Synergistic Effect Of Cisplatin Research Articles

Oxidative Status Determines the Cytotoxicity of Ascorbic Acid in Human Oral Normal and Cancer Cells.

Oral squamous cell carcinoma (OSCC) can arise anywhere in the oral cavity. OSCC's molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic mutations and altered levels of transcripts, proteins, and metabolites. Platinum-based drugs are the first-line treatment for OSCC; however, severe side-effects and resistance are challenging issues. Thus, there is an urgent clinical need to develop novel and/or combinatory therapeutics. In this study, we investigated the cytotoxic effects of pharmacological concentrations of ascorbate on two human oral cell lines, the oral epidermoid carcinoma meng-1 (OECM-1) cell and the Smulow-Glickman (SG) human normal gingival epithelial cell. Our study examined the potential functional impact of pharmacological concentrations of ascorbates on the cell-cycle profiles, mitochondrial-membrane potential, oxidative response, the synergistic effect of cisplatin, and the differential responsiveness between OECM-1 and SG cells. Two forms of ascorbate, free and sodium forms, were applied to examine the cytotoxic effect and it was found that both forms had a similar higher sensitivity to OECM-1 cells than to SG cells. In addition, our study data suggest that the determinant factor of cell density is important for ascorbate-induced cytotoxicity in OECM-1 and SG cells. Our findings further revealed that the cytotoxic effect might be mediated through the induction of mitochondrial reactive oxygen species (ROS) generation and the reduction in cytosolic ROS generation. The combination index supported the agonistic effect between sodium ascorbate and cisplatin in OECM-1 cells, but not in SG cells. In summary, our current findings provide supporting evidence for ascorbate to serve as a sensitizer for platinum-based treatment of OSCC. Hence, our work provides not only repurposing of the drug, ascorbate, but also an opportunity to decrease the side-effects of, and risk of resistance to, platinum-based treatment for OSCC.

MicroRNA-302a-3p induces ferroptosis of non-small cell lung cancer cells via targeting ferroportin

Ferroptosis is a newly described regulatedform ofcell deaththat contributes to the progression of non-small cell lung cancers (NSCLCs). MicroRNA-302a-3p (miR-302a-3p) plays critical roles in thetumorigenicity of different cancers; however, its function and underlying mechanism in ferroptosis and NSCLCs remain unclear.Human NSCLCs cells were incubated with miR-302a-3pmimic or inhibitorin the presence or absence of erastinor RSL3. Cell viability, colony numbers, lactate dehydrogenase (LDH) releases,lipid peroxidation and intracellular iron level were measured. Besides, the synergistic effects of cisplatin and paclitaxel with miR-302a-3p were determined.miR-302a-3p level was reduced in human NSCLCs cells and tissues. ThemiR-302a-3p mimic induced lipid peroxidation, iron overload and ferroptosis, thereby inhibiting cell growth and colony formation of NSCLCs cells. Conversely, the miR-302a-3p inhibitor blockederastin- or RSL3-related ferroptosis and tumor suppression. Additionally, we found that miR-302a-3p directly bound to the 3’-untranslational region of ferroportin to decrease its protein expression, and that ferroportin overexpression significantly prevented miR-302a-3p mimic-induced ferroptosis and tumor inhibition. Moreover, the miR-302a-3p mimic sensitized NSCLCs cells to cisplatin and paclitaxel chemotherapy. miR-302a-3p functions as a tumor inhibitor, at least partly, via targeting ferroportin to induce ferroptosis of NSCLCs.

Assessing the relative biological effectiveness of high-dose rate 60Co brachytherapy alone and in combination with cisplatin treatment on a cervical cancer cell line (HeLa)

ObjectiveCervical cancer is the fourth common malignancy in women for which combinational therapy is the main treatment regimen. This study aimed to determine the effects of 60Co γ-ray high dose rate brachytherapy on the survival of HeLa cells with respect to X-ray of 6 MV linear accelerator (EBRT, external beam radiation therapy) as a comprehensive radiobiological concept. Furthermore, alterations in relative biological effectiveness (RBE) values were examined in combined treatments of cisplatin and radiation. MethodsCell survival was evaluated following different treatments by clonogenic assay. The synergistic effects of cisplatin and X-ray were evaluated in terms of the combination index (CI). Moreover, fold change reduction of each treatment in combination therapy was determined by evaluating the dose reduction index (DRI). RBE values were also determined after different treatments. ResultsMaximum values of DRI for cisplatin and radiation were 128 and 2.2-fold reduction when used in combination, respectively. As a result of the CI and DRI values, pretreatment with 2 μg/ml cisplatin for 2 h was selected as the most effective concentration and time, and it was used in RBE evaluation. The RBE values at 50% cell survival after treatment with radiation alone and also combined with cisplatin were measured as 1.308 and 1.553, respectively. These RBE values indicate a more destructive effect of γ-radiation brachytherapy than X-ray EBRT. ConclusionThe results of combined treatment indicate a remarkable synergism. Furthermore, our data determined that 60Co γ-ray is more effective than EBRT X-ray to induce cell death in HeLa cells.

Suppression of DRP1‑mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy.

The efficacy of chemotherapy for hepatocellular carcinoma (HCC) remains unsatisfactory, primarily due to inherent self‑defense mechanisms (e.g., mitophagy and autophagy). In the present study, we aimed to explore the pro‑apoptotic effects of targeting mitophagy to potentiate the efficacy of chemotherapy for HCC. HCC cells were subjected to cisplatin, after which cisplatin‑induced mitophagy was quantified by immunofluorescence. Mdivi‑1, a specific dynamin‑related protein1 (DRP1) inhibitor, was used to study the role of DRP1 in cisplatin‑induced HCC mitophagy. The synergistic effect of cisplatin and the DRP1 inhibitor on HCC was assessed invitro and invivo. Accordingly, cisplatin induced mitophagy in surviving HCC cells by activating DRP1. The DRP1 inhibitor (Mdivi‑1) increased the apoptosis of cisplatin‑treated HCC cells by targeting mitophagy. Mechanistically, Mdivi‑1 upregulated Bax and downregulated Bcl‑xL, leading to an increase in mitochondrial membrane permeability and subsequent release of cytochromec from mitochondria into the cytosol, thereby aggravating cisplatin‑induced apoptosis in HCC cells. Moreover, Mdivi‑1 acted synergistically with cisplatin to suppress HCC xenograft growth invivo. Our results indicate that targeting cisplatin‑mediated mitophagy increases HCC apoptosis via DRP1 inhibition, providing preclinical proof of concept for combination therapy targeting mitophagy to potentiate the efficacy of chemotherapy.

Peptide-Based Autophagic Gene and Cisplatin Co-delivery Systems Enable Improved Chemotherapy Resistance.

Cisplatin-based chemotherapy is a widely used first-line strategy for numerous cancers. However, drug resistances are often inevitable accompanied by the long-term use of cisplatin in vivo, significantly hampering its therapeutic efficacy and clinical outcomes. Among others, autophagy induction is one of the most common causes of tumor resistance to cisplatin. Herein, a self-assembled nanoprodrug platform was developed with the synergistic effect of cisplatin and RNAi to fight against cisplatin-resistant lung cancer. The nanoprodrug platform consists of three molecular modules, including prodrug complex of Pt(IV)-peptide-bis(pyrene), DSPE-PEG, and cRGD-modified DSPE-PEG. The Pt(IV) is immobilized with peptide via amide bonds, allowing the Pt(IV) to be loaded with a loading efficiency of >95% and rapid-release active platinum ions (Pt(II)) in the presence of glutathione (GSH). Meanwhile, the peptide of the prodrug complex could efficiently deliver Beclin1 siRNA ( Beclin1 is an autophagy initiation factor) to the cytoplasm, thereby leading to autophagy inhibition. In addition, incorporation of DSPE-PEG and cRGD-modified DSPE-PEG molecules improves the biocompatibility and cellular uptake of the nanoprodrug platform. In vivo results also indicate that the nanoprodrug platform significantly inhibits the growth of a cisplatin-resistant tumor on xenograft mice models with a remarkable inhibition rate, up to 84% after intravenous injection.

The Potential Impact of Magnesium Supplementation on Cisplatin-Induced Nephrotoxicity in Adult Male Albino Rats

Background: Cisplatin has been considered one of the most effective chemotherapeutic agents. It is associated with numerous toxicities at therapeutic doses like ototoxicity, gastrotoxicity, myelosuppression, allergic reactions and nephrotoxicity. The synergistic effects of Cisplatin and magnesium deficiency are believed to contribute to renal dysfunction. Aim:The aim of this study was to study the nephrotoxicity of cisplatin and evaluate potential impact of magnesium supplementation on such toxicity. Materials and Methods: Thirty-two adult male albino rats were divided into four equal groups. Group I served as (Control group). Group II (magnesium treated group) received single injection of magnesium sulphate (90mg/kg), Groups III (Cisplatin treated group) received single injection of 5 mg/kg body weight of cisplatin and Group IV (Cisplatinand magnesium treated group) received single injection of 90mg/kg magnesium sulphate and 5mg of cisplatin. After 14 days,biochemical parameters in serum were studied: creatinine,BUN, magnesium andinflammatory marker (IL-6) levels.Kidneyswere examined by light microscope as well. Results: results indicated that: serum levels of the creatinine,IL-6 and BUN of treated rats showeda highly significantincreased compared to control animals, whereas serum magnesium showedhighly significantdecreased.Magnesiumsupplementationreverse these chages. In conclusion:Our study demonstrated that cisplatin induced andomized in the kidney function andMg supplementation ameliorates it. It is recommendedto do further investigations to determine therole of magnesium in cisplatin induced nephrotoxicity.

Synergistic effects of cisplatin–caffeic acid on cervical cancer cell lines

Synergistic effects of cisplatin–caffeic acid on cervical cancer cell lines

Synergistic effects of cisplatin and proteasome inhibitor bortezomib on human bladder cancer cells.

The proteasome inhibitor bortezomib is a promising novel agent in bladder cancer therapy; however, inducible cytoprotective mechanisms may limit its potential efficacy. To date, the cellular and molecular effects of proteasome inhibitors on bladder cancer cells have been poorly characterized. Despite the consistent rate of initial responses, cisplatin treatment typically results in the development of chemoresistance, leading to therapeutic failure. Therefore, the present study aimed to characterize the molecular mechanisms underlying the anti-proliferative effects of cisplatin and bortezomib combination therapy on the human T24 bladder cancer cell line, by analyzing the protein expression levels of apoptotic genes. Cytotoxic effects were measured using a water-soluble tetrazolium salt-1 assay, and the apoptosis-associated molecules were examined using western blot analysis and ELISA. It was observed that combined administration of cisplatin and bortezomib induced upregulation of caspase-3, -8 and -9, B-cell lymphoma-2 (Bcl-2)-like 11 and Bcl-2-interacting killer, but downregulated Bcl-2 and Bcl-extra large protein expression levels in T24 cells in a dose-dependent manner. Furthermore, enhanced protein expression of caspase-8 and -9, in line with the significantly increased caspase-3 activation, was detected when the cells were treated with a combination of cisplatin and bortezomib, compared with that of either agent alone. Bortezomib appeared to synergize with cisplatin to promote apoptosis via the extrinsic and intrinsic apoptotic pathways. Taken together, the results of the current study provide the preclinical framework for additional evaluation of the effects of combining bortezomib with other agents to induce apoptosis in bladder cancer cells.

MRE11A and SKP2 genes are associated with the increased cytotoxicity induced by the synergistic effects of cisplatin and gemcitabine in bladder cancer cells

The combination of gemcitabine and cisplatin has been shown previously to elicit a synergistic therapeutic effect on bladder cancer cell lines and result in reduced cell survival. However, the precise mechanism by which cells die has not been elucidated. Cell cycle-related genes are the predominant targets of chemotherapeutic protocols. Therefore, molecular biomarkers that are predictive of therapeutic outcomes associated with tumor sensitivity might be important for optimal treatment protocol selection. The aim of this study was to investigate the changes in gene expression in cell cycle-related genes that were induced by cisplatin, gemcitabine or a combined treatment using both agents in a low-grade urinary bladder transitional carcinoma cell line (RT4). The following three treatment protocols were used: 1.0 μM cisplatin, 1.56 μM gemcitabine and a combination of 1.0 μM cisplatin and 1.56 μM gemcitabine. Cytometry and morphology analysis (by phase-contrast photomicrography) were performed in addition to pathway-specific gene expression analysis using quantitative RT-PCR gene arrays. The following results were observed after 1.0 μM cisplatin treatment: (1) a decrease in cell number, (2) an increased percentage of scattered cells and (3) downregulated expression of genes related to cell cycle arrest, G1/S-to-mitotic cell cycle transition, DNA repair, apoptosis, transcription and mitosis. Treatment with 1.56 μM gemcitabine, or with both drugs simultaneously, induced the following effects: (1) a decrease in cell number, (2) an increased percentage of scattered and elongated cells, (3) the modulation of genes that are predominantly involved in DNA repair and (4) a significant upregulation of genes related to cell cycle arrest. Reduced cell density was observed after the combined treatment compared to the two other single-agent protocols. The downregulation of MRE11A and SKP2 was observed only in cells subjected to the combined treatment. In conclusion, cisplatin, gemcitabine and the combination of both drugs elicited distinct toxicogenomic effects in the RT4 bladder transitional carcinoma cell line, although disruptions in the expression of cell cycle control-related genes and other pathways responsible for cell survival were observed for all of the protocols. MRE11A and SKP2 downregulation appeared to be responsible for the synergistic therapeutic effects elicited by cisplatin and gemcitabine.

Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice.

Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

Therapy-related malignancies following treatment of germ cell cancer.

Given the young age at which testicular cancer is treated and the excellent prognosis for patients suffering from this disease, therapy-related malignancies represent a significant problem. Therapy-related solid tumors are associated mainly with the use of radiation therapy. The risk for developing a therapy-related solid tumor is approximately 2- to 3-fold increased compared with the general population. Therapy-related leukemias are associated predominantly with chemotherapy, particularly with the use of topoisomerase-II inhibitors and alkylating agents. In general, the cumulative incidence of therapy-related leukemia is low. It is approximately 0.5% and 2% at 5 years of median follow-up for patients receiving etoposide at cumulative doses < or = 2 g/m2 and > 2 g/m2, respectively. High cumulative doses of etoposide given over a short period of time appear to be less leukemogenic than a similar dose of etoposide given over a longer period of time. There might, additionally, be a synergistic effect of cisplatin and etoposide on the induction of therapy-related leukemia. For patients who receive high-dose chemotherapy with autologous stem-cell support, the risk of therapy-related myelodysplastic syndrome and leukemia appears to be substantially lower compared with that reported in non-Hodgkin's lymphoma patients undergoing high-dose chemotherapy. The transplantation procedure itself does not appear to add to the therapy-related leukemia risk. The risk-benefit analysis in patients with testicular cancer clearly favors the use of current treatment regimens including high-dose chemotherapy. However, even the acceptably low number of therapy-related leukemias should encourage the search for equally effective but less toxic therapies.

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The results of chemotherapy for tumors of the head and neck have been markedly improved since cisplatin was introduced. The synergistic effect of cisplatin and peplomycin has been especially favorable therapeutically. Although clinical experience has favored the use of these two drugs together, basic research has been lacking in an attempt to establish an ideal protocol with cisplatin and peplomycin based on cell kinetics and pharmacokinetics, we investigated in detail the in vitro actions of these drugs, as described in our previous reports. We have here attempted to determine the best schedule of administering peplomycin and cisplatin on the basis of study of pharmacokinetics and survival, using bromodeoxyuridine and fluorescein diacetate techniques. We found that tumor cell survival was the lowest and cytocidal effects were the highest when peplomycin was administered 3 days after cisplatin. The cell kinetics showed an accumulation in the S and G2M stage.Peplomycin appears to be the most effective when it is given 3 days after cisplatin.