CDDP+LowENA group (1.25 mg/kg, ENA), (10) CDDP+TEL group (10 mg/kg, TEL), (11) CDDP+LowTEL group (5 mg/kg, TEL), and (12) CDDP+LOS group (10 mg/kg, LOS). CDDP was administered intraperitoneally four times every 7 days, and each antihypertensive drug was administered orally from day 3 before CDDP administration until day 24 (six times a week). The degree of renal damage was assessed. The nephrotoxicity of each individual was evaluated by measuring serum creatinine and blood urea nitrogen levels. The degrees of renal fibrosis and epithelial-mesenchymal transition were also examined in kidney tissue sections. Results and DiscussionThe results suggest that combinatorial treatment of CDDP and renin-angiotensin system inhibitors, particularly ENA and TEL, may exacerbate CDDP-induced nephrotoxicity. This study clearly demonstrates the need for large-scale clinical studies to construct treatment regimens that do not interfere with the therapeutic intensity of CDDP.

Efficacy of cisplatin plus vinorelbine adjuvant chemotherapy with split-dose administration of cisplatin after complete resection of stage II-IIIA non-small cell lung cancer.

Although co-administration of cisplatin (CDDP) and vinorelbine (VNR) has been established as a standard of care adjuvant chemotherapy for non-small cell lung cancer (NSCLC), there is a lack of clinical data on its safety and efficacy in Japanese patients receiving split-dose administration of CDDP. The present study analyzed patients who received CDDP + VNR with split-dose administration of CDDP after undergoing complete resection of NSCLC. Patients received four courses of CDDP (40 mg/m2) and VNR (25 mg/m2) on days 1 and 8, every 3 weeks. There were 27 male and 13 female patients; the mean age was 65 years (range 38-78 years), the postoperative disease staging distribution was IIA/IIB/IIIA: 14/8/18 patients, and histological distribution was adenocarcinoma/squamous cell carcinoma/others: 24/12/4 patients, respectively. Of the 40 patients, 28 (70%) completed the four courses of treatment. The mean total dose administered was 279 mg/m2 CDDP (87.2%) and 172 mg/m2 VNR (86%). The major adverse events included Grade (G) 3 or higher neutropenia (80%), G3 phlebitis (5%) and vomiting (2.5%). There was no G2 or higher serum creatinine level elevation, G3 or higher anorexia and nausea, or any treatment-related deaths. The overall completion rate of four courses was 70 and 62.5% for patients aged 70 years and older, whereas the overall percentage of patients that could complete three or more courses was 85 and 87.5% for patients aged 70 years and older. The relapse-free survival rate was 60% at 3 years and 57.5% at 5 years. Overall survival rate was 80% at 3 years and 60% at 5 years. The present study demonstrated the sufficient tolerability, safety and efficacy of combined CDDP + VNR adjuvant chemotherapy with split-dose administration of CDDP, with a low risk of gastrointestinal toxicities or nephrotoxicity.

Analysis of Risk Factors for High-dose Cisplatin-induced Renal Impairment in Head and Neck Cancer Patients.

Concurrent chemoradiotherapy with high-dose cisplatin (CDDP-RT) is the standard therapy for advanced head and neck cancer; however, due to CDDP-induced renal impairment, dose reduction or discontinuation is frequently required. Therefore, the identification of risk factors for renal impairment is of importance to improve the efficacy and safety of CDDP-RT. We retrospectively investigated risk factors for renal impairment in advanced head and neck cancer patients receiving CDDP-RT. Renal impairment was defined as a >25% decrease from baseline in estimated glomerular filtration rate within 14 days after CDDP administration in the first cycle. Of the 82 patients analyzed in this study, 21 (26%) patients developed renal impairment. Multivariate logistic regression analysis showed that concomitant use of a calcium channel blocker or lower hemoglobin levels significantly contributed to the increased risk of CDDP-induced renal impairment (odds ratio=3.60, 95% confidence interval=1.04-12.40; odds ratio=0.71, 95% confidence interval=0.50-0.99, respectively), while concomitant use of proton pump inhibitors was a factor associated with a decreased risk of CDDP-induced renal impairment (odds ratio=0.20, 95% confidence interval=0.04-0.86). Renal function of patients receiving calcium channel blocker or patients with lower hemoglobin levels should be monitored cautiously when receiving CDDP-RT.