Anticancer Drug Oxaliplatin Research Articles

Opposing effects of mycotoxins alternariol and deoxynivalenol on the immunomodulatory effects of oxaliplatin and triapine.

Mycotoxin occurrence in food worldwide is estimated to increase due to climate change. Moreover, studies on how these food contaminants interfere with medications and especially anticancer therapies are rare. With the rise of anticancer immunotherapies, particularly mycotoxins with immunomodulatory activity, such as alternariol (AOH) or deoxynivalenol (DON), are of great concern. Both mycotoxins interfere with the pro-inflammatory nuclear factor kappa B (NF-κB) pathway in myeloid cells. This pathway not only plays an important role in the anticancer immune response but also inflammatory side effects induced by chemotherapeutic drugs. Consequently, the aim of this study was to investigate possible beneficial or detrimental immunomodulatory interactions between these mycotoxins and anticancer drugs. To assess the combined influence of mycotoxins and anticancer therapies on immune cell stimulation, THP-1 NF-κB reporter cells were utilized as monocytes as well as differentiated and polarized macrophages. Parameters for activation (NF-κB activity and protein expression), differentiation (CD14 and CD71 surface marker expression) and polarization (interleukin 10 (IL10), interleukin 8 (CXCL8), tumor necrosis factor α (TNF), prostaglandin-endoperoxide synthase 2 expression and CXCL8 secretion) were assessed upon combinatory treatment. Both mycotoxins affected the immunostimulatory effects of the pre-selected anticancer drugs oxaliplatin and triapine, although in opposing directions. While AOH generally suppressed a drug-induced activation and increased anti-inflammatory IL10 levels, DON potentiated activation and pro-inflammatory markers, such as CXCL8 and TNF in immune cells. In conclusion, AOH and DON have the potential to alter the immunological effects of anticancer therapies, which should be considered during therapy as well as in their future risk assessment.

Chitosan-graphene quantum dot-based molecular imprinted polymer for oxaliplatin release

Molecularly imprinted polymers (MIPs) have garnered the interest of researchers in the drug delivery due to their advantages, such as exceptional durability, stability, and selectivity. In this study, a biocompatible MIP drug adsorption and delivery system with high loading capacity and controlled release, was prepared based on chitosan (CS) and graphene quantum dots (GQDs) as the matrix, and the anticancer drug oxaliplatin (OXAL) as the template. Additionally, samples without the drug (non-imprinted polymers, NIPs) were created for comparison. GQDs were produced using the hydrothermal method, and samples underwent characterization through FTIR, XRD, FESEM, and TGA. Various experiments were conducted to determine the optimal pH for drug adsorption, along with kinetic and isotherm studies, selectivity assessments, in vitro drug release and kinetic evaluations. The highest drug binding capacity was observed at pH 6.5. The results indicated the Lagergren-first-order kinetic model (with rate constant of 0.038 min−1) and the Langmuir isotherm (with maximum adsorption capacity of 17.15 mg g−1) exhibited better alignment with the experimental data. The developed MIPs displayed significant selectivity towards OXAL, by an imprinting factor of 2.88, in comparison to two similar drugs (cisplatin and carboplatin). Furthermore, the analysis of the drug release profile showed a burst release for CS-Drug (87% within 3 h) at pH 7.4, where the release from the CS-GQD-Drug did not occur at pH 7.4 and 10; instead, the release was observed at pH 1.2 in a controlled manner (100% within 28 h). Consequently, this specific OXAL adsorption and delivery system holds promise for cancer treatment.

Enhanced fluorescent detection of oxaliplatin via BSA@copper nanoclusters: a targeted approach for cancer drug monitoring.

A new fluorescence sensing approach has been proposed for the precise determination of the anti-cancer drug oxaliplatin (Oxal-Pt). This method entails synthesizing blue-emitting copper nanoclusters (CuNCs) functionalized with bovine serum albumin (BSA) as the stabilizing agent. Upon excitation at 360 nm, the resultant probe exhibits emission at 460 nm. Notably, the fluorescence response of BSA@CuNCs substantially increases upon incubation with Oxal-Pt due to multiple binding interactions between the drug and the fluorescent probe. These interactions involve hydrogen bonding, hydrophobic interaction, and the high affinity between the SH groups (cysteine residues of BSA) and platinum (in Oxal-Pt). Consequently, this interaction induces aggregation-induced emission enhancement (AIEE) of BSA@CuNCs. The probe demonstrates a broad response range from 0.08 to 140.0 μM, along with a low detection limit of 20.0 nM, determined based on a signal-to-noise ratio of 3. Furthermore, the probe effectively detects Oxal-Pt in injections, human serum, and urine samples, yielding acceptable results. This study represents a significant advancement in the development of a straightforward and efficient sensor for monitoring platinum-containing anti-cancer drugs during chemotherapy.

Effect of a Single Dose of Oxaliplatin on the Induction of Peripheral Neuropathy in a Rat Model: An in Vivo Electrophysiological Study.

The anticancer drug oxaliplatin is associated with peripheral neuropathy as a side effect accompanied by mechanical and cold allodynia. Although the superficial layer of the spinal cord dorsal horn is known to receive information primarily from peripheral pain nerves, to our knowledge, no in vivo electrophysiological analyses have been conducted to determine whether oxaliplatin administration increases the excitability of superficial layer neurons. Therefore, in vivo extracellular recordings were performed to measure action potentials in the deep and superficial layers of the spinal cord dorsal horn in rats treated with a single dose (6 mg/kg) of oxaliplatin. Action potentials were produced by mechanical stimulation with von Frey filaments to the hindlimb receptive fields. The results revealed that the firing frequency of action potentials increased relative to the intensity of mechanical stimulation, and that both deep and superficial layer neurons in the spinal cord dorsal horn increased significantly in oxaliplatin-treated compared with vehicle-treated rats, especially in the superficial layer. Several superficial layer neurons showed spontaneous firing that was not seen in vehicle-treated rats. In addition, a clear increase was seen in the firing frequency of neurons in the superficial layer of oxaliplatin-treated rats in response to a cold stimulus (here, the addition of acetone to the hindlimb receptive field). This study suggests that the superficial spinal cord dorsal horn strongly reflects the pain pathophysiology in peripheral neuropathy induced by oxaliplatin administration, and that the superficial layer neurons are useful for in vivo electrophysiological analysis using this pathological model.

Controllable Regulation of Ag2 S Quantum Dots-Mediated Protein Nanoassemblies for Imaging-Guided Synergistic PDT/PTT/Chemotherapy Against Hypoxic Tumor.

The combination of phototherapy and chemotherapy holds great potential for cancer treatment, while hypoxia in tumor as well as unexpected drug release largely restrict anticancer therapy. Inspired by the natural intelligence, herein we present for the first time a "bottom-up" protein self-assembly strategy mediated by NIR quantum dots (QDs) with multicharged electrostatic interactions to develop a tumor microenvironment (TME)-responsive theranostic nanoplatform for imaging-guided synergistic PDT/PTT/chemotherapy. Catalase (CAT) possesses diverse surface charge distribution under different pH conditions. After modification by Ce6, the formulated CAT-Ce6 with patchy negative charges can be assembled with NIR Ag2 S QDs by regulating their electrostatic interactions, allowing for effective incorporation of specific anticancer drug oxaliplatin (Oxa). Such Ag2 S@CAT-Ce6@Oxa nanosystems are able to visualize nanoparticle accumulation to guide the subsequent phototherapy, together with significant alleviation of tumor hypoxia to further enhance PDT. Moreover, the acidic TME triggers controllable disassembly through weakening the CAT surface charge to disrupt electrostatic interactions in assemblies, allowing for sustained drug release. Both in vitro and in vivo results demonstrate remarkable inhibition of colorectal tumor growth with a synergistic effect. Overall, this multicharged electrostatic protein self-assembly strategy provides a versatile platform for realizing TME-specific theranostics with high efficiency and safety, promising for clinical translation. This article is protected by copyright. All rights reserved.

Characterization of β-Cyclodextrin Hybridized Diatomite as Potential Delivery Systems of Oxaliplatin and 5-Fluorouracil Drugs; Equilibrium Modeling of Loading and Release Kinetics

The present study involved the functionalization of diatomite’s bio-siliceous frustules with polymeric chains of β-cyclodextrin (β-CD/Di) to serve as advanced delivery structures for the anticancer drugs oxaliplatin (OXPL) and 5-Fluorouracil (5-Fu). The β-CD/Di carrier demonstrated significant loading capabilities, particularly at saturation (324.8 mg/g (OXPL) and 425 mg/g (5-Fu). Both OXPL and 5-Fu were loaded onto the β-CD/Di according to the kinetic properties of the traditional pseudo-first order model (R 2 > 0.90) and the isotherm assumptions of the classic Langmuir model (R 2 = 0.99). The density of occupied active sites on the β-CD/Di was found to be 38.76 mg/g and 88.19 mg/g during the loading process of OXPL and 5-Fu, respectively. The loading energies, which were less than 40 KJ/mol, confirmed the primary and significant influences of the physical mechanisms. The observed release profiles of OXPL and 5-Fu exhibited significant sustained and prolonged characteristics for up to 100 h. The release kinetic modeling and diffusion exponent values (>0.45) verified the release of OXP and 5-Fu based on non-Fickian transport features and the erosion/diffusion process. The β-CD/Di carrier significantly augmented the cytotoxic effects of OXPL and 5-Fu on HCT-116 cancer cell lines (OXPL (9.72% cell viability), and 5-Fu (4.17% cell viability)).

Nanocomposite of reduced nanographene oxide with β-lactoglobulin protein (rNGO/β-Lg) as a carrier of the anticancer drug oxaliplatin (Eloxatin)

In this study, reduced nanographene oxide (rNGO) together with β-lactoglobulin (β-Lg) protein is used for better and more effective encapsulation, loading and release of oxaliplatin (OXP) drug in colon tumor cells. Drug distribution, loading and encapsulation on graphene oxide/reduced β-lactoglobulin (rNGO/β-Lg) nanocomposite is investigated and confirmed by IR, Uv-Vis, fluorescence and zeta sizer analysis. The rNGO/β-Lg nanocomposite shows a promising loading capacity. So that the percentage of encapsulation and loading for the anticancer drug oxaliplatin is 70 % and 55 %, respectively, and the results show that the penetration and diffusion mechanism is non-Fickian diffusion. Due to the electronic stereo resonance of the drug with the nanocomposite, rNGO/β[email protected] has low toxicity in healthy tissues and higher toxic effects on colon cancer cells than the free oxaliplatin drug. The interaction mechanism of β-Lg with rNGO, drug loading and release on nanocomposite (rNGO/β[email protected]) will be simulated and discussed by DFT method based on M06-2×/aug-cc-pVDZ-PP calculations. The calculation results show that β-Lg reacts on the rNGO surface by forming a π-π bond. The adsorption energy (Eads = −25.99 kcal.mol-1) and the calculated thermodynamic functions indicate a favorable interaction between them, which causes the formation of rNGO/β-Lg nanocomposite at ambient temperature. By encapsulating the drug by nanocomposite, the softness of the chemical structure of the drug and its reactivity have decreased and the synthetic stability has increased. The value of charge transfer (ΔNmax = −0.16)) calculated for rNGO/β[email protected] indicates the transfer of electrons from the drug to the nanocomposite and the creation of stereo electronic resonance, hardening and stabilization of their geometric structure. It reduces the release rate of the drug and reduces its accumulation and toxicity in the body.

Assessment of the relevance of osmolality measurement as a criterion for the stability of solutions

Abstract Objectives The measurement of osmolality is used by many authors as an additional stability criterion of a drug in solution. In the current state of knowledge, no scientific publication correlates the osmolality values and the stability of a solution. To study the relevance of this analytical technique by measuring the osmolality of injectable solutions whose instability has been chemically demonstrated by high performance liquid chromatography (HPLC). Methods Selection of 13 drug preparations whose chemical instability has been demonstrated in the literature. Realization of three identical samples per selected preparation and measurements of the osmolality of the freshly prepared solutions, then, at various storage times until a chemical degradation of the molecule validated by HPLC of at least 10% and possibly up to 40%. Results Measurements of the osmolality were performed on five antibiotics (amoxicillin/clavulanic acid, cefepime, cefoxitine, meropenem and temocillin and cefoxitin) and five anticancer drugs (azacitidine, bendamustine, busulfan, fotemustine and oxaliplatin). Osmolality varied from −6.30 to 11.10% for antibiotics and from 0.57 to 2.04%. Conclusions Among the preparations tested, only two formulations have a variation in osmolality in accordance with the chemical degradation. For the other 11 formulas, the variations in osmolality values where not correlated with the degradation measured by HPLC. In view of these results, osmolality does not seem to be a criterion of choice for the study of drug stability. In the majority of the unstable solutions studied, the variation of osmolality measurements does not correlate with the loss of concentration and the appearance of degradation products.

Interspecies and in vitro-in vivo scaling for quantitative modeling of whole-body drug pharmacokinetics in patients: Application to the anticancer drug oxaliplatin.

Quantitative systems pharmacology holds the promises of integrating results from laboratory animals or in vitro human systems into the design of human pharmacokinetic/pharmacodynamic (PK/PD) models allowing for precision and personalized medicine. However, reliable and general in vitro-to-in vivo extrapolation and interspecies scaling methods are still lacking. Here, we developed a translational strategy for the anticancer drug oxaliplatin. Using ex vivo PK data in the whole blood of the mouse, rat, and human, a model representing the amount of platinum (Pt) in the plasma and in the red blood cells was designed and could faithfully fit each dataset independently. A "purely physiologically-based (PB)" scaling approach solely based on preclinical data failed to reproduce human observations, which were then included in the calibration. Investigating approaches in which one parameter was set as species-specific, whereas the others were computed by PB scaling laws, we concluded that allowing the Pt binding rate to plasma proteins to be species-specific permitted to closely fit all data, and guaranteed parameter identifiability. Such a strategy presenting the drawback of including all clinical datasets, we further identified a minimal subset of human data ensuring accurate model calibration. Next, a "whole body" model of oxaliplatin human PK was inferred from the ex vivo study. Its three remaining parameters were estimated, using one third of the available patient data. Remarkably, the model achieved a good fit to the training dataset and successfully reproduced the unseen observations. Such validation endorsed the legitimacy of our scaling methodology calling for its testing with other drugs.

In Vitro Pain Assay Using Human iPSC-Derived Sensory Neurons and Microelectrode Array.

Drug-induced peripheral neuropathy occurs as an adverse reaction of chemotherapy. However, a highly accurate method for assessing peripheral neuropathy and pain caused by compounds has not been established. The use of human-induced pluripotent stem cell (hiPSC)-derived sensory neurons does not require animal experiments, and it is considered an effective method that can approach extrapolation to humans. In this study, we evaluated the response to pain-related compounds based on neural activities using in vitro microelectrode array (MEA) measurements in hiPSC-derived sensory neurons. Cultured sensory neurons exhibited gene expression of the Nav1.7, TRPV1, TRPA1, and TRPM8 channels, which are typical pain-related channels. Channel-dependent evoked responses were detected using the TRPV1 agonist capsaicin, a TRPA1 agonist, allyl isothiocyanate (AITC), and TRPM8 agonist menthol. In addition, the firing frequency increased with an increase in temperature from 37°C to 46°C, and temperature sensitivity was observed. In addition, the temperature of the peak firing rate differed among individual neurons. Next, we focused on the increase in cold sensitivity, which is a side effect of the anticancer drug oxaliplatin, and evaluated the response to AITC in the presence and absence of oxaliplatin. The response to AITC increased in the presence of oxaliplatin in a concentration-dependent manner, suggesting that the increased cold sensitivity in humans can be reproduced in cultured hiPSC-derived sensory neurons. The in vitro MEA system using hiPSC-derived sensory neurons is an alternative method to animal experiments, and it is anticipated as a method for evaluating peripheral neuropathy and pain induced by compounds.

Neuronal alarmin IL-1α evokes astrocyte-mediated protective signals: Effectiveness in chemotherapy-induced neuropathic pain

The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis.The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3–100μM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor β1, mostly produced by astrocytes.In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die−1). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype.Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.

Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host-guest chemistry.

A new [PdPtL4]4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL4]4+ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p-tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL4]4+ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host-guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD3CN. No HG interactions were observed in the more polar d6-DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC50) values in the range of 25-35 μM. Most [PdPtL4]4+-drug mixtures tested had higher IC50 values than the hosts. However, the [PdPtL4]4+ cages, and [PdPtL4]4+:drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil.

Decellularized organ biomatrices facilitate quantifiable in vitro 3D cancer metastasis models.

Metastatic cancers are chemoresistant, involving complex interplay between disseminated cancer cell aggregates and the distant organ microenvironment (extracellular matrix and stromal cells). Conventional metastasis surrogates (scratch/wound healing, Transwell migration assays) lack 3D architecture and ECM presence. Metastasis studies can therefore significantly benefit from biomimetic 3D in vitro models recapitulating the complex cascade of distant organ invasion and colonization by collective clusters of cells. We aimed to engineer reproducible and quantifiable 3D models of highly therapy-resistant cancer processes: (i) colorectal cancer liver metastasis; and (ii) breast cancer lung metastasis. Metastatic seeds are engineered using 3D tumor spheroids to recapitulate the 3D aggregation of cancer cells both in the tumor and in circulation throughout the metastatic cascade of many cancers. Metastatic soil was engineered by decellularizing porcine livers and lungs to generate biomatrix scaffolds, followed by extensive materials characterization. HCT116 colorectal and MDA-MB-231 breast cancer spheroids were generated on hanging drop arrays to initiate clustered metastatic seeding into liver and lung biomatrix scaffolds, respectively. Between days 3-7, biomatrix cellular colonization was apparent with increased metabolic activity and the presence of cellular nests evaluated via multiphoton microscopy. HCT116 and MDA-MB-231 cells colonized liver and lung biomatrices, and at least 15% of the cells invaded more than 20 μm from the surface. Engineered metastases also expressed increased signatures of genes associated with the metastatic epithelial to mesenchymal transition (EMT). Importantly, inhibition of matrix metalloproteinase-9 inhibited metastatic invasion into the biomatrix. Furthermore, metastatic nests were significantly more chemoresistant (>3 times) to the anti-cancer drug oxaliplatin, compared to 3D spheroids. Together, our data indicated that HCT116 and MDA-MB-231 spheroids invade, colonize, and proliferate in livers and lungs establishing metastatic nests in 3D settings in vitro. The metastatic nature of these cells was confirmed with functional readouts regarding EMT and chemoresistance. Modeling the dynamic metastatic cascade in vitro has potential to identify therapeutic targets to treat or prevent metastatic progression in chemoresistant metastatic cancers.

Oxaliplatin inhibits angiogenin proliferative and cell migration effects in prostate cancer cells

Angiogenin (Ang) is a potent angiogenic protein that is overexpressed in many types of cancer at concentration values correlated to the tumor aggressiveness. Here, by means of an integrated multi-technique approach based on crystallographic, spectrometric and spectroscopic analyses, we demonstrate that the anti-cancer drug oxaliplatin efficiently binds angiogenin. Microscopy cellular studies, carried out on the prostate cancer cell (PC-3) line , show that oxaliplatin inhibits the angiogenin prompting effect on cell proliferation and migration, which are typical features of angiogenesis process. Overall, our findings point to angiogenin as a possible target of oxaliplatin, thus suggesting a potential novel mechanism for the antineoplastic activity of this platinum drug and opening the avenue to novel approaches in the combined anti-cancer anti-angiogenic therapy.

Synergistic effects of metformin and curcumin on cytotoxicity of chemotherapy drugs using a gastric cancer cell line model.

Gastric cancer has a weak prognosis and its usual treatments depend on surgery and chemotherapy. These treatments suffer from some drawbacks such as high rates of local recurrence and metastasis, low survival rates, and significantly decreased life quality. Therefore, new therapeutic methods for improved gastric cancer care with minimal side effects seem necessary. Currently, combinatorial treatments for cancer are preferred and recently, metformin (Met) and curcumin (Cur) have been interesting options for this type of therapy. The aim of the present study was to investigate anticancer effects of metformin and curcumin in both single and combinatorial treatment forms on AGS gastric cancer cell line. In comparison to single treatments with each substance, the results of co-treatments with metformin and curcumin indicated synergistic inhibitory effects on cell viability, wound healing, cell migration and invasion, and primary tumor formation. To determine the selective effect of combination of “Met + Cur” on cancerous cells, very low doses of 8 anticancer drugs (cisplatin, carboplatin, oxaliplatin, epirubicin, doxorubicin, docetaxel, paclitaxel, and methotrexate) used in MTT assay were comparatively tested on AGS cancer cells and normal HDF cells for 48 and 72 hours. The results indicated that the combination of “Met + Cur” significantly increased cytotoxic effects of all anticancer drugs of AGS cells. It is while in normal HDF cells, combination of “Met + Cur” along with anticancer drugs had no effect. This can be inferred as selectively additive effect.

Anticancer activity and cell death mechanism of Pt(II) complexes: Their in vitro bio-transformation to Pt(II)-DNA adduct formation and BSA binding study by spectroscopic method

Pt(II) complex cis-[Pt(PEA)(OH2)2] X2, C-2 (where, PEA = 2-Pyridylethylamine and X = ClO4− or NO3–) was synthesized by hydrolysis of cis-[Pt(PEA)Cl2] C-1. Glutathione (GSH) and DL-penicilamine (DL-pen) substituted complexes cis-[Pt(PEA)(GSH)],C-3 and cis-[Pt(PEA)DL-pen)]X C-4 were synthesized and characterized by spectroscopic methods. Kinetic studies were traced on complex C-2 with the thiols, GSH and DL-pen. Pt(II)-Sulfur adduct formation mechanisms of the substituted products C-3 and C-4 were established from the kinetic investigation. At pH 4.0, C-2 - thiols interactions follow two consecutive steps: the first step is dependent, and the second is independent of [thiol]. The association equilibrium constant (KE), substitution rate constants for both steps (k1 & k2), and activation parameters (ΔH‡ and ΔS‡) have been assessed to propose the mechanism. Agarose gel electrophoresis mobilization pattern of DNA with complexes was performed to visualize the interaction nature. CT-DNA and BSA binding activities of the complexes have been executed by electronic, fluorescence spectroscopy, and viscometric titration methods. Evaluation of thermodynamic parameters (ΔH0, ΔS0, and ΔG0) from BSA binding constants was executed to propose the driving forces of interaction between these species. A molecular docking study was performed to evaluate the binding mode of complexes with BDNA strands. Anticancer activity of the complexes C-1 to C-4 was explored on both A549 and HEp-2 cell lines, compared with approved anticancer drugs cisplatin, carboplatin, and oxaliplatin. All these complexes were tested by NBT assay on normal cell line skeletal muscle cells (L6 myotubes) to observe the adverse effects compared to recognized anticancer medications. The ultimate aim is to explore the role of anticancer agents on cell death mechanism, which has been performed by flow-cytometer on HEp-2 cell lines.

Oxaliplatin-Induced Senescence in Colorectal Cancer Cells Depends on p14ARF-Mediated Sustained p53 Activation

Simple SummaryChemotherapy can lead to cellular senescence in tumor cells. Here we demonstrate that oxaliplatin induces senescence in p53-proficient colorectal cancer (CRC) cells and leads to the G2-phase arrest in all lines studied (HCT116p53+/+, HCT116p53−/−, LoVo, SW48, and SW480). At early times the p53-competent lines activate p53 and p21CIP1, however, at later times, only LoVo cells showed sustained p53/p21CIP1 activation, accompanied by a strong induction of senescence and senescence-associated secretory phenotype (SASP) factors. Opposite to LoVo, the p53/p21CIP1 response and senescence induction is much weaker in the other p53-proficient cells, due to p14ARF deficiency. LoVo cells express p14ARF protein and siRNA-mediated knockdown of p14ARF significantly reduces sustained p53/p21CIP1 activation and senescence. Vice versa, ectopic expression of p14ARF enhances oxaliplatin-induced senescence in SW48 and SW480 cells. Our data show that oxaliplatin-induced senescence in CRC cells depends on p53 proficiency; however, a significant induction can only be observed upon p14ARF-mediated p53 stabilization.Senescence is an important consequence of cytostatic drug-based tumor therapy. Here we analyzed to which degree the anticancer drug oxaliplatin induces cell death, cell cycle arrest, and senescence in colorectal cancer (CRC) cells and elucidated the role of p53. Oxaliplatin treatment resulted in the G2-phase arrest in all CRC lines tested (HCT116p53+/+, HCT116p53−/−, LoVo, SW48 and SW480). Immunoblot analysis showed that within the p53-competent lines p53 and p21CIP1 are activated at early times upon oxaliplatin treatment. However, at later times, only LoVo cells showed sustained activation of the p53/p21CIP1 pathway, accompanied by a strong induction of senescence as measured by senescence-associated β-Gal staining and induction of senescence-associated secretory phenotype (SASP) factors. Opposite to LoVo, the p53/p21CIP1 response and senescence induction was much weaker in the p53-proficient SW48 and SW480 cells, which was due to deficiency for p14ARF. Thus, among lines studied only LoVo express p14ARF protein and siRNA-mediated knockdown of p14ARF significantly reduced sustained p53/p21CIP1 activation and senescence. Vice versa, ectopic p14ARF expression enhanced oxaliplatin-induced senescence in SW48 and SW480 cells. Our data show that oxaliplatin-induced senescence in CRC cells is dependent on p53 proficiency; however, a significant induction can only be observed upon p14ARF-mediated p53 stabilization.

The Combination of Amygdalin with Some Anticancer, Antiparasitic, and Antigout Drugs Against MG63, Saos2, SW1353, and FL Cells In Vitro.

Osteosarcoma has a poor prognosis and survival rate due to inadequate chemotherapy, high recurrence ability, high metastasis potential, and almost no radiotherapy being applied. One of the strategies to solve these problems is to develop the pharmacologically active plant metabolite, amygdalin, in combination therapeutic systems. In this project, the antiproliferative effects of amygdalin alone and in binary or ternary combinations with some anticancer drugs (cisplatin, 5-fluorouracil, oxaliplatin, and camptothecin), antiparasitic drugs (metronidazole and miltefosine), and an antigout drug (colchicine) were examined using human bone osteosarcoma cell lines (MG-63 and Saos2), the chondrosarcoma cell line (SW1353), and the normal human cell line (FL). Known half-maximal inhibitory concentration values of the drugs were taken into consideration, and the recommended combination ratios were used in the Chou-Talalay method. The strong synergistic effect commonly seen in the combination of amygdalin with miltefosine, metronidazole, camptothecin, colchicine, oxaliplatin, 5-fluorouracil, and cisplatin dual drug indicates that these combinations can be used in cancer treatment. The synergistic effect caused by amygdalin decreases toxicity by increasing drug yield. However, amygdalin antagonism seen in several combinations may prevent these pairs from being used together. In combination with antagonistic effects, it may be preferable to use amygdalin alone as it generally causes strong antiproliferative effects. Besides, there is a more potent synergism between amygdalin and triple drug combinations. Overall, these results emphasize that amygdalin combinations in treatment of bone cancer are significant.

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.

Poly(Ethylene Glycol)-b-Poly(D,L-Lactide) Nanoparticles as Potential Carriers for Anticancer Drug Oxaliplatin.

Nanoparticles based on biocompatible methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG113-b-P(D,L)LAn) copolymers as potential vehicles for the anticancer agent oxaliplatin were prepared by a nanoprecipitation technique. It was demonstrated that an increase in the hydrophobic PLA block length from 62 to 173 monomer units leads to an increase of the size of nanoparticles from 32 to 56 nm. Small-angle X-ray scattering studies confirmed the “core-corona” structure of mPEG113-b-P(D,L)LAn nanoparticles and oxaliplatin loading. It was suggested that hydrophilic oxaliplatin is adsorbed on the core-corona interface of the nanoparticles during the nanoprecipitation process. The oxaliplatin loading content decreased from 3.8 to 1.5% wt./wt. (with initial loading of 5% wt./wt.) with increasing PLA block length. Thus, the highest loading content of the anticancer drug oxaliplatin with its encapsulation efficiency of 76% in mPEG113-b-P(D,L)LAn nanoparticles can be achieved for block copolymer with short hydrophobic block.