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"An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle." (MeSH 2013)

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Latest Research Publications

Web Resources: Cisplatin (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Sung PS, Yang K, Bae SH, et al.
Reduction of Intrahepatic Tumour by Hepatic Arterial Infusion Chemotherapy Prolongs Survival in Hepatocellular Carcinoma.
Anticancer Res. 2019; 39(7):3909-3916 [PubMed] Related Publications
BACKGROUND/AIM: This study aimed to identify the survival benefit of intrahepatic tumour control by hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) or extrahepatic metastasis.
PATIENTS AND METHODS: Between 2010 and 2017, a total of 187 consecutive patients with advanced HCC were treated with HAIC. The survival outcomes and response rates to HAIC were analysed.
RESULTS: The intrahepatic objective response (OR) rate of all enrolled patients was 18.7%. The survival outcome of patients with OR was significantly better from those without OR, irrespective of initial distant metastasis. Achievement of intrahepatic OR by HAIC and favourable liver function at the time of best response evaluation were two independent factors associated with better OS.
CONCLUSION: HAIC-induced intrahepatic tumour reduction significantly prolonged patient survival, irrespective of PVTT or initial distant metastasis.

Gerogianni I, Pitaraki E, Jagirdar RM, et al.
2-Deoxy-glucose Enhances the Effect of Cisplatin and Pemetrexed in Reducing Malignant Pleural Mesothelioma Cell Proliferation But Not Spheroid Growth.
Anticancer Res. 2019; 39(7):3809-3814 [PubMed] Related Publications
BACKGROUND/AIM: Malignant pleural mesothelioma (MPM) is a therapy-resistant neoplasm of the pleura. Standard chemotherapy consists of a combination of cisplatin (CPDD) and pemetrexed (PEM). The aim of this study was to assess whether inhibition of aerobic glycolysis by 2-deoxy-glucose (2DG) would enhance the effects of standard chemotherapy.
MATERIALS AND METHODS: MeT-5A, M14K, MSTO and ZL34 cell lines were used. Cell viability with 2DG and cell proliferation and spheroid formation with CPDD+PEM alone and with 2-DG were tested.
RESULTS: Viability with 2-DG was dose-dependent. Cell proliferation with CPDD+PEM on 2D surface was reduced in all cell types, 2-DG inclusion demonstrated a synergistic effect in MSTO and ZL34 cells. Spheroid growth in 3D with CPDD+PEM or CPDD+PEM+2-DG lowered spheroid growth in all cell types.
CONCLUSION: 2-DG synergizes with CPDD+PEM in lowering MPM cell proliferation in 2D to <20%. In 3D MPM spheroid growth 2-DG synergism with CPDD+PEM treatment is not maintained.

Alampi DM, Ciusani E, Carenini N, et al.
AXL Downstream Targeting Unravels Synergistic Drug Combinations in Ovarian Carcinoma Cells.
Anticancer Res. 2019; 39(7):3803-3808 [PubMed] Related Publications
BACKGROUND: Platinum-based therapy represents the main pharmacological treatment for ovarian carcinoma. Since molecular targeting of receptor tyrosine kinases (RTK) affects factors that may modulate drug response, the aim of this study was to examine whether downstream targets of AXL RTK could be exploited to improve cell response to cisplatin.
MATERIALS AND METHODS: Inhibitors of p38 (SB203580) and of signal transducer and activator of transcription 3 (stattic) were employed in combination with cisplatin in ovarian carcinoma cell lines. Apoptosis assay and western blot analysis were performed to evaluate cell response after treatment.
RESULTS: SB203580 produced a synergistic effect in combination with cisplatin in cisplatin-resistant IGROV-1/Pt1 cells. In addition, a favorable drug interaction was observed in A2780 cells when pre-incubated with cisplatin prior to stattic. The analysis of cell response after combined treatment showed down-regulation of the pro-apoptotic protein BCL2-associated agonist of cell death (BAD).
CONCLUSION: Our results support the notion that downstream targets of AXL in ovarian carcinoma cells can be exploited to increase cisplatin activity in ovarian carcinoma models.

Drąg-Zalesińska M, Saczko J, Choromańska A, et al.
Cisplatin and Vinorelbine -Mediated Electrochemotherapeutic Approach Against Multidrug Resistant Small Cell Lung Cancer (H69AR)
Anticancer Res. 2019; 39(7):3711-3718 [PubMed] Related Publications
BACKGROUND/AIM: Small cell lung cancer (SCLC) originates from neuroendocrine branchial cells (15-20%). It is regarded as distinct from other lung cancers due to its biological and clinical features. In most cases of SCLC, surgery or radiotherapy alone is not an effective cure. The aim of our study was to examine the cytotoxic effects of chemotherapy supported by electroporation (EP) on a resistant SCLC model, in vitro.
MATERIAL AND METHODS: The multidrug resistant small lung cell line H69AR was used to evaluate the cytotoxic effects of cisplatin (CPPD) and vinorelbine (Navirel®; NAV) at lower doses when used with EP. Cells were treated with different concentrations of CPPD and NAV, alone or in combination with the following EP parameters: 400-1200 V/cm, 8 pulses of 100 μs duration, at 1Hz. The cell viability was estimated by MTT assay after 24 and 48 h. Apoptotic cells were detected by neutral comet assay and immunofluorescence assay with PARP-6.
RESULTS: CPPD and NAV alone showed a dose-dependent effect on cell viability. Cytostatic drugs combined with EP revealed increased anticancer activity. Lower doses of CPPD or NAV delivered by EP were as effective as higher doses of these drugs without EP. The electrochemotherapeutic protocols increased the number of apoptotic cells and increased immunoreactivity of PARP-6. Our results indicated higher sensitivity of H69AR cells to NAV supported by EP.
CONCLUSION: In SCLC cells, an increased anticancer activity was potentiated by exposure of cells to high intensity electric pulses and low drug doses. It is suggested that this method could be effectively applied in the treatment of lung cancer.

Addeo R, Caraglia M, Vincenzi B, et al.
Efficacy and Safety of Cetuximab plus Radiotherapy in Cisplatin-Unfit Elderly Patients with Advanced Squamous Cell Head and Neck Carcinoma: A Retrospective Study.
Chemotherapy. 2019; 64(1):48-56 [PubMed] Related Publications
INTRODUCTION: Concurrent platinum-based chemoradiation currently represents the standard treatment for advanced head and neck cancer (HNC), but it induces a significant toxicity, in particular among elderly patients. Elderly and unfit patients have been underrepresented in clinical trials and there is a need for tailored guidelines.
METHODS: A retrospective review of clinical data of HNC patients treated at the Operative Oncology Unit of the San Giovanni di Dio Hospital in Frattamaggiore (Naples, Italy) was performed. At study entry, a comprehensive assessment including absolute contraindications for cisplatin use, as well as comorbidities, socioeconomic status, BMI, and weight loss, was performed. The treatment included high-dose radiotherapy plus weekly cetuximab (initially at a dose of 400 mg/m2of body surface area and thereafter at 250 mg weekly during the whole radiotherapy). The aim of this study was to evaluate the activity and toxicity of this schedule in a series of patients aged older than 69 years.
RESULTS: Between May 30, 2013, and March 30, 2015, sixty-four patients (age range, 69-87 years; median age, 73.7 years; male/female ratio, 46/18) were treated. The overall response rate was 67% in this series of patients. The disease control rate was 76%. Disease progression was recorded in 25% of the patients. The median duration of loco-regional control was 17 months (range, 15.8-17.7 months). PFS was 14.8 months (range, 13.9-15.5 months). The overall survival was 34 months, with a median follow-up of 41.0 months (range, 31.1-36.8 months). The main grade 3/4 adverse events were acne rash in 52% and radiation dermatitis in 32% of the cases.
CONCLUSION: Cetuximab plus radiotherapy appears to be feasible and active in elderly patients unsuitable for cisplatin treatment. The treatment was supported by a favorable toxicity profile.

Khan MW, Zhao P, Khan A, et al.
Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity.
Int J Nanomedicine. 2019; 14:3753-3771 [PubMed] Free Access to Full Article Related Publications

Chen S, Yang C, Sun C, et al.
miR-21-5p Suppressed the Sensitivity of Hepatocellular Carcinoma Cells to Cisplatin by Targeting FASLG.
DNA Cell Biol. 2019; 38(8):865-873 [PubMed] Related Publications
Accumulating evidence has suggested that microRNAs play important roles in the development of hepatocellular carcinoma (HCC) and are involved in drug resistance. miR-21-5p was overexpressed in a variety of cancers and promoted the tumorigenesis; however, the function of miR-21-5p in HCC still remains unknown. In this study, our results showed that miR-21-5p was highly expressed in HCC tissues and cell lines. Notably, the level of miR-21-5p was relatively higher in cisplatin (DDP)-resistant HCC patients. Overexpression of miR-21-5p attenuated the inhibitory effect of DDP on the proliferation and apoptosis of HCC cells. Mechanistically, the luciferase report assay-identified FAS ligand (FASLG) was a direct target of miR-21-5p. Overexpression of miR-21-5p decreased both the mRNA and protein levels of FASLG in HCC cells. FASLG was downregulated in HCC tissues and was significantly negatively correlated with the expression of miR-21-5p. Restoring the expression of FASLG upregulated the chemosensitivity of HCC cells expressing miR-21-5p. In conclusion, our results demonstrated that miR-21-5p targeted FASLG and suppressed the sensitivity of HCC cells to DDP treatment.

Zarei S, Reza JZ, Jaliani HZ, et al.
Effects of carfilzomib alone and in combination with cisplatin on the cell death in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines.
Bratisl Lek Listy. 2019; 120(6):468-475 [PubMed] Related Publications
BACKGROUND: Previous studies on the efficacy of platinum-based drugs and selective inhibitors of proteasome have revealed promising outcomes. This study is aimed to evaluate the effects of the combination of cisplatin and carfilzomib on the cell death induction and drug efflux transporters expression in cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cells lines.
METHODS: MTT cytotoxic assay was conducted to determine the cytotoxicity. Drug interactions were analyzed based on Chou-Talalay's principles and real-time PCR analysis was performed to determine possible alterations in mRNA levels of MRP1 and BCRP.
RESULTS: A2780s cells were more susceptible to both cisplatin and carfilzomib while analyses of drug interactions between the two agents showed synergistic effects in all affected fractions of drug-treated A2780s and A2780cp cells (CI<0.9) with the combination indices being significantly lower in A2780cp cells (p < 0.01). We also found that although mRNA levels of BCRP and MRP1 were significantly altered in both cells exposed to each drug alone, only the combination regimen was able to significantly reduce the mRNA levels of these genes in A2780cp cells (p<0.001).
CONCLUSION: This combination might be a potential strategy for suppressing cell growth via downregulating the drug efflux transporters expression, especially in cisplatin-resistant ovarian cancer cells (Fig. 3, Ref. 45).

Cao M, Long M, Chen Q, et al.
Development of β-elemene and Cisplatin Co-Loaded Liposomes for Effective Lung Cancer Therapy and Evaluation in Patient-Derived Tumor Xenografts.
Pharm Res. 2019; 36(8):121 [PubMed] Related Publications
PURPOSE: β-elemene and cisplatin combined chemotherapy currently is one of the most important settings available for lung cancer therapy in China. However, the clinical outcome is limited by their pharmacokinetic drawbacks. On the other hand, most of nanomedicines have failed in clinical development due to the huge differences between heterogeneous clinical tumor tissues and homogenous cell-derived xenografts. In this work, we fabricated a β-elemene and cisplatin co-loaded liposomal system to effectively treat lung cancer.
METHOD: In vitro cytotoxicity of co-loaded liposomes was studied by MTT, trypan and Hoechst/PI staining, and western blot in A549, A549/DDP, and LCC cells. In vivo antitumor efficacy was evaluated in cell-derived and clinically relevant patient-derived xenografts.
RESULTS: Co-loaded liposomes were more cytotoxic to cancer cells, especially than the combination of single-loaded liposomes, benefiting from their simultaneous drug internalization and release. As a result, they exhibited desirable therapeutic outcome in both cell-derived and patient-derived xenografts.
CONCLUSION: β-elemene and cisplatin co-loaded liposomes are a clinically promising candidate for effective lung cancer therapy.

Qian G, Dai L, Yu T
Thioridazine Sensitizes Cisplatin Against Chemoresistant Human Lung and Ovary Cancer Cells.
DNA Cell Biol. 2019; 38(7):718-724 [PubMed] Related Publications
Human lung cancer cell lines A549 and A549/DDP, and ovarian cancer cell lines SKOV3 and SKOV3/DDP were subjected to thioridazine (Thio), cisplatin, or the combination; A549/DDP and SKOV3/DDP were the cisplatin-resistant sublines. Cell viability, apoptosis, and cell cycle were detected; the mitochondrial membrane potential and proteins related to mitochondrial apoptosis were determined. Thio induced cell death, and the combination of Thio and cisplatin led to the highest percentage of dead cells in four cells lines. Thio and the combined modality led to cell apoptosis by inducing G

Mai L, Luo M, Wu JJ, et al.
The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.

Chapman BV, Swanick CW, Ning MS, et al.
Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.
Gynecol Oncol. 2019; 154(1):22-28 [PubMed] Related Publications
OBJECTIVE: To identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer.
METHODS: We retrospectively identified 249 women with FIGO 2009 stage IIIC endometrial cancer at our institution who underwent surgical staging from 1985 to 2015 followed by external beam radiotherapy (RT), chemotherapy (CT), or a combination of CT + RT. Survival rates were calculated using the Kaplan-Meier method.
RESULTS: The 5-year disease-specific survival (DSS) rate for all patients was 65%. Adjuvant CT + RT conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P = 0.04 and 67% vs. 38%, P = 0.02, respectively). Among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P = 0.02). The 3-year pelvic recurrence rate was 5% with RT ± CT and 35% with CT alone (P < 0.001) for all patients. No paraaortic nodal failures were observed following extended-field RT, but 14% of patients who received pelvic-only RT or CT alone developed recurrences in the paraaortic nodes (P < 0.001).
CONCLUSIONS: Combined-modality therapy including adjuvant external beam pelvic radiotherapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer. The most pronounced DSS advantage from adjuvant chemoradiotherapy was evident in women with non-endometrioid endometrial cancer.

Yu D, Zhang S, Feng A, et al.
Methotrexate, doxorubicin, and cisplatinum regimen is still the preferred option for osteosarcoma chemotherapy: A meta-analysis and clinical observation.
Medicine (Baltimore). 2019; 98(19):e15582 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We designed the study to investigate whether methotrexate, doxorubicin, and cisplatinum (MAP) chemotherapy strategy was still the preferred option for the survival of osteosarcoma patients.
METHOD: We collected some trials of osteosarcoma to make a meta-analysis first. Then, we retrospectively collected data from 115 patients with osteosarcoma and performed further analysis to verify the impact of MAP regimen on the survival of patients.
RESULTS: Seven studies including 3433 participants met the preliminary inclusion criteria. Meta-analysis of the 3-year disease-free survival (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 0.88-1.28; P = .52) and overall survival (OR = 1.21, 95% CI: 0.70-2.11; P = .54), 5-year disease-free survival (OR = 1.07, 95% CI: 0.87-1.30; P = .54) and overall survival (OR = 0.86, 95% CI: 0.65-1.12; P = .26), and mortality rate (OR = 0.90, 95% CI: 0.70-1.17; P = .44), showed no statistically significant differences. The most common grade 3/4 adverse events were neutropenia (498 [85.9%] patients in MAP vs 533 [93.3%] in MAP plus ifosfamide and etoposide, or other adjuvant therapy drugs [MAP]). MAP was associated with less frequent toxicities than MAP group with statistical significance in thrombocytopenia, febrile neutropenia, anemia, and hypophosphatemia. The same phenomenon could also be seen in the analysis of clinical data.
CONCLUSION: MAP regimen remains the preferred option for osteosarcoma chemotherapy.

Jiang S, Chang H, Deng S, Fan D
Icariin enhances the chemosensitivity of cisplatin‑resistant ovarian cancer cells by suppressing autophagy via activation of the AKT/mTOR/ATG5 pathway.
Int J Oncol. 2019; 54(6):1933-1942 [PubMed] Free Access to Full Article Related Publications
Icariin is a flavonoid derived from Epimedium sagittatum, and has a wide range of biological and pharmacological effects; however, little is known regarding its effect on drug‑resistant ovarian cancer and the signal transduction pathways underlying the regulation of apoptosis and autophagy. The present study aimed to investigate the re‑sensitization effects of icariin exerted on an ovarian cancer cell line. Autophagy was analyzed in a SKVCR cell line that had been treated with icariin. We investigated the sensitivity of SKVCR cells to cisplatin, as well as the effects of an autophagy agonist (rapamycin) on autophagy, apoptosis, and the protein kinase B (AKT) signaling pathway. Finally, the mechanism underlying the effects of autophagy‑related (ATG) protein ATG5 overexpression on autophagy, apoptosis and AKT signaling in SKVCR cells were determined. The results revealed that treatment with icariin inhibited cell viability and autophagy, but promoted G0/G1 phase cell cycle arrest and apoptosis as determined by Cell Counting Kit‑8, immunofluorescence and flow cytometry assays, respectively. Icariin reduced the resistance of SKVCR cells to cisplatin in vitro by inducing G1/S cell cycle transition, apoptosis and inhibiting autophagy. Furthermore, enhanced autophagy induced by rapamycin treatment or overexpression of ATG5 partially reversed the effect of icariin on cisplatin resistance and autophagy in SKVCR cells. At the molecular level, rapamycin treatment or overexpression of ATG5 reversed the effects of icariin on the expression of autophagy‑associated proteins, including microtubule‑associated protein 1 light chain 3β, Beclin‑1, ATG5 and p62, and the AKT/mammalian target of rapamycin (mTOR) pathway. Collectively, our results suggested that icariin enhances the chemosensitivity of SKVCR cells by suppressing autophagy via activation of the AKT/mTOR signaling pathway.

Sheng J, Shen L, Sun L, et al.
Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial-lysosomal crosstalk.
Cell Prolif. 2019; 52(3):e12609 [PubMed] Related Publications
OBJECTIVES: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells.
MATERIALS AND METHODS: Huh7 and HepG2 cells were subjected to different treatments. Flow cytometry was conducted to detect mitochondrial reactive oxygen species, mitochondrial mass, lysosomal function, mitochondrial membrane potential and apoptosis. Western blotting was performed to evaluate protein levels. The oxygen consumption rate was measured to evaluate mitochondrial function.
RESULTS: Cisplatin activated mitophagy and lysosomal biogenesis, resulting in crosstalk between mitochondria and lysosomes and cisplatin resistance in HCC cells. Furthermore, a combination of cisplatin with the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor PKI-402 induced lysosomal membrane permeabilization. This effect changed the role of the lysosome from a protective one to that of a cell death promoter, completely destroying the mitochondrial-lysosomal crosstalk and significantly enhancing the sensitivity of HCC cells to cisplatin.
CONCLUSIONS: This is the first evidence of the importance of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells and of the destruction of this crosstalk by a PI3K/mTOR inhibitor to increase the sensitivity of HCC cells to cisplatin. This mechanism could be developed as a novel target for treatment of HCC in the future.

Chen B, Shen Z, Wu D, et al.
Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway.
Biomed Res Int. 2019; 2019:7640547 [PubMed] Free Access to Full Article Related Publications
Purpose: Reactive oxygen species (ROS)-induced cytotoxicity is an important mechanism by which cisplatin kills tumor cells. Glutathione peroxidase family (GPXs) is an important member of antioxidant system which metabolizes intracellular ROS and maintains homeostasis of cells. Altered expressions of GPXs enzymes, especially GPX1, have been described in a variety of human cancers. However, their functional roles in cisplatin-based chemoresistance in human malignancies including non-small cell lung cancer have never been explored.
Methods: A panel of NSCLC cell lines were selected for this study. GPX1 expression was detected using quantitative RT-PCR and Western blot. Cisplatin-induced cell killing was analyzed by CCK8 assay. Intracellular ROS levels were detected by fluorescence-based flow cytometry analysis. In vitro overexpression and knockdown of GPX1 expression were performed using GPX1 expression vector and siRNA approaches. Protein levels of PTEN, NF-
Results: GPX1 expression was upregulated in a subset of NSCLC cell lines resistant to cisplatin treatment. Expression vector-mediated forced overexpression of GPX1 significantly increased cisplatin resistance in NSCLC cell lines, whereas RNA inference-mediated downregulation of GPX1 could restore sensitivity to cisplatin. Overexpression of GPX1 significantly suppressed elevation of intracellular ROS and activation of AKT pathway when NSCLC cell lines were exposed to different concentrations of cisplatin. Activation of the AKT pathway inhibited proapoptotic cascade and subsequently led to cisplatin resistance in NSCLC cells. Inhibition of NF-
Conclusions: Our findings suggested that overexpression of GPX1 is a novel molecular mechanism for cisplatin-based chemoresistance in NSCLC. GPX1 overexpression blocks cisplatin-induced ROS intracellular accumulation, activates PI3K-AKT pathway by increased AKT phosphorylation, and further leads to cisplatin resistance in NSCLC cells. Inhibition of NF-

Kosmidis C, Sapalidis K, Zarogoulidis P, et al.
Inhaled Cisplatin for NSCLC: Facts and Results.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Although we have new diagnostic tools for non-small cell lung cancer, diagnosis is still made in advanced stages of the disease. However, novel treatments are being introduced in the market and new ones are being developed. Targeted therapies and immunotherapy have brought about a bloom in the treatment of non-small cell lung cancer. Still we have to find ways to administer drugs in a more efficient and safe method. In the current review, we will focus on the administration of inhaled cisplatin based on published data.

Cheng L, Li C, Yuan S, et al.
Reaction of Histone H1 with trans-Platinum Complexes and the Effect on DNA Platination.
Inorg Chem. 2019; 58(9):6485-6494 [PubMed] Related Publications
Transplatin is an inactive platinum drug; however, a number of analogues, such as trans-EE and trans-PtTz, demonstrate promising antitumor activity in vitro and in vivo. Although the ultimate target is nuclear DNA, increasing evidence indicate that proteins also play important roles in the display of antitumor activity. The linker histone H1 is situated by the portal between the unwrapped DNA and the nucleosome core. Our recent study revealed that H1 can readily react with cisplatin, and the adducts tend to form ternary complexes with DNA. In this work, we have investigated the reaction of histone H1 with two antitumor-active trans-oriented complexes, trans-EE and trans-PtTz, and the effect of H1 upon the platination of DNA. The results show that trans-platinum drugs are much more reactive than cisplatin toward H1. Interestingly, in addition to the expected bidentate adducts (by displacement of the two labile chlorido ligands), also a tridentate adduct can be formed by displacement of one nonlabile carrier ligand of trans-EE or trans-PtTz. The trans-Pt/H1 adducts can then react with DNA and generate protein-Pt-DNA ternary complexes. Additionally, platinum can be transferred from trans-Pt/H1 adducts to DNA, generating binary trans-Pt/DNA complexes. Such a transfer of the platinum agent to DNA was not observed in the reaction of cisplatin. Furthermore, the detailed investigation carried out on a model peptide indicates that H1 promotes the DNA platination by trans- EE, while it reduces that of trans-PtTz and cisplatin. These results suggest that H1 can play a key role in the DNA platination and modulate the efficacy of different platinum agents.

Quintanilha JCF, Saavedra KF, Visacri MB, et al.
Role of epigenetic mechanisms in cisplatin-induced toxicity.
Crit Rev Oncol Hematol. 2019; 137:131-142 [PubMed] Related Publications
Cisplatin (CDDP) is a highly effective antineoplastic agent, widely used in the treatment of various malignant tumors. However, its major problems are side effects associated to toxicity. Considerable inter-individual differences have been reported for CDDP-induced toxicity due to genetic and epigenetic factors. Genetic causes are well described; however, epigenetic modifications are not fully addressed. In the last few years, many evidences were found linking microRNA to the development of CDDP-mediated toxicity, particularly nephrotoxicity. In this review, we described how genetic and epigenetic modifications can be important determinants for the development of toxicity in patients treated with CDDP, and how these alterations may be interesting biomarkers for monitoring toxicity induced by CDDP. Considering the validation in different studies, we suggest that miR-34a, -146b, -378a, -192, and -193 represent an attractive study group to evaluate potential biomarkers to detect CDDP-related nephrotoxicity.

Rao C, Miao X, Zhao G, et al.
MiR-219a-5p enhances cisplatin sensitivity of human non-small cell lung cancer by targeting FGF9.
Biomed Pharmacother. 2019; 114:108662 [PubMed] Related Publications
Cisplatin (DDP) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). MicroRNA-219a-5p (miR-219a-5p) has been reported to be a tumor suppressor in several cancers, but whether it regulates chemosensitivity in NSCLC remains unclear. Here, using quantitative real time PCR analysis, we observed that miR-219a-5p was down-regulated in responding tumor tissues compared with that in non-responding tumor tissues from NSCLC patients received DDP-based chemotherapy. Consistently, miR-219a-5p expression was lower in cisplatin (DDP)-resistant NSCLC cell lines (A549-R and SPC-A1-R) than that in corresponding parental cells (A549 and SPC-A1). Gain of-function assay showed ectopic expression of miR-219a-5p reversed DDP chemoresistance of NSCLC cells in vitro and in vivo. Using bioinformatics prediction and dual-luciferase reporter assays, we identified the FGF9 gene as a novel direct target of miR-219a-5p. Moreover, restoration of FGF9 expression reversed the miR-219a-5p-mediated chemosensitivity. In conclusion, this study demonstrated miR-219a-5p plays a crucial role in the development of acquired drug resistance to DDP in NSCLC cells by targeting FGF9 and might be a therapeutic target for DDP resistance in clinical practice.

Rouvinov K, Plimack ER, Zibelman M, et al.
Update on perioperative systemic therapy for urothelial carcinoma.
Clin Adv Hematol Oncol. 2019; 17(3):176-183 [PubMed] Related Publications
Level 1 evidence supports cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive urothelial bladder cancer (MIUBC). Recent data from small prospective trials with neoadjuvant immune checkpoint inhibitors are encouraging, but long-term follow-up is required. Randomized trials have failed to accrue a sufficient number of patients and have not demonstrated a survival benefit with adjuvant chemotherapy in MIUBC, but for those with high-risk features at surgery, adjuvant cisplatin-based therapy is appropriate. In upper tract urothelial carcinoma, several retrospective trials and one recent phase 2 prospective trial support the use of NAC, and a randomized trial with adjuvant chemotherapy demonstrated improved disease- and metastasis-free survival and a trend toward improved overall survival.

Miyamoto K, Minegaki T, Tanahashi M, et al.
Synergistic Effects of Olaparib and DNA-damaging Agents in Oesophageal Squamous Cell Carcinoma Cell Lines.
Anticancer Res. 2019; 39(4):1813-1820 [PubMed] Related Publications
BACKGROUND/AIM: Chemotherapy is an important first-line treatment for oesophageal squamous cell carcinoma (ESCC). However, there are few secondary options. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, enhances the cytotoxicity of various anticancer drugs and has been used to treat advanced ovarian and breast cancers. This study examined the effect of olaparib on the cytotoxicity of anticancer drugs in ESCC cell lines.
MATERIALS AND METHODS: ESCC KYSE70 and KYSE140 cells were grown in Dulbecco's modified Eagle's medium and treated with 5-fluorouracil (5-FU), cisplatin, docetaxel, doxorubicin, SN-38, or temozolomide without or with olaparib.
RESULTS: Olaparib enhanced the cytotoxicity of all tested anticancer drugs and increased the effects of cisplatin, doxorubicin, SN-38, and temozolomide synergistically. These anticancer drugs caused the accumulation of phospho-histone H2AX Ser139 (γH2AX), a biomarker of DNA damage, and olaparib increased this accumulation.
CONCLUSION: PARP inhibitors may potentiate the anticancer activity of DNA-damaging agents in ESCC patients synergistically.

He C, Sun Z, Hoffman RM, et al.
P-Glycoprotein Overexpression Is Associated With Cisplatin Resistance in Human Osteosarcoma.
Anticancer Res. 2019; 39(4):1711-1718 [PubMed] Related Publications
BACKGROUND/AIM: Osteosarcoma (OS) is a diagnosed primary cancer of the bone. Despite the great advances that have been made during the past decades in OS therapy, drug resistance and tumor recurrence are still major problems. It is urgent to find novel strategies to overcome drug resistance in order to prolong the survival time of OS patients.
MATERIALS AND METHODS: Cell viability was investigated by the cell count kit-8 (CCK-8) and colony formation assays. P-Glycoprotein (P-gp) expression was analyzed by RT-qPCR and western blot. A xenograft mouse model was used to identify the synergistic efficacy of a P-gp inhibitor with cisplatin. Student's t-test was used to determine statistically significant differences.
RESULTS: P-gp expression levels were associated with cisplatin efficacy in OS patients. OS cells with higher P-gp expression were more resistant to cisplatin. Knockdown or inhibition of P-gp sensitized OS cells to cisplatin.
CONCLUSION: Down-regulating the expression of P-gp in OS maybe a promising strategy to overcome cisplatin resistance.

Liu JB, Jian T, Yue C, et al.
Chemo-resistant Gastric Cancer Associated Gene Expression Signature: Bioinformatics Analysis Based on Gene Expression Omnibus.
Anticancer Res. 2019; 39(4):1689-1698 [PubMed] Related Publications
BACKGROUND/AIM: This study aimed to identify biomarkers for predicting the prognosis of advanced gastric cancer patients who received docetaxel, cisplatin, and S-1 (DCS).
MATERIALS AND METHODS: Gene expression profiles were obtained from the Gene Expression Omnibus database (GSE31811). Gene-Ontology-enrichment and KEGG-pathway analysis were used for evaluating the biological functions of differentially-expressed genes. Protein-protein interaction (PPI) network and Kaplan-Meier survival analyses were employed to assess the prognostic values of hub genes.
RESULTS: A total of 1,486 differentially expressed genes (DEGs) were identified, including 13 up-regulated and 1,473 down-regulated genes. KEGG pathways such as metabolic pathways, cell adhesion molecules (CAMs), PI3K-Akt signaling pathway and pathways in cancer were significantly represented. In the PPI network, the top ten hub genes ranked by degree were GNG7, PLCB1, CALML5, FGFR4, GRB2, JAK3, ADCY7, ADCY9, GNAS and KDR. Five DEGs, including ANTXR1, EFNA5, GAMT, E2F2 and NRCAM, were associated with relapse-free survival and overall survival.
CONCLUSION: ANTXR1, EFNA5, GAMT, E2F2 and NRCAM are potential biomarkers and therapeutic targets for DCS treatment in GC.

Zhang DF, Dou PH, Zhao DX, et al.
Weekly cisplatin for the treatment of patients with ovarian cancer: A protocol for a systematic review of randomized controlled trial.
Medicine (Baltimore). 2019; 98(14):e15001 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer (OC) is one of the most leading causes of deaths in the Chinese women. The objective of this protocol is to perform a full-scale systematic review on the efficacy of weekly cisplatin (WC) for the treatment of patients with OC.
METHODS: Data sources will comprise of PubMed, PsycINFO, Scopus, Opengrey, Cochrane Central Register of Controlled Trials, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database. All relevant randomized controlled trials from searched databases will be identified from their inception to the present. A defined search strategy will be implemented along with eligibility criteria. Relevant data will be extracted according to the predefined data collection form. Methodologic quality will be assessed by using Cochrane risk of bias tool; and data pooled and meta-analysis will be conducted by using fixed-effects, or random-effects model with RevMan 5.3 software.
RESULTS: This proposed systematic review will evaluate the efficacy of WC for patients with OC.
CONCLUSION: The findings of this study may summarize the latest evidence for the WC on OC.
ETHICS AND DISSEMINATION: Ethical approval is not required for this study, because it will be based on published studies, and existing sources of literature. The results of this study will be disseminated through peer-reviewed journal.

Fernandez-Gil BI, Guerra-Librero A, Shen YQ, et al.
Melatonin Enhances Cisplatin and Radiation Cytotoxicity in Head and Neck Squamous Cell Carcinoma by Stimulating Mitochondrial ROS Generation, Apoptosis, and Autophagy.
Oxid Med Cell Longev. 2019; 2019:7187128 [PubMed] Free Access to Full Article Related Publications
Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 

Qin Y, Li W, Long Y, Zhan Z
Relationship between p-cofilin and cisplatin resistance in patients with ovarian cancer and the role of p-cofilin in prognosis.
Cancer Biomark. 2019; 24(4):469-475 [PubMed] Related Publications
OBJECTIVE: This study aims to determine the correlation between p-cofilin expression and cisplatin resistance in patients with ovarian cancer, and also to investigate the role of p-cofilin in prognosis.
PATIENTS AND METHODS: The ovarian cancer cell line A2780/DDP resistant to cisplatin was prepared. The cell resistance to cisplatin was measured via MTT assay. The cell invasion capacity was identified via Transwell assay. The mRNA expression and protein level was evaluated via semi-quantitative PCR and Western blot, respectively. The tumor tissues of patients with cisplatin-resistant ovarian cancer were collected. The relationship between prognosis and p-cofilin expression was analyzed.
RESULTS: The growth rate of A2780 was similar to that of A2780/DDP. The sensitivity of A2780 to cisplatin was significantly higher than that of A2780/DDP (p< 0.01). The migration capacity of A2780/DDP was significantly increased compared to that of A2780 (p< 0.01), indicating that the cisplatin-resistant cell lines were successfully constructed. Both CFL1 mRNA level and p-cofilin level in A2780/DDP was significantly higher than that in A2780 (p< 0.01). The p-cofilin level in cancer tissues in patients with cisplatin-resistant ovarian cancer was significantly higher than that in patients with cisplatin-sensitive ovarian cancer (p< 0.01). The cisplatin resistance was positively correlated with the p-cofilin expression level (r= 0.802, p= 0.023). The survival time of patients with normal or low level of p-cofilin was significantly longer than that of patients with high expression.
CONCLUSION: The cisplatin resistance of ovarian cancer is closely related to the expression level of p-cofilin, which affects the prognosis of patients with ovarian cancer.

Steuperaert M, Debbaut C, Carlier C, et al.
A 3D CFD model of the interstitial fluid pressure and drug distribution in heterogeneous tumor nodules during intraperitoneal chemotherapy.
Drug Deliv. 2019; 26(1):404-415 [PubMed] Free Access to Full Article Related Publications
Although intraperitoneal chemotherapy (IPC) has evolved into an established treatment modality for patients with peritoneal metastasis (PM), drug penetration into tumor nodules remains limited. Drug transport during IPC is a complex process that depends on a large number of different parameters (e.g. drug, dose, tumor size, tumor pressure, tumor vascularization). Mathematical modeling allows for a better understanding of the processes that underlie drug transport and the relative importance of the parameters influencing it. In this work, we expanded our previously developed 3D Computational Fluid Dynamics (CFD) model of the drug mass transport in idealized tumor nodules during IP chemotherapy to include realistic tumor geometries and spatially varying vascular properties. DCE-MRI imaging made it possible to distinguish between tumorous tissues, healthy surrounding tissues and necrotic zones based on differences in the vascular properties. We found that the resulting interstitial pressure profiles within tumors were highly dependent on the irregular geometries and different zones. The tumor-specific cisplatin penetration depths ranged from 0.32 mm to 0.50 mm. In this work, we found that the positive relationship between tumor size and IFP does not longer hold in the presence of zones with different vascular properties, while we did observe a positive relationship between the percentage of viable tumor tissue and the maximal IFP. Our findings highlight the importance of incorporating both the irregular tumor geometries and different vascular zones in CFD models of IPC.

Zhou JW, Tang JJ, Sun W, Wang H
PGK1 facilities cisplatin chemoresistance by triggering HSP90/ERK pathway mediated DNA repair and methylation in endometrial endometrioid adenocarcinoma.
Mol Med. 2019; 25(1):11 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Endometrial carcinoma represents one of the most common cancer types of the female reproductive tract. If diagnosed at an early stage, the 5-year survival rate is promising. However, recurrence and chemoresistance remain problematic for at least 15% of the patients. In the present study, we aim to reveal the mechanism by which PGK1 regulates chemoresistance in endometrial carcinoma.
METHODS: qPCR was performed to detect expression of PGK1 in clinical tissue samples of endometrial carcinoma. Specific shRNAs were employed to knockdown PGK1 expression in endometrial cancer cell lines. MTT assay was used to evaluate cell viability and cisplatin sensitivity of endometrial carcinoma cell lines. Western blot was performed to assess the effects of PGK1 knockdown on the expression levels of HSP90, DNA repair-associated proteins (c-JUN, FOSL1, and POLD1), and DNA methylation-related enzymes (DNMT1, DNMT3A and DNMT3B). Immunoprecipitation was performed to verify direct binding between PGK1 and HSP90.
RESULTS: We first showed that PGK1 expression is elevated in tumor tissues of endometrial cancer, and high PGK1 levels are associated with clinical stages and metastasis. Knockdown of PGK1 inhibits proliferation of endometrial cancer cells, and enhances the inhibitory effect of cisplatin on cell viability. In addition, knockdown of PGK1 down-regulates the expression of DNA repair-related proteins, methylation-related enzymes, and total cellular methylation level. PGK1 was next shown to interact directly with HSP90 and exhibit pro-tumor effects by modulating the ATPase activity of HSP90.
CONCLUSIONS: We propose that PGK1 mediates DNA repair and methylation through the HSP90/ERK pathway, and eventually enhances the chemoresistance to cisplatin. The results provide new insights on functions of PGK1 and HSP90, which might make them as promising targets for endometrial cancer chemotherapy.

Bhandari A, Bansal A, Singh A, et al.
Comparison of transport of chemotherapeutic drugs in voxelized heterogeneous model of human brain tumor.
Microvasc Res. 2019; 124:76-90 [PubMed] Related Publications
Systemic administration of chemotherapeutic drugs is widely used in the treatment of cancer. However, a good understanding of drug transport barriers that influence the treatment efficacy is still lacking. In this study, a voxelized numerical model based on dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and computational fluid dynamics (CFD) is employed to study the transport and efficacy of three different chemotherapeutic drugs, namely methotrexate, doxorubicin and cisplatin in human brain tumors. DCE-MRI data provides realistic heterogeneous vasculature of the tumor, the permeability of tissue to contrast agent, interstitial volume fraction (porosity) of the tissue and patient-specific arterial input function (AIF). The permeability of tissue to aforementioned drugs is determined by correlating it with the permeability of tissue to the contrast agent. The model is employed to simulate drug concentration in the tissue and compare the effect of heterogeneous vasculature on the distribution of the drugs in the tumor. The drug accumulation is observed to be higher in high permeability areas initially, and in higher porosity areas at later times. Furthermore, it is observed that methotrexate remains in the interstitial space of the tumor in higher concentration for a longer duration as compared to other two drugs, facilitating more tumor cell killing.

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