Concentration Of Oxaliplatin Research Articles

Albumin Nanoparticle Enhances Oxaliplatin Concentration in the Colorectal Region to Treat Colon Cancer with Increased Efficacy

Albumin Nanoparticle Enhances Oxaliplatin Concentration in the Colorectal Region to Treat Colon Cancer with Increased Efficacy

Effect of N-substituted aliphatic glycine presence on bioactivity, cytotoxicity, and selectivity of Pt(II) and Pd(II) complexes in cancer treatment

In this study, four new platinum (II) and palladium(II) complexes were synthesized to develop metallo-drugs that can attach to DNA and prevent the division of cancer cells. The complexes, 1: [Pt(bipy)(LP)]NO3, 2: [Pt(bipy)(LA)]NO3, 3: [Pd(bipy)(LP)]NO3, and 4: [Pd(phen)(LP)]NO3 (where LP is propylglycine, LA is 2-heptyl glycine, bipy is 2,2-bipyridine, and phen is 1,10-phenanthroline), were structurally characterized using computational and experimental analysis. Their stability, solubility, and lipophilicity were evaluated. Single-crystal X-ray and powder X-ray crystallographic analyses were performed for [Pt(bipy)(LA)]NO3. Density functional theory calculations were performed to investigate the reactivity, stability descriptors, and natural bond orbital analysis of these complexes. The in vitro cytotoxicity of these substances was examined against the human colorectal carcinoma (HCT116), A549 (Human Caucasian lung carcinoma), MCF7 (breast cancer), and HFF (Human Freskin Fibroblast) cell lines. According to the findings, complexes 4 and 3 had near oxaliplatin concentrations and more than carboplatin due to lipophilic ligands in their structure. Also, regarding IC50 values on normal HFF cell line, 4 is selectively toxic against the A549 cancer cell line with SI=5.6. Fluorescence, electronic absorption spectroscopy, and CD spectroscopy were used to investigate the binding affinities of compounds to CT-DNA and HSA. The results revealed that they could interact with CT-DNA through groove mode and with HSA via hydrogen bond and van der Waals forces. Electronic absorption and CD spectra indicated that compounds changed the way the HSA folded by increasing the proportion of a-helix. The binding posture of the metal complex to both biomolecules was predicted using docking simulation, which also verified the groove binding for DNA-complex. The findings indicated that complex 4 had a greater negative docking energy and a higher propensity for CT-DNA and HSA interaction.

PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX): An open label, non-comparative phase 1/2 dose escalation and expansion trial.

e15561 Background: Withmodern systemic chemotherapy, survival remain poor for patient withadvanced isolated peritoneal metastases from gastrointestinal tract. We aimed to assess the safety and efficacy of PIPAC to oxaliplatin in combination or not with systemic chemotherapy. Methods: We did a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC to oxaliplatin forpatients with peritoneal cancer index (PCI) more than 5, 13 and 15 for respectively a gastric, small bowell and colorectal cancer primary; who had received at least three months of systemic chemotherapy. PIPAC cycle lengths was 4 to 6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin concentration tumor was assessed every PIPAC cycles. Main endpoints were, tolerability, tumor response and survival. Results: Between2017 to 2020, 34 for patients were enrolled in three centers, in this phase 1/2 study of whom 25 were evaluable at recommanded dose of phase I of 90 mg/m2 plus systemic 5-FU. At this dose, safety profile showed acceptable tolerability. 8 patients (32%) had grade 3/4 treatment related adverse event. Minors (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76%) and nausea (n = 16, 64%). Before inclusion patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. Median PFS was 6.1 months and median OS was 13 months. Conclusions: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required. Clinical trial information: NCT03294252 .

The potential therapeutic effect of melatonin in oxaliplatin combination therapy against chemoresistant colorectal cancer cells.

Oxaliplatin is one of the main therapeutics in colorectal cancer (CRC) chemotherapy. However, in light of multidrug resistance (MDR) phenotype development, the efficacy of oxaliplatin has decreased. This study aimed to assess the potential therapeutic effect of melatonin in oxaliplatin combination therapy for drug-resistant colorectal cancer cells. Initially, the oxaliplatin-resistant cell line was created of LS174T (LS174T/DR) by using the oxaliplatin IC50 concentration and resting cycles. MTT assays and flow cytometry were applied for assessing cell viability and apoptotic cells. The mRNA expression level of Bax, Bcl2, MT1, MT2, and ABCB1 as well as protein levels of ABCB1, Bcl2, BAX were measured by the qRT-PCR and western blot techniques respectively. P-gp activity was assessed by Rho123 staining. The IC50 concentration of oxaliplatin in resistant cells was increased from 500.7 ± 0.2 nM to 7119 ± 0.1 nM. Bcl2, MT1, MT2, and ABCB1 mRNA plus protein expression levels of Bcl2 and ABCB1 were significantly reduced in resistant cells, along with a marked increase in Bax mRNA and protein levels compared to parental cells. Rho 123 staining revealed a marked reduction in P-gp activities in the combination-treated group compared to the oxaliplatin-treated group. The results of cytotoxicity assays, MTT, and flow cytometry revealed that the combination of melatonin and oxaliplatin exerts synergistic effects on induction of oxaliplatin's cytotoxicity in CRC. Our research suggests that combining the treatments of melatonin and oxaliplatin may be considered as a new approach to overcoming oxaliplatin resistance in CRC patients.

Oxaliplatin regulates the autophagy of skin squamous cell carcinoma cell line through HMGB1 pathway

Purpose: To determine the influence of oxaliplatin on skin squamous cell carcinoma cell line, and the involvement of autophagy- regulating pathway of high mobility group box 1 (HMGB1) in the process.
 Methods: A431 cells cultured in vitro were used. The cells were divided into groups A (treated with different concentrations of oxaliplatin) and B (treated with different concentrations of oxaliplatin combined with autophagy inhibitor 5 mmol/l3-ma). Changes in expression levels of autophagy marker molecules LC3-Ⅰ, LC3-Ⅱ, p62 and HMGB1 in A431 cells treated with different concentrations of oxaliplatin and different concentrations of HMGB1 were evaluated by Western blotting. Viability of A431 cells in both groups was assessed by CCK-8 assay.
 Results: With increase in oxaliplatin concentration, LC3-Ⅱ levels in A431 cells were up-regulated, p62 expression decreased, while autophagy level was increased significantly (p < 0.05). With increase in HMGB1 protein concentration, LC3-Ⅱ level in A431 cells was raised, while p62 level was reduced, while the level of autophagy was significantly increased (p < 0.05). Oxaliplatin treatment led to significantly higher expression level of HMGB1 in the experimental group than in the control group without oxaliplatin treatment. The viability of oxaliplatin-treated group was dose-dependently and significantly lower (p < 0.05) than that of the control group. Compared with the control group, the cell viability of the 3-mA + oxaliplatin group also showed a downward trend, and the decrease was greater than that of oxaliplatin-treated group (p < 0.05).
 Conclusion: Oxaliplatin upregulates autophagy by promoting HMGB1 protein expression, which may be a protective mechanism of tumor cells against oxaliplatin cytotoxicity thereby making HMGB1 protein a potential target in skin cancer therapy.

Electrochemical detection of oxaliplatin as an anti-cancer drug for treatment of breast cancer using TiO2 nanoparticles incorporated graphitic carbon nitride

Accurate and effective oxaliplatin (OXP) concentration detection is essential for maximizing therapeutic advantages and reducing negative effects of this anti-cancer therapy. Using a nanocomposite-based sensor, we present in this paper a novel method for electrochemical OXP detection. It is made of graphitic carbon nitride (g-C3N4) and titanium dioxide (TiO2) nanoparticles embedded on a glassy carbon electrode (GCE) using the hydrothermal method. The X-ray diffractometer (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) structural investigations revealed that the g-C3N4-TiO2 nanocomposite material is composed of anatase TiO2 and g-C3N4 phases. Using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) analyses, electrochemical tests demonstrated that g-C3N4-TiO2/GCE was a sensitive and selective OXP sensor. According to the results, the sensor has a linear range of 10 to 2030 μM, a sensitivity value of 0.04811μA/μM, and a detection limit of 0.010 μM. The recommended sensor's effectiveness in detecting OXP in prepared real samples from blood serum and urine samples of volunteers demonstrated significant recovery values (yielding recovery values exceeding 94.00%) and satisfactory precision (with a relative standard deviation of less than 4.23%), demonstrating that the g-C3N4-TiO2/GCE sensor was dependable and accurate for measuring OXP levels in serum and urine samples.

Environmental Monitoring and Ecological Risk Assessment of Platinum Complex Drugs in Wastewater Effluent: A Case Study in Qom, Iran

Background: The presence of anticancer drugs in water sources has become critical in recent years. Anticancer drugs are used in controlled amounts and conditions in medical centers. Cancerostatic platinum complexes (CPC) like cisplatin, carboplatin, and oxaliplatin are used in oncology centers to treat many cancers. Objectives: We determined the environmental risk of these compounds in municipal wastewater effluent of Qom, Iran. Methods: The LC-MS/MS technique quantified platinum complex drugs in wastewater effluent. Based on the blank laboratory method, the limit of detection (LOD) was determined as 0.009 µg/L, 0.013 µg/L, and 0.017 µg/L for oxaliplatin, carboplatin, and cisplatin, respectively. Results: The cisplatin, carboplatin, and oxaliplatin concentrations in wastewater effluent were 0.19 ± 0.098, 0.22 ± 0.094, and 0.12 ± 0.059 µg/L, respectively. Ecological risk assessment results indicated that RQsw for cisplatin, carboplatin, and oxaliplatin was 0.017, 0.013, and 0.02, respectively, showing that the platinum complex drugs had insignificant ecological exposure risk. Furthermore, ΣRQsw was estimated at < 1. Conclusions: Managing cytotoxic waste from hospital oncology wards is vital for environmental pollution control. The use of other methods to remove these compounds, such as advanced oxidation processes and membrane systems, is inevitable.

Effects of Leea indica leaf extracts and its phytoconstituents on natural killer cell-mediated cytotoxicity in human ovarian cancer

BackgroundThe rich biodiversity of medicinal plants and their importance as sources of novel therapeutics and lead compounds warrant further research. Despite advances in debulking surgery and chemotherapy, the risks of recurrence of ovarian cancer and resistance to therapy are significant and the clinical outcomes of ovarian cancer remain poor or even incurable. ObjectiveThis study aims to investigate the effects of leaf extracts from a medicinal plant Leea indica and its selected phytoconstituents on human ovarian cancer cells and in combination with oxaliplatin and natural killer (NK) cells.MethodsFresh, healthy leaves of L. indica were harvested and extracted in 70% methanol by maceration. The crude extract was partitioned with n-hexane, dichloromethane and ethyl acetate. Selected extracts and compounds were analyzed for their effects on cell viability of human ovarian cancer cells, NK cell cytotoxicity, and stress ligands expression for NK cell receptors. They were also evaluated for their effects on TNF-α and IL-1β production by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated human U937 macrophages.ResultsLeaf extracts of L. indica increased the susceptibility of human ovarian tumor cells to NK cell-mediated cytotoxicity. Treatment of cancer cells with methyl gallate but not gallic acid upregulated the expression of stress ligands. Tumor cells pretreated with combination of methyl gallate and low concentration of oxaliplatin displayed increased levels of stress ligands expression and concomitantly enhanced susceptibility to NK cell-mediated cytolysis. Further, NK cells completely abrogated the growth of methyl gallate-pretreated ovarian cancer cells. The leaf extracts suppressed TNF-α and IL-1β production in human U937 macrophages. Methyl gallate was more potent than gallic acid in down-regulating these cytokine levels.ConclusionsWe demonstrated for the first time that leaf extracts of L. indica and its phytoconstituent methyl gallate enhanced the susceptibility of ovarian tumor cells to NK cell cytolysis. These results suggest that the combined effect of methyl gallate, oxaliplatin and NK cells in ovarian cancer cells warrants further investigation, for example for refractory ovarian cancer. Our work is a step towards better scientific understanding of the traditional anticancer use of L. indica.

Transcription factor B-MYB activates lncRNA CCAT1 and upregulates SOCS3 to promote chemoresistance in colorectal cancer

Currently, resistance to oxaliplatin (OXA) has become an important obstacle to improving the clinical outcome of patients with colorectal cancer (CRC). Moreover, long non-coding RNAs (lncRNAs) have been documented in cancer chemoresistance, and our bioinformatic analysis suggested an involvement of lncRNA CCAT1 in CRC development. In this context, this study aimed to clarify the upstream and downstream mechanisms underpinning the effect of CCAT1 in the resistance of CRC to OXA. The expression of CCAT1 and the upstream B-MYB in the CRC samples was predicted by bioinformatics analysis and then verified using RT-qPCR in CRC cell lines. Accordingly, overexpression of B-MYB and CCAT1 was observed in CRC cells. SW480 cell line was used for the construction of OXA-resistant cell line (SW480R). Ectopic expression and knockdown experiments of B-MYB and CCAT1 were conducted in SW480R cells to delineate their roles in the malignant phenotypes and half-maximal (50%) inhibitory concentration (IC50) of OXA. It was found that CCAT1 promoted the resistance of CRC cells to OXA. Mechanistically, B-MYB transcriptionally activated CCAT1, which recruited DNMT1 to inhibit SOCS3 expression through elevating the SOCS3 promoter methylation. By this mechanism, the resistance of CRC cells to OXA was enhanced. Meanwhile, these in vitro findings were reproduced in vivo on xenografts of SW480R cells in nude mice. To sum up, B-MYB might promote the chemoresistance of CRC cells to OXA via regulating the CCAT1/DNMT1/SOCS3 axis.

Macrophage-derived exosomes regulate gastric cancer cell oxaliplatin resistance by wrapping circ 0008253

ABSTRACT Oxaliplatin (OXA) is a first-line chemotherapy drug for gastric cancer. We aimed to investigate the effect of circ 0008253, contained in M2 polarized macrophage-derived exosomes, on OXA resistance of gastric carcinoma cells. Flow cytometry was performed to detect the differentiation of macrophages and cell apoptosis. Cell Counting Kit-8 assay was conducted to examine the cell viability. Transmission electron microscopy, Nanoparticle Tracking Analysis, Western bolt, and Immunofluorescence were carried out. Cell proliferation was detected with a colony formation experiment. Levels of CD206, Arg1, IL-10, and TGF-β were increased in M2 polarized macrophages. Cell viability was decreased gradually with the increase of time and OXA concentration. Apoptosis of gastric carcinoma cells was decreased after co-culture with M2-polarized macrophages. Exosomes isolated from M2-polarized macrophages (M2-Exos) could be co-located with gastric carcinoma cells. M2-Exos enhanced drug resistance, reduced apoptosis and OXA resistance. Bioinformatics analysis showed that circ 0008253 could be transferred from M2-Exos to gastric carcinoma cells. Overexpressing circ 0008253 increased cell viability, tumor size, and ABCG2 levels, decreased OXA sensitivity. Circ 0008253, contained in M2-Exos, was directly transferred from tumor-associated macrophage to gastric carcinoma cells, finally enhancing OXA resistance.

N6-methyladenosine (m6A) writer KIAA1429 accelerates gastric cancer oxaliplatin chemoresistance by targeting FOXM1.

Chemical modification plays a critical role in regulating human cancer progression, especially N6-methyladenosine (m6A). However, m6A writer KIAA1429-mediated m6A modification in gastric cancer (GC) tumorigenesis remains largely unknown. The levels of mRNA and protein were detected using RT-qPCR and western blot. Thehalf maximal inhibitory concentration (IC50)of oxaliplatin (OXA) resistance isdetected using CCK-8 assay. The binding within moleculars was identified using RIP-PCR. Results found that KIAA1429 was upregulated in GC tissue samples and its high expression acted as a prognostic factor of poor survival in patients with GC. Functional assays indicated that KIAA1429 promoted the proliferation of GC cells, besides, KIAA1429 accelerated the half maximal inhibitory concentration (IC50) of oxaliplatin (OXA) resistance. Mechanistically, online prediction found that there was possible m6A modification site on FOXM1 mRNA. KIAA1429 could target the m6A modification site on FOXM1. Notably, KIAA1429 facilitated the GC OXA resistance in GC cells by promoting FOXM1 mRNA stability. Taken together, our study reveals the functions and mechanism for KIAA1429 and exposes KIAA1429 as a key player in GC chemoresistance.

Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) involves mixing oxaliplatin with 5% dextrose solution (5DW) to prevent the structural degradation of oxaliplatin in chloride-containing fluids. This study evaluated oxaliplatin degradation in carrier fluids containing different chloride ion concentrations to determine a carrier fluid that is optimal for use in oxaliplatin-based HIPEC. Five types of carrier fluids (normal saline, half saline, 5DW, Dianeal PD-2 peritoneal dialysis solution, and non-chloride Dianeal solution) were compared. An in vitro study was performed that monitored an oxaliplatin concentration of 1 ml (2 mg/ml) oxaliplatin mixed in 24 ml of each carrier fluid during 3 days to evaluate the rate of oxaliplatin degradation in each carrier fluid. An in vivo study, which subjected Sprague-Dawley rats to HIPEC for 60 min, also was performed. The efficacy of each carrier fluid for preserving oxaliplatin was evaluated using area under the curve (AUC) ratios between peritoneal fluid and plasma. The degradation rate of oxaliplatin in non-chloride fluids was significantly lower than in chloride-containing fluids. However, the rate was less than 10 to 15% at 30 min. The in vivo study indicated that oxaliplatin concentrations in peritoneal fluids did not differ significantly, whereas those in plasma did differ. The AUC ratios of both normal saline and Dianeal were higher than those of 5DW and non-Cl- Dianeal solutions. Chloride-containing fluids, such as normal saline or Dianeal, which display high absorption rates of oxaliplatin and acceptable degradation rates, may be more beneficial for use in oxaliplatin-based HIPEC than 5DW.

WD repeat domain 62 (WDR62) promotes resistance of colorectal cancer to oxaliplatin through modulating mitogen-activated protein kinase (MAPK) signaling

ABSTRACT WD repeat domain 62 (WDR62) is involved in embryonic brain growth through regulation of glial and neural cell populations. WDR62 is also implicated in the carcinogenesis of various cancers. The role of WDR62 in progression and chemoresistance of colorectal cancer (CRC) was investigated. Firstly, oxaliplatin-resistant CRC cells (HCT116/R and HT29/R) were sequentially exposed to an increasing concentration of oxaliplatin. The results showed that WDR62 was elevated in CRC tissues, and oxaliplatin resistance conferred up-regulation of WDR62 in CRC cells. Knockdown of WDR62 reduced cell proliferation and promoted the apoptosis of oxaliplatin-resistant CRC cells. Moreover, silencing of WDR62 increased fluorescence intensity of γH2AX, and decreased protein expression of p-DNA-PK and Rad51 in the oxaliplatin-resistant CRC cells. The protein expression of p-ERK, p-JNK, and p-p38 in oxaliplatin-resistant CRC cells were down-regulated by knockdown of WDR62. In conclusion, silencing of WDR62 suppressed oxaliplatin resistance and DNA damage repair of CRC cells through inactivation of MAPK signaling.

Comparative Study of Autophagy in Oxaliplatin-Sensitive and Resistant SNU-C5 Colon Cancer Cells.

Few studies have evaluated the role of autophagy in the development of oxaliplatin (OXT) resistance in colon cancer cells. In this study, we compared the role of autophagy between SNU-C5 colon cancer cells and OXT-resistant SNU-C5 (SNU-C5/OXTR) cells. At the same concentration of OXT, the cytotoxicity of OXT or apoptosis was significantly reduced in SNU-C5/OXTR cells compared with that in SNU-C5 cells. Compared with SNU-C5 cells, SNU-C5/OXTR cells exhibited low levels of autophagy. The expression level of important autophagy proteins, such as autophagy-related protein 5 (Atg5), beclin-1, Atg7, microtubule-associated proteins 1A/1B light chain 3B I (LC3-I), and LC3-II, was significantly lower in SNU-C5/OXTR cells than that in SNU-C5 cells. The expression level of the autophagy-essential protein p62 was also lower in SNU-C5/OXTR cells than in SNU-C5 cells. In SNU-C5/OXTR cells, the production of intracellular reactive oxygen species (ROS) was significantly higher than that in SNU-C5 cells, and treatment with the ROS scavenger N-acetylcysteine restored the reduced autophagy levels. Furthermore, the expression of antioxidant-related nuclear factor erythroid 2-related factor 2 transcription factor, heme oxygenase-1, and Cu/Zn superoxide dismutase were also significantly increased in SNU-C5/OXTR cells. These findings suggest that autophagy is significantly reduced in SNU-C5/OXTR cells compared with SNU-C5 cells, which may be related to the production of ROS in OXT-resistant cells.

Circular RNA mitochondrial translation optimization 1 correlates with less lymph node metastasis, longer disease-free survival, and higher chemotherapy sensitivity in gastric cancer.

ObjectiveCircular‐mitochondrial translation optimization 1 (circ‐MTO1) inhibits the progression of gastric cancer by regulating the growth, apoptosis, and invasion of tumor cells. However, its clinical potential as a biomarker for gastric cancer remains to be further evaluated. This study aimed to assess circ‐MTO1 expression and its correlation with clinical features and prognosis in gastric cancer patients, as well as the effect of circ‐MTO1 on the sensitivity to chemotherapy in gastric cancer cells.MethodsCirc‐MTO1 in tumor and adjacent tissues of 97 gastric cancer patients undergoing resection was examined by reverse transcription‐quantitative polymerase chain reaction. HGC‐27 and NCI‐N87 cells transfected by circ‐MOT1 overexpression plasmid (OE‐circ‐MOT1) and negative control (OE‐NC) were treated with 0‒6.4 μM oxaliplatin. Relative cell viability was detected using Cell Counting Kit‐8.ResultsCirc‐MTO1 was insufficiently expressed in gastric tumor tissue (median (interquartile range): 0.403 (0.288‒0.518)) compared with adjacent tissue (median (interquartile range): 1.000 (0.715‒1.524)) (p < 0.001). Besides, tumor circ‐MTO1 was correlated with less lymph node metastasis (p = 0.014) and low TNM stage (p = 0.039), while was not correlated with demographic features or other clinical characteristics (all p > 0.05). Furthermore, tumor circ‐MTO1 high expression was independently correlated with prolonged disease‐free survival (DFS) (p = 0.013, adjusted hazard ratio (95% confidential interval): 0.314 (0.126‒0.782)), but was not correlated with overall survival (p > 0.05). Lastly, in gastric cancer cells, OE‐circ‐MTO1 apparently decreased relative cell viabilities at oxaliplatin concentrations of 0.4, 0.8, 1.6, and 3.2 μM (all p < 0.05).ConclusionCirc‐MTO1 correlates with less lymph node metastasis, prolonged DFS, and improved chemotherapy sensitivity in gastric cancer.

The Damaging Outcome of the POLAR Phase III Trials Was Due to Avoidable Time-Dependent Redox Interaction between Oxaliplatin and PledOx.

On 2 July 2021, highly negative results were reported from the POLAR A and M phase III trials in patients with colorectal cancer, treated with an oxaliplatin-based regimen and co-treated with calmangafodipir (CaM; PledOx®; PledPharma AB/Egetis Therapeutics AB) or placebo. The results revealed persistent chemotherapy-induced peripheral neuropathy (CIPN) in 54.8% of the patients treated with PledOx, compared with 40.0% of the patients treated with the placebo (p < 0.05), i.e., a 37% increase in incidence of the side effect that the trial was aimed to prevent. The damaging outcome of the trials differed diametrically from an in-parallel conducted mice study and from a clinical trial with mangafodipir, the active ingredient of CaM. According to the authors of the POLAR report, the etiology of the profound increase in CIPN in the PledOx arm is unclear. However, these devastating effects are presumably explained by intravenous administrations of PledOx and oxaliplatin being too close in time and, thereby, causing unfavorable redox interactions between Mn2+ and Pt2−. In the mice study as well as in the preceding phase II clinical trial (PLIANT), PledOx was administered 10 min before the start of the oxaliplatin infusion; this was clearly an administration procedure, where the devastating interactions between PledOx and oxaliplatin could be avoided. However, when it comes to the POLAR trials, PledOx was administered, for incomprehensible reasons, “on Top of Modified FOLFOX6” at day one, i.e., after the two-hour oxaliplatin infusion instead of before oxaliplatin. This is a time point when the plasma concentration of oxaliplatin and Pt2+-metabolites is at its highest, and where the risk of devastating redox interactions between PledOx and oxaliplatin, in turn, is at its highest.

Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly

BackgroundAutophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors.ResultsIn this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin.ConclusionsTH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics.Graphical

High concentration of oxaliplatin may be a risk factor for vascular pain.

Oxaliplatin (L-OHP) is an antineoplastic agent that frequently causes vascular pain. However, the risk factors for vascular pain are unclear, and prevention methods have not been established. We retrospectively investigated patients who were treated with L-OHP to examine the influence of patient characteristics and concomitant analgesic use on the incidence of vascular pain. We collected information about the presence or absence of vascular pain, age, sex, treatment dose and analgesic use of patients who received L-OHP at Tokyo Medical University Hachioji Medical Center. We analysed the relevance of each factor between the vascular pain onset and non-onset groups. Thirty-two patients (average age: 68.6years; 69.8% and 30.2% men and women, respectively) were classified into the vascular pain onset (n=64) and non-onset groups (n=68). The multivariate logistic regression analysis revealed that L-OHP concentration (>358.5mg/L) was an independent determinant of vascular pain development (odds ratio: 2.422, 95% CI: 1.117-5.252). Intergroup differences in age, sex, body mass index, non-steroidal anti-inflammatory drug use, and underlying pain from cancer and other comorbidities were not significant. High L-OHP concentration was identified as a significant risk factor for L-OHP-induced vascular pain. Our results indicate that the dilution of L-OHP may reduce the incidence of vascular pain.

All-trans Retinoic Acid combined with oxaliplatin suppressed proliferation of chemo-resistant hepatocellular carcinoma cells by inducing G2/M cell cycle arrest

IntroductionTo investigate the effects and mechanisms of all-trans retinoic acid (ATRA) with and without oxaliplatin (OXA) on chemotherapy-resistant hepatocellular carcinoma cell lines.Material and methodsOXA-resistant cell lines (CSQT-2-R and Hep3b-R) and subcutaneous xenograft model were used in this study. MTT assay, flow cytometry, crystal violet assay, transwell assay and western-blotting were conducted to evaluate the effects of co-treatment with ATRA and OXA on OXA-resistant HCC in vivo and in vitro. The differences between two groups were analyzed using ANOVA. All statistical tests in the study were two-sided, and statistical significance was set at P&lt;0.05.ResultsWe established two oxaliplatin-Resistant HCC cell lines (CSQT-2-R and Hep3b-R). The drug resistance ability can be increased up to 100% than their parental cells(CSQT-2 and Hep3b) in certain concentration of OXA. ATRA alone could not inhibited the viability of CSQT-2-R and Hep3b-R, but it can enhance the ability of OXA on apoptosis than OXA alone (75% vs 35%, p&lt;0.05), which may be related to decreased p-AKT expression. Moreover, the co-treatment of two drugs arrest the cell cycle of OXA-resistant cell at G2/M phase by up-regulating CylinB1 protein.ConclusionsATRA combined with OXA can elicit cell cycle arrest of CSQT-2-R and Hep3b-R at G2/M phase, thereby inhibiting the proliferation of resistant HCC cell, which provides a new treatment for chemotherapy-resistant HCC.

Ultrasensitive and selective molecularly imprinted electrochemical oxaliplatin sensor based on a novel nitrogen-doped carbon nanotubes/Ag@cu MOF as a signal enhancer and reporter nanohybrid.

Asensitive and selective molecular imprinted polymeric network (MIP) electrochemical sensor is proposed for the determination of anti-cancer drug oxaliplatin (OXAL). The polymeric network [poly(pyrrole)] was electrodeposited on a glassy carbon electrode (GCE) modified with silver nanoparticles (Ag) functionalized Cu-metal organic framework (Cu-BDC) and nitrogen-doped carbon nanotubes (N-CNTs). The MIP-Ag@Cu-BDC /N-CNTs/GCE showed an observable reduction peak at -0.14V, which corresponds to the Cu-BDC reduction. This peak increased and decreased by eluting and rebinding of OXAL, respectively. The binding constant between OXAL and Cu-BDC was calculated to be 3.5 ± 0.1 × 107mol-1L. The electrochemical signal (∆i) increased with increasing OXAL concentration in the range 0.056-200ngmL-1 with a limit of detection (LOD, S/N = 3) of 0.016ngmL-1. The combination of N-CNTs and Ag@Cu-BDC improves both the conductivity and the anchoring sites for binding the polymer film on the surface of the electrode. The MIP-based electrochemical sensor offered outstanding sensitivity, selectivity, reproducibility, and stability. The MIP-Ag@Cu-BDC /N-CNTs/GCE was applied to determine OXAL in pharmaceutical injections, human plasma, and urine samples with good recoveries (97.5-105%) and acceptable relative standard deviations (RSDs = 1.8-3.2%). Factors affecting fabrication of MIP and OXAL determination were optimized using standard orthogonal design using L25 (56) matrix. This MIP based electrochemical sensor opens a new venue for the fabrication of other similar sensors and biosensors.