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Chemotherapy, particularly cisplatin, is a prevalent cancer treatment. Unfortunately, many tissues, for instance the submandibular salivary glands, are toxically affected by cisplatin. Of significant interest, phytopharmaceuticals rich in flavonoids have demonstrated exceptional defense against chemotherapy induced toxicity, like chrysin (Chr); nevertheless, its low solubility and poor bioavailability have remained cornerstone issues. Accordingly, Chr was successfully encapsulated in the poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) scaffold. The developed chrysin-loaded poly(d, l-lactide-co-glycolide) nanoparticles (Chr-loaded PLGA NPs) were meticulously evaluated via comprehensive in vitro-in vivo investigations. Saliently, the outcomes of in vivo studies exhibited admirable in vivo counteraction effectiveness against cisplatin-induced toxicity in submandibular salivary glands in Albino rats upon comparing Chr-loaded PLGA NPs treated group with pure Chr as well as blank NPs treated ones. Inclusively, Chr-loaded PLGA NPs can be regarded as promising therapy to create recent vistas for dampening myriad adverse effects of different chemotherapies.

Background Nephrotoxicity is the dose-limiting side effect of cisplatin justifying the assessment of renal function for dose adjustment. Objective To determine whether appropriate dose adjustment is made in patients with renal impairment using the Cockcroft–Gault (CG) or the abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the glomerular filtration rate (GFR). Setting The study was conducted in a 1,000-bed university hospital. Method Two years of cisplatin prescriptions were retrospectively compared to the 4 and 3 ranges estimated glomerular filtration rate (eGFR)-stratified dosing recommendations (4RR and 3RR respectively). Main outcome measure Cisplatin dose in mg/m 2 based on kidney function and according to the dosing recommendations. Results Among 1,364 cycles of cisplatin, 156 (11.4 %) were prescribed for 70 patients with eGFR < 60 mL/min and a median age of 67.4 years. For 57 (36 %) of these cycles, doses were not reduced. When reduced, prescribed doses were not different than recommended doses according to 4RR using CG (% of protocol, 63 ± 12 vs. 64 ± 17) while it was significantly lower using aMDRD (% of protocol, 66 ± 12 vs. 81 ± 22, p  < 0.01) and significantly higher according to 3RR using both CG and aMDRD (% of protocol, 63 ± 12 vs. 50 ± 3 and 66 ± 12 vs. 50.7 ± 4.0 respectively, p  < 0.01). Prescription of at least one appropriate dose according to 4RR and using aMDRD was associated with a statistically significant higher median total cumulative dose (% of protocol, 89.9 vs. 75.1 % respectively, p  < 0.01) without higher decrease of eGFR over time. Conclusion Cisplatin dose adjustment in patients with renal impairment must be improved. Estimating GFR with the aMDRD formula and adding an intermediary level of dose reduction for patients with eGFR from 50 to 59.9 mL/min may result in a higher cumulative dose of cisplatin without higher renal toxicity, which may significantly impact on the effectiveness of the chemotherapy. A prospective evaluation remains needed to assess the benefit/risk ratio of this dose adaptation schedule, taking into account the variability of the GFR estimates.

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.

Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.

Background Genomic mutations caused by cytotoxic agents used in cancer chemotherapy may cause secondary malignancies as well as contribute to the evolution of treatment-resistant tumour cells. The stable diploid genome of the chicken DT40 lymphoblast cell line, an established DNA repair model system, is well suited to accurately assay genomic mutations. Results We use whole genome sequencing of multiple DT40 clones to determine the mutagenic effect of eight common cytotoxics used for the treatment of millions of patients worldwide. We determine the spontaneous mutagenesis rate at 2.3 × 10 –10 per base per cell division and find that cisplatin, cyclophosphamide and etoposide induce extra base substitutions with distinct spectra. After four cycles of exposure, cisplatin induces 0.8 mutations per Mb, equivalent to the median mutational burden in common leukaemias. Cisplatin-induced mutations, including short insertions and deletions, are mainly located at sites of putative intrastrand crosslinks. We find two of the newly defined cisplatin-specific mutation types as causes of the reversion of BRCA2 mutations in emerging cisplatin-resistant tumours or cell clones. Gemcitabine, 5-fluorouracil, hydroxyurea, doxorubicin and paclitaxel have no measurable mutagenic effect. The cisplatin-induced mutation spectrum shows good correlation with cancer mutation signatures attributed to smoking and other sources of guanine-directed base damage. Conclusion This study provides support for the use of cell line mutagenesis assays to validate or predict the mutagenic effect of environmental and iatrogenic exposures. Our results suggest genetic reversion due to cisplatin-induced mutations as a distinct mechanism for developing resistance.

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%–35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

The platinum-based drug cisplatin is a widely used first-line therapy for several cancers. Cisplatin interacts with DNA mainly in the form of Pt-d(GpG) di-adduct, which stalls cell proliferation and activates DNA damage response. Although cisplatin shows a broad spectrum of anticancer activity, its utility is limited due to acquired drug resistance and toxicity to non-targeted tissues. Here, by integrating genome-wide high-throughput Damage-seq, XR-seq, and RNA-seq approaches, along with publicly available epigenomic data, we systematically study the genome-wide profiles of cisplatin damage formation and excision repair in mouse kidney, liver, lung and spleen. We find different DNA damage and repair spectra across mouse organs, which are associated with tissue-specific transcriptomic and epigenomic profiles. The framework and the multi-omics data we present here constitute an unbiased foundation for understanding the mechanisms of cellular response to cisplatin. Our approach should be applicable for studying drug resistance and for tailoring cancer chemotherapy regimens. Cisplatin, a platinum chemotherapeutic agent, is widely used to treat several cancers. Here Yimit et al. revert to genome-wide approaches to map and analyze cisplatin damage formation and excision repair with single nucleotide resolution across different mice organs following platinum treatment.

Background Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury (AKI) which develop due to renal accumulation and biotransformation of CDDP. The alleviation or prevention of CDDP-caused nephrotoxicity is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis which is considered for high-dose CDDP-treated patients. However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical use of safe and efficacious renoprotective drug as an additive therapy for high dose CDDP-treated patients. Main body In this review article we describe in detail signaling pathways involved in CDDP-induced apoptosis of renal tubular cells, oxidative stress and inflammatory response in injured kidneys in order to pave the way for the design of new therapeutic approaches that can minimize CDDP-induced nephrotoxicity. Most of these molecular pathways are, at the same time, crucially involved in cytotoxic activity of CDDP against tumor cells and potential alterations in their function might mitigate CDDP-induced anti-tumor effects. Conclusion Despite the fact that many molecules were designated as potential therapeutic targets for renoprotection against CDDP, modulation of CDDP-induced nephrotoxicity still represents a balance on the knife edge between renoprotection and tumor toxicity.

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

The most widely used platinum-derived drug is cisplatin in neuroblastoma (NB) chemotherapy, which is severely neurotoxic. Acetyl- l -Carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. The aim of this study was to determine the effects of ALC on cisplatin induced cytotoxicity and oxidative stress in NB cells. SH-SY5Y (N-Myc negative) and KELLY (N-Myc positive) human NB cell lines were used. Cisplatin induced apoptosis was assessed by using a Cell Death Detection ELISA PLUS kit. Lipid peroxidation levels were determined by HPLC analysis. Glutathione levels were determined spectrophotometrically. ALC was used prophylactic or after cisplatin application. The level of cisplatin doses were determined in both type of NB cells at which 50% cell death occurred along with synchronized apoptosis induced. Prophylactic 10 and 50 μmol of ALC concentrations were decreased cisplatin induced lipid peroxidation compared to controls that normally exhibited apoptosis especially in SH-SY5Y cells. Cisplatin caused oxidative stress through decreasing glutathione levels in both cell types. ALC were effectively inhibited the increase in cisplatin induced oxidized glutathione and lipid peroxidation formation in NB cells. We suggested that prophylactic ALC would be a useful agent for cisplatin induced toxicity in NB cells.