TY - JOUR. T1 - O6-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma. AU - Chen, Shang Hung. AU - Kuo, Ching Chuan. AU - Li, Chien Feng. AU - Cheung, Chun Hei Antonio. AU - Tsou, Tsui Chun. AU - Chiang, Huai Chih. AU - Yang, Yun Ning. AU - Chang, Shin Lun. AU - Lin, Li Ching. AU - Pan, Hsin Yi. AU - Chang, Kwang Yu. AU - Chang, Jang Yang. PY - 2015/9/1. Y1 - 2015/9/1. N2 - Cisplatin (CDDP) is an important anti-cancer drug commonly used in various human cancers, including nasopharyngeal carcinoma (NPC). How to overcome the drug resistance of CDDP provides opportunities to improve clinical outcomes of NPC. O6-methylguanine-DNA methyltransferase (MGMT) has been well-characterized to be a therapeutic determinant of O6-alkylguanine alkylating drugs. However, the underlying mechanism and clinical relevance between MGMT and CDDP remain poorly defined in NPC. In this study, we showed that MGMT-proficient ...
TY - JOUR. T1 - Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. AU - Woessmann, Willi. AU - Chen, Xinbin. AU - Borkhardt, Arndt. PY - 2002. Y1 - 2002. N2 - Activation of the mitogen-activated protein kinases ERK1/2 by the chemotherapeutic agent cisplatin has been shown to result in either survival or cell death. The downstream mediators of these opposing effects are unknown, as are the upstream signaling molecules. Activation of ERK is required for accumulation and phosphorylation of p53 following cisplatin treatment. We studied the role of ERK activation after cisplatin treatment under p53-negative and p53-positive conditions using a tetracycline-dependent expression vector in Saos-2 osteosarcoma cells. Dose-dependent activation of ERK first occurred 3-6 h after a 2-h cisplatin incubation and declined after 12-24 h in several tumor cell lines. Incubation of cell lines with the MEK1 inhibitors PD98059 or UO126 ...
TY - JOUR. T1 - The effects of the antioxidant α-tocopherol succinate on cisplatin-induced ototoxicity in HEI-OC1 auditory cells. AU - Kim, Sung Kyun. AU - Im, Gi Jung. AU - An, Yun Suk. AU - Lee, Se Hee. AU - Jung, Hak Hyun. AU - Park, Sang Yoo. PY - 2016/7/1. Y1 - 2016/7/1. N2 - Conclusion: D-α-tocopherol succinate significantly reduced a cisplatin-induced hair cell loss in HEI-OC1 cell lines. These effects were mediated by its scavenging activity against reactive oxygen species (ROS) and inhibition of apoptosis. Objectives: Alpha-tocopherol is a class of methylated phenols, known as fat-soluble antioxidants, and is a different form of vitamin E, which reduces free radicals and acts as an antioxidant. We hypothesized that the antioxidative effect of α-tocopherol could protect against cisplastin-induced cytotoxicity, and thus evaluated its effects on cisplatin-induced ototoxicity in HEI-OC1 auditory cells. Methods: HEI-OC1 cells were pretreated with D-α-tocopherol succinate at a ...
In the present work, we studied the molecular mechanisms by which sodium butyrate sensitizes cancer cells towards cisplatin. HeLa cells were treated with 5 mM butyrate, with 8 μM cis-diaminedichloroplatinum II (cisplatin), or with both. Cells treated with both agents showed approximately two-fold increase of the mortality rate in comparison with cells treated with cisplatin only. Accordingly, the life span of albino mice transfected with Ehrlich ascites tumor was prolonged almost two-fold by treatment with cisplatin and butyrate in comparison with cisplatin alone. This showed that the observed synergism of cisplatin and butyrate was not limited to specific cell lines or in vitro protocols, but was also expressed in vivo during the process of tumor development. DNA labeling and fluorescence activated cell sorting experiments showed that cisplatin treatment inhibited DNA synthesis and arrested HeLa cells at the G1/S transition and early S phase of the cell cycle. Western blotting and chromatin ...
Background: Cisplatin is a commonly used anti-cancer drug. However, its use is associated with severe side effects including ototoxicity that affects a large fraction of cisplatin-treated patients. Approved therapies that reduce cisplatin-induced ototoxicity are lacking. Among the candidate therapeutics, dexamethasone stands out. There is extensive experience of its use in combination with cisplatin for the prevention of chemotherapy-induced nausea and vomiting indicating that dexamethasone does not affect the anti-cancer effects of cisplatin. Objective: The objective of this study is to assess the potential of dexamethasone for the prevention of cisplatin-induced ototoxicity by a systematic analysis of the available evidence. Results: We identified 16 relevant original research articles. The analyzed studies reported conflicting results on the effects of dexamethasone on cisplatin-induced ototoxicity. However, studies in which dexamethasone was used prior to cisplatin treatment and directly ...
Our study analyzes the effect of magnesium supplementation on nephrotoxicity in patients receiving cisplatin for head and neck cancer. We retrospectively reviewed the medical records of patients with head and neck cancer who received two doses of cisplatin (80 mg/m2) and 5-fluorouracil (800 mg/m2) 3 weeks apart from August 2008 to October 2012. The regimen prior to 2011 (crystalloid-only) involved the administration of 1000 mL of lactated Ringers solution on the day prior to cisplatin infusion and 2000 mL of continuous infusion of saline on the day of cisplatin infusion. The regimen after 2011 (magnesium-supplemented) did not involve hydration on the day before cisplatin administration but used 1000 mL of 0.9% saline with magnesium sulfate (20 mEq) administered for 3 hours before cisplatin infusion. Sixty-five patients were treated with the crystalloid-only regimen and 56 patients with the magnesium-supplemented regimen. The mean creatinine clearance in the magnesium-supplemented group decreased by 4.9
The efficacy of treatment with a combination of radiotherapy and chemotherapy in the yeast Saccharomyces cerevisiae as suitable eukaryotic model is demonstrated by following the induction and repair of DNA double-strand breaks. These may be induced by ionizing radiation. Furthermore, the chemotherapeutic agent cisplatin may induce DNA double-strand breaks through cellular repair mechanisms. The aim of this study is to investigate the induction and repair of DNA double-strand breaks after a combination of treatment with cisplatin and radiation versus radiation alone under hypoxic conditions.The number of induced double-strand breaks caused by radiation under hypoxic conditions is dependent on dose. Following combined treatment with cisplatin and radiation, the radiation-induced double-strand breaks simply add to those induced by cisplatin. We identified no difference in the repair kinetics of double-strand breaks following radiation between cells treated with cisplatin and those not treated with ...
This study assigned subjects to either cisplatin/vinorelbine or cisplatin/pemetrexed chemotherapy using a genomic based expression profile to determine chemotherapy sensitivity in completely resected early stage non-squamous non-small-cell lung cancer (NSCLC). The vinorelbine-sensitive tumors group received Vinorelbine followed by cisplatin, while the pemetrexed-sensitive tumors group received pemetrexed followed by cisplatin. The primary objective of this trial was to determine whether genomic-based adjuvant chemotherapy treatment increased the 2-year progression-free survival rate in completely resected patients with NSCLC compared to historic controls. Secondary objectives included: 1) estimation of the percentage of completely resected NSCLC tumors that can be adequately analyzed and used to direct specific adjuvant chemotherapy; 2) estimation of the proportion of patients who are assigned to treatment with vinorelbine and pemetrexed; 3) evaluation of drug sensitivity patterns of cisplatin ...
This study determined the in vitro permeability of cisplatin through isolated human sclera as delivered by a collagen matrix vehicle. Short-term and long-term intraocular levels of cisplatin were also measured in the rabbit eye after a subconjunctival injection. Cisplatin in either a collagen matrix vehicle or a control balanced salt solution (BSS) vehicle was applied to human sclera mounted in a specially designed in vitro perfusion chamber. The amount of cisplatin that diffused across the sclera was measured in hourly samples for 24 h using atomic absorption spectrometry. In vivo studies were also performed in Dutch Belted rabbits given subconjunctival injections of cisplatin in collagen matrix or in BSS. Eyes were enucleated at 1.5 h and 2 weeks after injection, frozen, and dissected to determine the intraocular cisplatin concentrations. Cisplatin had a peak in vitro scleral permeability constant of 8.3+/-1.2 x 10(-6) and 20.1+/-1.8 x 10(-6) cm/s, delivered in collagen matrix and in BSS, respectively
The impact of cumulative dose of cisplatin on clinical outcomes of nasopharyngeal carcinoma (NPC) patients who received intensity-modulated radiotherapy (IMRT) was evaluated. This study included 491 consecutive patients with histologically confirmed NPC who were treated with concurrent chemoradiotherapy with IMRT. The patients were divided into three groups: low- (cumulative dose ≤100 mg/m2), medium- (cumulative dose |100 mg/m2 and ≤200 mg/m2), and high- (cumulative dose |200 mg/m2) dose groups. Subgroups of patients included pre-treatment levels of Epstein-Barr Virus DNA (EBV DNA) |4000 copies/ml and pre-treatment EBV DNA ≥4000 copies/ml. To test for independent significance, the Kaplan-Meier with the log-rank test and the Cox proportional hazards model were used. The 5-year overall survival (OS) rates of the low-, medium-, and high-dose groups were 64.1 %, 91.1 %, and 89.4 %, respectively (P = 0.002). Based on multivariate analysis, patients who were in the medium- and high-dose groups had
Gemcitabine and cisplatin treatment were administered to patients with advanced-stage, non-small-cell lung cancer. During phase II studies, the treatment is performed using a 28-day cycle, with gemcitabine administered on days 1, 8, and 15. Although it is advised that cisplatin not be administered...
TY - JOUR. T1 - Peripheral neuroglial death induced by cisplatin administration in newborn rats. AU - Sugimoto, Tomosada. AU - Takeyama, Akihiro. AU - Fujita, Masako. AU - Ichikawa, Hiroyuki. AU - Takano-Yamamoto, Teruko. PY - 2001/1/22. Y1 - 2001/1/22. N2 - To determine the target of cytotoxicity of cisplatin (CDDP), we injected newborn rats with 2mg/kg CDDP and examined the trigeminal ganglion for possible cell death. A nick translation method for DNA fragmentation revealed CDDP-induced glial cell death. DNA fragmentation was detected in both Schwann cells and satellite cells. Satellite cell death was observed as early as 0.5 day after injection, most frequent at 1-3 days and subsided thereafter. The incidence of neuronal death was very low and comparable to that observed in vehicle control rats. CDDP has selective toxicity to peripheral glial cells, though the damage did not culminate in cell death in adults. The glial toxicity may contribute to clinical symptoms of CDDP neuropathy.. AB - To ...
To the editor: We wish to call to your readers attention an unexpectedly severe and disabling neurotoxicity due to very-high-dose cisplatin therapy for cancer of the ovary. The attainment of complete remission, proven by second-look surgery, is the first step toward achieving prolonged survival and cure of stage III cancer of the ovary. Recently, Ozols and associates (1) have reported that administration of very high doses of cisplatin (200 mg/m2 body surface area over 5 consecutive days) has achieved frequent tumor regression in patients with advanced cancer of the ovary previously refractory to conventional doses of cisplatin. To improve complete ...
Drug resistance is still a major obstacle for efficient treatment of hepatocellular carcinoma (HCC) during the cisplatin-based chemotherapy. Recent studies have demonstrated that CD133 positive population of cancer cells are responsible for multiple drug resistance. We are supposed to take strategies to sensitize CD133+ HCC cells to cisplatin treatment. In the present study, CD133+ HCC cells showed significant cisplatin-resistance compared to the CD133- HCC cells. Downregulation of miR-124 was observed in CD133+ HCC cells. However, enforced expression of miR-124 can increase the sensitivity of CD133+ HCC cells to cisplatin treatment in vitro and in vivo. Mechanically, overexpression of miR-124 was found to inhibit the expression of SIRT1 and thus promoted the generation of ROS and phosphorylation of JNK. As the results, overexpression of miR-124 expanded the apoptosis in cisplatin-treated CD133+ HCC cells. We then demonstrated that
The combination of pemetrexed and cisplatin shows good clinical activity against mesothelioma and lung cancer. In order to study the potential cellular basis for this, and provide leads as to how to optimize the combination, we studied the schedule-dependent cytotoxic effects of pemetrexed and cisplatin against four human cancer cell lines in vitro. Tumor cells were incubated with pemetrexed and cisplatin for 24 h at various schedules. The combination effects after 5 days were analyzed by the isobologram method. Both simultaneous exposure to pemetrexed and cisplatin for 24 h and sequential exposure to cisplatin for 24 h followed by pemetrexed for 24 h produced antagonistic effects in human lung cancer A549, breast cancer MCF7, and ovarian cancer PA1 cells and additive effects in colon cancer WiDr cells. Pemetrexed for 24 h followed by cisplatin for 24 h produced synergistic effects in MCF7 cells, additive/synergistic effects in A549 and PA1 cells, and additive effects in WiDr cells. Cell cycle ...
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin
TY - JOUR. T1 - Use of organotypic cultures of Cortis organ to study the protective effects of antioxidant molecules on cisplatin-induced damage of auditory hair cells. AU - Kopke, Richard D.. AU - Liu, Wei. AU - Gabaizadeh, Ramin. AU - Jacono, Andrew. AU - Feghali, Joseph. AU - Spray, David. AU - Garcia, Phil. AU - Steinman, Howard. AU - Malgrange, Bridgitte. AU - Ruben, Robert J.. AU - Rybak, Leonard. AU - Van De Water, Thomas R.. PY - 1997/9/1. Y1 - 1997/9/1. N2 - Hypothesis: Cisplatin causes the generation of reactive oxygen species (ROS), which interferes with the antioxidant defense system of Cortis organ and results in damage to the hair cells. Background: Cisplatin is a widely used chemotherapeutic agent with the dose-limiting side effect of ototoxicity. Evidence is accumulating that cisplatin interferes with the antioxidant defense system of Cortis organ. Methods: Organotypic explants of P-3 rat organ of Corti were the in vitro model system. Presence of intact auditory hair cells and ...
TY - JOUR. T1 - Effect of miR-29 on cisplatin sensitivity of ovarian cancer cells. AU - Yu, Pei Ning. AU - Lin, Wen-Chi. AU - Kuo, Chih Chi. AU - Huang, Rui-Lan. AU - Yan, Ming De. AU - Shih, Yu Lueng. AU - Chou, Yu Ching. AU - Lai, Hung-Cheng. AU - Lin, Ya Wen. PY - 2014/11/21. Y1 - 2014/11/21. N2 - Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, ILIn clinical practice, the main dilemma to a successful ovarian cancer therapy is the development of drug resistance. The mounting evidence demonstrated that microRNAs (miRNAs) not only controlled cell proliferation, invasion and metastasis but also therapeutic resistance of ovarian cancer cell. Recently, we isolated CP70sps(CP70 side population spheres) from CP70 ovarian cancer cell line and proved that CP70sps exhibited more resistant to cisplatin than CP70. This phenomenon was correlated to other study which supported that side population of cancer cells was responsible for chemoresistance. In this study, we ...
A statistically significant (p=0.0039) increase in IL6 was shown in the blood plasma of the cisplatin animals (131.9±31.91 pg/ml) compared to the vehicle animals (38.00±6.748 pg/ml). There were no significant differences between cisplatin and vehicle animals in dorsal horn neurones or astrocytes at either time point. Microglia cell counts in the dorsal horn were significantly decreased at the juvenile time point in the Cisplatin treatment group. Cisplatin induced significant increases in dorsal horn expression of Aβ-fibre and non-peptidergic C-fibre terminations at both time-points, in the Cisplatin treatment group. TrkA expression in dorsal horn peptidetgic C-fibre terminations was increased at both time-points, however, CGRP expression was only initially increased at the juvenile time-point but showed no difference to the veh at the adult time-point. Interneuron expression was increased at both time-points ...
Patients. Twenty-eight cancer patients were included in this study and were treated with locoregional standard radiotherapy and simultaneous cisplatin-containing chemotherapy. They gave their written informed consent to be included in this study, which was approved by the local ethics committee. Patients were irradiated for intrathoracic, pelvic, or head and neck tumors in 21, 4, and 3 cases, respectively. All patients received cisplatin-containing chemotherapy concurrent with radiotherapy at weekly or longer intervals. The cisplatin doses per application ranged from 20 to 50 mg/m2 and were given at days 0 and 7 of each 21- to 28-d cycle. Cisplatin was given according to three schedules, either as cisplatin monochemotherapy or, for non-small cell lung cancer patients (n = 14), as cisplatin 50 mg/m2 and navelbine 15 mg/m2 doublet at days 0 and 7 after the start of radiotherapy (day −1). For small-cell lung cancer patients (n = 4), it was given as cisplatin 45 to 50 mg/m2 at days 0 and 7 ...
An unanswered question in first line treatment of non small cell lung cancer (NSCLC) is whether the administration of more than 2 active drugs provides greater efficacy than a two-drug combination. Docetaxel/gemcitabine combination is a well tolerated regimen, which has comparable efficacy to docetaxel/cisplatin or vinorelbine/cisplatin. In a recent phase II study in first line treatment of advanced or metastatic NSCLC, the sequential administration of vinorelbine/cisplatin followed by docetaxel/gemcitabine produced a response rate of 45.8% and a 1-year survival rate of 51%. The addition of bevacizumab to a platinum-based regimen provided a survival benefit in patients with advanced or metastatic NSCLC ...
Cisplatin-based chemotherapy is the standard therapy used for the treatment of several types of cancer. However, its efficacy is largely limited by the acquired drug resistance. To date, little is known about the RNA expression changes in cisplatin-resistant cancers. Identification of the RNAs related to cisplatin resistance may provide specific insight into cancer therapy. In the present study, expression profiling of 7 cancer cell lines was performed using oligonucleotide microarray analysis data obtained from the GEO database. Bioinformatic analyses such as the Gene Ontology (GO) and KEGG pathway were used to identify genes and pathways specifically associated with cisplatin resistance. A signal transduction network was established to identify the core genes in regulating cancer cell cisplatin resistance. A number of genes were differentially expressed in 7 groups of cancer cell lines. They mainly participated in 85 GO terms and 11 pathways in common. All differential gene interactions in the ...
Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic ...
Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic ...
Background. Erythropoietin (Epo) is a growth factor whose synthesis mainly takes place in the kidney. Epo has been shown to support the growth not only of erythroid progenitor cells but also of certain other cell types. We attempted to establish whether Epo enhances the recovery from acute renal failure induced by cisplatin.. Methods. Sprague‐Dawley rats were randomized into three groups. In the cisplatin group, animals received one intraperitoneal injection of cisplatin (6 mg/kg) and a daily injection of placebo for 9 days. In the cisplatin+Epo group, animals received intrapertoneal cisplatin and a daily injection of Epo (100 IU/kg) for 9 days. In the control group, animals received both placebo preparations alone. Para‐aminohippuric acid and inulin clearances were determined after 4 and 9 days to evaluate renal blood flow and glomerular filtration rate. In addition, light microscopy and immunohistochemistry examinations were performed, and in situ proliferating cell nuclear antigen (PCNA) ...
Objective: To study the therapeutic efficacy of intraperitoneal perfusion of Compound Matrine injection and Cisplatin on malignant ascites. Methods: Forty- two patients of malignant ascites were randomly divided into treatment group and control group. 22 patients were treated with Compound Matrine injection and Cisplatin intraperitoneal perfusion( treatment group),and 20 patients were treated with Cisplatin intraperitoneal perfusion only( control group). The changes in volume of ascites and treatment side effects were observed. Results: The objective response rate( CR and PR) of treatment group and control group were 90. 9% and 65. 0% respectively,and the difference was significant( P 0. 05). The treatment group had a slighter side effect on abdominal pain,gastrointestinal rection and bone marrow depression,and the difference was significant( P 0. 05). Conclusion: The results suggest that intraperitoneal perfusion of Compound Matrine injection and Cisplatin is safe and effective in treating malignant
Using a combination of tandem affinity purification tagging and mass spectrometry, we characterized a novel, evolutionarily conserved protein phosphatase 4 (PP4)-containing complex (PP4cs, protein phosphatase 4, cisplatin-sensitive complex) that plays a critical role in the eukaryotic DNA damage response. PP4cs is comprised of the catalytic subunit PP4C; a known regulatory subunit, PP4R2; and a novel protein that we termed PP4R3. The Saccharomyces cerevisiae PP4R3 ortholog Psy2 was identified previously in a screen for sensitivity to the DNA-damaging agent and anticancer drug cisplatin. We demonstrated that deletion of any of the PP4cs complex orthologs in S. cerevisiae elicited cisplatin hypersensitivity. Furthermore human PP4R3 complemented the yeast psy2 deletion, and Drosophila melanogaster lacking functional PP4R3 (flfl) exhibited cisplatin hypersensitivity, suggesting a highly conserved role for PP4cs in DNA damage repair. Finally we found that PP4R3 may target PP4cs to the DNA damage ...
Transcription factor AP-2 alpha (AP-2α or TFAP2A) is a newly identified prognostic marker of chemotherapy; its expression is positively correlated with chemosensitivity and survival of cancer patients. Using computational programs, we predicted that the coding region of AP-2α gene contains a potential miRNA response element (MRE) of miR-193a-5p, and the single nucleotide polymorphism (SNP) site (c.497A,G, rs111681798) resides within the predicted MRE. The results of luciferase assays and Western blot analysis demonstrated that miR-193a-5p negatively regulated the expression of AP-2α proteins, but have no influence on the mutant AP-2α (c.497A,G). Infection with lentiviral AP-2α gene or miR-193a-5p inhibitor in the bladder cancer cells decreased migration and cisplatin resistance, while knockdown of AP-2α gene or overexpression of miR-193a-5p in the urothelial cell line SV-HUC-1 increased migration and cisplatin resistances. We concluded that miR-193a-5p induced cisplatin resistance by ...
705 The treatment of alkylating cytotoxic drug cisplatin is often limited by high incidence rate of resistance. In the present study, the potential involvement of the transcription factor Nrf2 in determination of cisplatin cytotoxicity has been investigated. Nrf2-deficient murine embryonic fibroblasts showed increased cell death, cytotoxicity, and apoptosis in response to cisplatin treatment compared to wild-type cells. Cisplatin-resistant human ovarian cancer SK-OV cells, which are retaining 25-fold higher levels of GSH than murine fibroblasts, could be sensitized by inhibition of Nrf2. Transfection with Nrf2 siRNA into SK-OV cells resulted in severe degree of GSH depletion and exacerbated cytotoxicity following cisplatin treatment compared to scrambled RNA control. In conclusion, we propose that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to oxidants, cytotoxic chemicals, and radiation. ...
The standard of care for resected stage II - IIIA non-small-cell lung cancer includes adjuvant chemotherapy based on the results of randomized trials using cisplatin regimens. A recent meta-analysis (Lung Adjuvant Cisplatin Evaluation) showed no surv
The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat
Malignant melanoma causes the highest mortality rate in skin cancers. Although cisplatin has proved efficacious in the treatment of various solid tumors, melanoma seems particularly resistant to this chemotherapeutic drug. Reports show that melanoma patients whose tumors express nitric oxide (NO) synthase and/or nitrotyrosine are often faced with poor prognosis. Moreover, it has been shown that NO produced by melanoma cells sustains lower sensitivity to cisplatin toxicity in vitro. Because inflammatory products such as NO and reactive oxygen species (ROS) are associated with the genesis and evolution of cancer, we hypothesized that these oxidative species may regulate key components of the response of melanoma to cisplatin. Using a system for controlled delivery of NO to simulate the NO levels believed to occur during inflammation, we showed that human melanoma (A375) cells pre-exposed to submicromolar NO concentrations were protected from a subsequent challenge with cisplatin. This protection ...
The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. However, there are only limited reports regarding its expression and biological functions in colon cancer. Here, we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C, and SW620) in the presence or absence of cisplatin that was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was upregulated after cisplatin treatment in a dose-dependent manner. Both immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, ...
The latest results from the groups research to create a DNA targeting, light activated anticancer drug will be presented at the 231st American Chemical Society national meeting in Atlanta on March 26-30. Chemistry professor Karen J. Brewer reports that the group has developed supramolecular complexes that combine light-absorbing PDT agents and cisplatin like units. Previous anticancer molecules created by the group have contained platinum-based molecules that bind DNA. They have also developed new light activated systems able to photocleave DNA. This report combines these two approaches to target the drug to DNA using cisplatin like units, directing the light activation to tumor cells and the sub-cellular target, DNA. "In the past, our light activated systems had to find the DNA within the cell, an often inefficient process. Now we have added the DNA targeting drug," Brewer said. "We were working on cisplatin analogs before, so we have tied it to light activated systems." Cisplatin begins its ...
TY - JOUR. T1 - Application of HPLC-ICP-MS to speciation of cisplatin and its degradation products in water containing different chloride concentrations and in human urine. AU - Hann, S.. AU - Koellensperger, G.. AU - Stefánka, Zs. AU - Stingeder, G.. AU - Fürhacker, M.. AU - Buchberger, W.. AU - Mader, R. M.. PY - 2003/12/1. Y1 - 2003/12/1. N2 - Cisplatin, mono- and diaquacisplatin were measured in aquatic samples and in diluted urine of a cancer patient by HPLC-ICP-MS. On-line IDMS was applied for accurate, species unspecific quantification. Limits of detection of 0.74, 0.69 and 0.65 μg L-1 (3 s criterion) were calculated for cisplatin, monoaqua- and diaquacisplatin, respectively. Degradation kinetics of 6 × 10-6 M cisplatin were determined over a period of 48 h in solutions containing 100, 50 and 0 mg L-1 chloride, showing the suitability of the HPLC-ICP-MS method for kinetic model studies. The first order rate constants k1 of cisplatin aquation for the three chloride concentrations were ...
Abstract: Cisplatin is a widely used chemotherapeutic drug which causes ototoxicity. Previous studies from this laboratory using the rat have shown that cisplatin ototoxicity may be mediated by the production of free oxygen radicals. The ototoxic effects of cisplatin can be reduced by treatment with reducing agents such as diethyldithiocarbamate, methylthiobenzoic acid, ebselen, D-methionine, or sodium thiosulfate. The injury to the inner ear caused by cisplatin is potentiated by noise exposure. The greatest degree of cochlear damage in the guinea pig was observed when noise exposure precedes the administration of cisplatin [G. Laurell, Ann. Otol. 101, 969--976 (1992)]. These findings could be explained by an increase in oxidative stress produced by noise exposure, which could predispose to further injury by subsequent cisplatin administration. [Work supported by NIH ...
The results of the study revealed a true potential for these chemicals, or similar more advanced chemicals, to aid in chemotherapy. During cisplatin treatment massive apoptosis occurs. In the experiment, the group that was just given cisplatin treatment the RPTC cell apoptosis was 53%, but when treated with SAHA prior to the cisplatin treatment the cell apoptosis was reduced significantly to 21%. Similarly, when RPTC cells were treated with TSA the cisplatin was reduced by 17%. Both chemicals inhibit the negative apoptosis that the cisplatin treatment causes. This part of the experiment was conducted over a short period of time. For practical use the success of SAHA and TSA needs to be long-term the experimenters also observed its success over an extended period. Forty-eight hours after cisplatin treatment the morphology and amount of cell protein recovered was observed for each of the experimental and control groups. In the group of RPTC cells that were just issued the cisplatin treatment the ...
Treatment of multifunctional diseases such as cancer typically cannot be achieved by therapeutic agents that inhibit a single target.1 Single agent therapeutics often lead to development of drug resistance as well as limited accessibility of drug to tumour tissue due to intra-tumour heterogeneity.2 Moreover, in order to achieve therapeutically relevant concentrations within the tumour, high systemic doses of chemotherapy agents need to be administered, often resulting in severe toxic side effects.3 This is the case with drugs such as cisplatin and other platinum derivative drugs that are widely used in the treatment of ovarian cancer and head and neck squamous cell carcinoma (HNSCC).4,5 The primary mechanism of action of cisplatin is through DNA damage.6 However, several cellular pathways are activated by cisplatin exposure, including DNA repair pathways that remove the damage and result in the emergence of drug resistance.7 It has been shown that a combination of multiple anticancer drugs can ...
Cisplatin (cis-diamminedichloroplatinum II, CDDP) is a chemotherapeutic agent that induces nephrotoxicity associated with oxidative/nitrosative stress. Sulforaphane (SFN) is an isothiocyanate produced by the enzymatic action of myrosinase on glucorophanin, a glucosinolate contained in cruciferous vegetables. SFN is able to induce cytoprotective enzymes through the transcription factor Nrf2. The purpose of this study was to evaluate whether SFN induces a cytoprotective effect on the CDDP-induced nephrotoxicity. Preincubation of LLC-PK1 cells with 0.5-5 microM SFN by 24 h was able to prevent, in a concentration-dependent way, CDDP-induced cell death. Immunofluorescent staining confirmed the nuclear translocation of Nrf2 after treatment with SFN. In the in vivo studies, CDDP was given to Wistar rats as a sole i.p. injection at a dose of 7.5 mg/kg. SFN (500 microg/kg i.v.) was given two times (24 h before and 24 after CDDP-injection). Animals were killed three days after CDDP-injection.. SFN ...
By targeting mitochondria with the anticancer drug cisplatin, chemists have developed a new way to kill cancer cells that have shown resistance to cisplatin.. Cisplatin is a chemotherapy drug given to more than half of all cancer patients. The drug kills cells very effectively by damaging nuclear DNA, but if tumors become resistant to cisplatin they often grow back.. A new study from MIT and the University of Toronto offers a possible way to overcome that resistance. The researchers found that when cisplatin was delivered to cellular structures called mitochondria. DNA in this organelle was damaged, leading to cancer cell death. Moreover, the mitochondrial-targeted drug could overcome cisplatin resistance.. "These results suggest that the mitochondria can be an important target for platinum-based drugs," says Robert Radford, an MIT postdoc and an author of a paper describing the findings in the October 31 online edition of the journal Biology & Chemistry.. Mitochondria-targeting cisplatin might ...
TY - JOUR. T1 - Cisplatin nephrotoxicity as a model of chronic kidney disease. AU - Shi, Mingjun. AU - McMillan, Kathryn L.. AU - Wu, Junxia. AU - Gillings, Nancy. AU - Flores, Brianna. AU - Moe, Orson W. AU - Hu, Ming C. PY - 2018/6/1. Y1 - 2018/6/1. N2 - Cisplatin (CP)-induced nephrotoxicity is widely accepted as a model for acute kidney injury (AKI). Although cisplatin-induced chronic kidney disease (CKD) in rodent has been reported, the role of phosphate in the cisplatin-induced CKD progression is not described. In this study, we gave a single peritoneal injection of CP followed by high (2%) phosphate diet for 20 weeks. High dose CP (20 mg/Kg) led to high mortality; whereas a lower dose (10 mg/Kg) resulted in a full spectrum of AKI with tubular necrosis, azotemia, and 0% mortality 7 days after CP injection. After consuming a high phosphate diet, mice developed CKD characterized by low creatinine clearance, interstitial fibrosis, hyperphosphatemia, high plasma PTH and FGF23, low plasma ...
TAp73 expression and P1 promoter methylation, a potential marker for chemoresponsiveness to cisplatin therapy and survival in muscle-invasive bladder cancer (MIBC)
TY - JOUR. T1 - Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy. AU - Trendowski, Matthew R.. AU - El-Charif, Omar. AU - Ratain, Mark J.. AU - Monahan, Patrick. AU - Mu, Zepeng. AU - Wheeler, Heather E.. AU - Dinh, Paul C.. AU - Feldman, Darren R.. AU - Ardeshir-Rouhani-Fard, Shirin. AU - Hamilton, Robert J.. AU - Vaughn, David J.. AU - Fung, Chunkit. AU - Kollmannsberger, Christian. AU - Mushiroda, Taisei. AU - Kubo, Michiaki. AU - Hannigan, Robyn. AU - Strathmann, Frederick. AU - Einhorn, Lawrence H.. AU - Fossa, Sophie D.. AU - Travis, Lois B.. AU - Eileen Dolan, M.. PY - 2019/10/1. Y1 - 2019/10/1. N2 - Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 ...
The purpose of this investigation was to evaluate the efficacy of cisplatin chemotherapy in BRCA1 mutation carriers with metastatic breast cancer. In a phase II, open-label study, 20 patients with metastatic breast cancer who carried a mutation in BRCA1 were treated with cisplatin 75 mg/m2 intravenously every 3 weeks as part of a 21-day cycle for 6 cycles. Restaging studies to assess response were performed after cycles 2 and 6, and every three months thereafter. Between July 2007 and January 2009, 20 patients were enrolled. Baseline characteristics were as follows: 65% had prior adjuvant chemotherapy, 55% had prior chemotherapy for metastatic breast cancer; mean age was 48 years (ranges 32 to 70); 30% estrogen receptor (ER) or progesterone receptor (PR)+, 70% ER/PR/Human Epidermal Growth Factor Receptor 2 (HER2)- and 0% HER2+. Overall response rate was 80%; nine patients experienced a complete clinical response (45%) and seven experienced a partial response (35%). Overall survival was 80% at one year,
Cisplatin, the most common chemotherapeutic drug for the treatment of advanced stage cervical cancers has limitations in terms of drugs resistance observed in patients partly due to functional DNA damage repair (DDR) processes in the cell. Mediator of DNA damage checkpoint 1 (MDC1) is an important protein in the Ataxia telangiectasia mutated (ATM) mediated double stranded DNA break (DSB) repair pathway. In this regard, we investigated the effect of MDC1 change in expression on the cisplatin sensitivity in cervical cancer cells. Through modulation of MDC1 expression in the cervical cancer cell lines; Hela, SiHa and Caski, we found that all the three cell lines silenced for MDC1 exhibited higher sensitivity to cisplatin treatment with inefficiency in accumulation of p γH2AX, Ser 139 foci and increased accumulation of pChk2 Thr 68 at the damaged chromatin followed by enhanced apoptosis. Further, we observed the increased p53 Ser 15 phosphorylation in the MDC1 depleted cells. Our studies suggest that MDC1
Background: Docetaxel and cisplatin in combination with fluorouracil (DCF) regimen is accepted to be one of the standard regimens in the treatment of advanced gastric cancer. However, substantial toxicity has limited its use in daily clinical practice. Therefore, modification of DCF regimens, including introduction of capecitabine has been investigated to improve the safety profiles. In the present study, the efficacy and toxicity of a regimen with a modified dose of docetaxel and cisplatin in combination with oral capecitabine (DCX) was evaluated in untreated patients with HER2-negative advanced gastric cancer. Materials and Methods: Fifty-four patients with HER2-negative locally advanced or metastatic gastric cancer were included in this cohort. Patients received docetaxel |TEX|$60mg/m^2$|/TEX| plus cisplatin |TEX|$60mg/m^2$|/TEX| (day 1) combined with capecitabine |TEX|$1650mg/m^2$|/TEX| (days 1-14) every 3 weeks. Treatment response, survival, and toxicity were retrospectively analyzed. Results:
This study is investigating the efficacy and safety of cisplatin combined with gimeracil/oteracil/tegafur [S-1] compared with cisplatin combined with
Like other forms of radiotherapy or chemotherapy, administration of cisplatin causes DNA damage and activates the cellular DDR pathway. In this study, we report that in some oral/laryngeal SCC cell lines, expression of several DDR factors, including ATM, Mre11, and H2AX, is significantly reduced. We showed that DDR signaling is partially defective in these cells, in correlation with chemoresistance to cisplatin. These findings are in line with several previous studies in head and neck cancer. For example, Parikh and colleagues have previously shown that partial loss of the chromosome 11q21-23 region that harbors Mre11, ATM, and H2AX genes frequently occurs in oral SCCs (25). Although the sensitivity of these cells to cisplatin was not examined, the authors reported that these cells exhibit decreased sensitivity to ionizing radiation in clonogenic survival assays (25). Moreover, independent studies discovered reduced ATM expression in a portion of head and neck cancer cases, in correlation with ...
The emergence of cisplatin resistance is a major stumbling block to the successful treatment of ovarian cancer. To effectively treat or overcome the problem, one has to understand the various mechanisms behind the resistance to cisplatin. Study of various platinum resistance models has shown several putative cisplatin resistance mechanisms including: (a) decreased platinum accumulation; (b) increased drug inactivation; (c) enhanced platinum-DNA adduct repair capacity; and (d) an increased ability to tolerate platinum-DNA damage (7, 8, 9, 10, 11, 12 , 22 , 23) .. Recent evidence from our laboratory indicated that the ability of cells to repair DNA damage may be a critical determinant of cisplatin sensitivity and resistance in our cisplatin resistance model (13) . In our model system, NER activity was higher in resistant cells as determined by a single lesion assay, and the amount of ERCC1 RNA expression was also elevated in cells resistant to platinum. Moreover, complementation of ERCC1 and XPF ...
This study aims to treat locally-advanced nasopharyngeal cancer by concurrent conventional irradiation at 2.0 Gy/day five days per week up to a total dose of 68 Gy, and daily intra-arterial infusion of cisplatin 3 mg/m2 plus 24 hours intravenous drip infusion of 5-fluorouracil 150 mg/m2 per day, five days per week. All of five enrolled patients completed the schedule, and treatment compliance was considered to be identical. Of the five patients evaluable for response, four with complete response (80%) and one with partial response (20%), with an overall response rate of 100% was achieved. The median survival time was 26 months. Two-year survival of the patients was 80%. This regimen showed marginal mucositis but well tolerated. We concluded that this treatment option is safe and effective for the locally-advanced nasopharyngeal cancer.. Keywords: chemoradiotherapy, low dose intra-arterial cisplatin, 5-fluorouracil, stage IV nasopharyngeal ...