Platinum-based Chemotherapy Drugs Research Articles

Harnessing External Irradiation for Precise Activation of Metal-Based Agents in Cancer Therapy.

Cancer is a significant global health issue. Platinum-based chemotherapy drugs, including cisplatin, are crucial in clinical anti-cancer treatment. However, these drugs have limitations such as drug resistance, non-specific distribution, and irreversible toxic and side effects. In recent years, the development of metal-based agents has led to the discovery of other anti-cancer effects beyond chemotherapy. Precise spatiotemporal controlled external irradiation can activate metal-based agents at specific sites and play a different role from traditional chemotherapy. These strategies can not only enhance the anti-cancer efficiency, but also show fewer side effects and non-cross-drug resistance, which are ideal approaches to solve the problems caused by traditional platinum-based chemotherapy drugs. In this review, we focus onvarious metal-based agent-mediated cancer therapies that are activated by three types of external irradiation: near-infrared (NIR) light, ultrasound (US), and X-ray, and give some prospects. We hope that this review will promote the generation of new kinds of metal-based anti-cancer agents.

Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

Integrated imaging and proteomics sensors detect proteome aggregation induced by platinum-based chemotherapy drugs in living cells and mice model

Proteome aggregation is challenging to analyze given its loss of defined 3-D structures to develop chemo- and bio-sensors. Herein, we present integrated chemical sensors to image the occurrence of proteome aggregation and dissect its proteomic composition. Via these combinative sensors, we systematically reveal for the first time platinum-based drugs can deteriorate proteome stability, compromise protein homeostasis (proteostasis) network, and consequently cause proteome aggregation. Fluorescent protein aggregation imaging sensors (AggStain and AggRetina) not only confirms these drugs generally induce intracellular proteome aggregation but also quantifies the compactness (polarity) heterogeneity inside these aggregates. Chemical proteomics sensor (AggLink) further captures and profiles the composition of aggregated proteome, which uncovers the fluctuations of proteostasis network and metabolic pathways. In mice model, proteome aggregation and oxidative stress are imaged in multi-organs with platinum enrichment. Together, we integrate imaging and proteomics sensors to provide an alternative mechanism-of-action for platinum-based drugs’ anti-cancer function in addition to their common DNA intercalation mechanism.

Deciphering the immunological and prognostic features of bladder cancer through platinum-resistance-related genes analysis and identifying potential therapeutic target P4HB.

To identify the molecular subtypes and develop a scoring system for the tumor immune microenvironment (TIME) and prognostic features of bladder cancer (BLCA) based on the platinum-resistance-related (PRR) genes analysis while identifying P4HB as a potential therapeutic target. In this study, we analyzed gene expression data and clinical information of 594 BLCA samples. We used unsupervised clustering to identify molecular subtypes based on the expression levels of PRR genes. Functional and pathway enrichment analyses were performed to understand the biological activities of these subtypes. We also assessed the TIME and developed a prognostic signature and scoring system. Moreover, we analyzed the efficacy of immune checkpoint inhibitors. Then we conducted real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments to detect the expression level of prolyl 4-hydroxylase subunit beta (P4HB) in BLCA cell lines. Transfection of small interference ribonucleic acid (siRNA) was performed in 5637 and EJ cells to knock down P4HB, and the impact of P4HB on cellular functions was evaluated through wound-healing and transwell assays. Finally, siRNA transfection of P4HB was performed in the cisplatin-resistant T24 cell to assess its impact on the sensitivity of BLCA to platinum-based chemotherapy drugs. In a cohort of 594 BLCA samples (TCGA-BLCA, n=406; GSE13507, n=188), 846 PRR-associated genes were identified by intersecting BLCA expression data from TCGA and GEO databases with the PRR genes from the HGSOC-Platinum database. Univariate Cox regression analysis revealed 264 PRR genes linked to BLCA prognosis. We identified three molecular subtypes (Cluster A-C) and the PRR scoring system based on PRR genes. Cluster C exhibited a better prognosis and lower immune cell infiltration compared to the other Clusters A and B. The high PRR score group was significantly associated with an immunosuppressive tumor microenvironment, poor clinical-pathological features, and a poor prognosis. Furthermore, the high PRR group showed higher expression of immune checkpoint molecules and a poorer response to immune checkpoint inhibitors than the low PRR group. The key PRR gene P4HB was highly expressed in BLCA cell lines, and cellular functional experiments in vitro indicate that P4HB may be an important factor influencing BLCA migration and invasion. Our study demonstrates that the PRR signatures are significantly associated with clinical-pathological features, the TIME, and prognostic features. The key PRR gene, P4HB, s a biomarker for the individualized treatment of BLCA patients.

Necroptosis-related regulatory pattern and scoring system for predicting therapeutic efficacy and prognosis in ovarian cancer.

Ovarian cancer is difficult to treat and is, therefore, associated with a high fatality rate. Although targeted therapy and immunotherapy have been successfully used clinically to improve the diagnosis and treatment of ovarian cancer, most tumors become drug resistant, and patients experience relapse, meaning that the overall survival rate remains low. There is currently a lack of effective biomarkers for predicting the prognosis and/or outcomes of patients with ovarian cancer. Therefore, we used published transcriptomic data derived from a large ovarian cancer sample set to establish a molecular subtyping model of the core genes involved in necroptosis in ovarian cancer. Clustering analysis and differential gene expression analyses were performed to establish the genomic subtypes related to necroptosis and to explore the patterns of regulatory gene expression related to necroptosis in ovarian cancer. A necroptosis scoring system (NSS) was established using principal component analysis according to different regulatory patterns of necroptosis. In addition, this study revealed important biological processes with essential roles in the regulation of ovarian tumorigenesis, including external encapsulating structure organization, leukocyte migration, oxidative phosphorylation, and focal adhesion. Patients with high NSS scores had unique immunophenotypes, such as more abundant M2 macrophages, monocytes, CD4+ memory T cells, and regulatory T cells. Immune checkpoint CD274 had a greater expression in patients with high NSS values. This NSS could be used as an independent predictor of prognosis to determine the sensitivity of ovarian cancer to various small-molecule inhibitors, immune checkpoint inhibitors, and platinum-based chemotherapy drugs.

In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis.

Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.

Neoadjuvant chemotherapy or upfront surgery in hepatoblastoma: A multicenter retrospective study.

We retrospectively investigated the role of neoadjuvant chemotherapy in low-risk patients with hepatoblastoma (HB) who underwent curative resection between February 2009 and December 2017. We also verified the feasibility of the risk stratification system to select the optimal patients for upfront surgery. We compared 5-year overall survival (OS) and event-free survival (EFS) between the upfront surgery (n = 26) and neoadjuvant chemotherapy (n = 104) groups at three oncology centers in Beijing, China. To reduce the effect of covariate imbalance, propensity score matching (PSM) was used. We explored whether preoperative chemotherapy affected surgical outcomes and identified the risk factors for events and death, including resection margin status, PRETreatment EXTent of disease stages, age, sex, pathology classification, and α-fetoprotein levels. The median follow-up period was 64 (interquartile range 60-72) months. After PSM, 22 pairs of patients were identified, and the patient characteristics were similar for all variables included in PSM. In the upfront surgery group, the 5-year EFS and OS rates were 81.8% and 86.3%, respectively. In the neoadjuvant chemotherapy group, the 5-year EFS and OS rates were 81.8% and 90.9%, respectively. No significant differences in EFS or OS were observed between the groups. Pathological classification was the only risk factor for death, disease progression, tumor recurrence, other tumors found during HB diagnosis, and death from any cause (p = .007 and .032, respectively). Upfront surgery achieved long-term disease control in low-risk patients with resectable HB, thus reduced the cumulative toxicity of platinum-based chemotherapy drugs.

CUL4B increases platinum-based drug resistance in colorectal cancer through EMT: A study in its mechanism.

Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers.

Simple SummaryClinical management of ovarian cancer remains a major clinical challenge as many patients develop resistance to standard platinum-based chemotherapy drugs over time. Testing novel targeted strategies and combination therapies may open the door to new possibilities for the treatment of this disease. One such approach includes targeting p53 with a peptide called ReACp53. While mutations in p53 are common in many cancers, ovarian cancers, in particular, are characterized by the dysfunction of this protein. The aim of this study is to evaluate the potential of combining ReACp53 with standard platinum-based chemotherapy to target ovarian cancer tumor cells. Using in vitro and in vivo preclinical models, we demonstrate enhanced efficacy when combining ReACp53 and carboplatin to target a subset of ovarian cancer cell lines and primary patient tumor samples. Collectively, our results indicate that this combinatorial approach may be applicable for targeting human ovarian tumors.Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.

Platinum Accumulation and Cancer-Related Fatigue, Correlation With IL-8, TNF-α and Hemocytes.

Platinum-based chemotherapy drugs cause platinum accumulation and result in cancer-related fatigue (CRF), which is related to immune response through still ambiguous mechanisms. We aimed to explore the correlation between platinum and CRF from the perspective of platinum accumulation. After allowing for complete metabolism of the administered platinum drugs, we collected blood samples from 135 patients who had at least two platinum chemotherapy rounds, correlated the platinum concentration (C-Pt), pro-inflammatory cytokines IL-8 and TNF-α, hematological index with therapeutic effect, adverse reactions and fatigue. The median platinum concentration was higher in patients treated with cisplatin than oxaliplatin (424.0 vs 211.3 μg/L), and the occurrence of fatigue was 64.4% in all subjects. Separately, the incidence and degree of fatigue were 74.1% and 9.5 in the patients with higher platinum concentration compared to 57.1% and 2.0 in the lower group. C-Pt, IL-8 and TNF-α were positively correlated with the degree of CRF, while erythrocyte count and hemoglobin were negatively correlated with the degree of CRF. Mediating effect analysis showed that increased IL-8 concentration mediated 57.4%, while decreased erythrocyte count mediated 24.1% of the C-Pt effect on CRF. Platinum accumulation may involve increasing IL-8, cause inflammation or aggravate anemia, which in combination lead to CRF.

DOCK4 Is a Platinum-Chemosensitive and Prognostic-Related Biomarker in Ovarian Cancer.

Ovarian carcinoma (OV) is a lethal gynecological malignancy. Most OV patients develop resistance to platinum-based chemotherapy and recurrence. Peroxisome proliferator-activated receptors (PPARs) are the ligand activating transcription factor of the nuclear receptor superfamily. PPARs as important transcriptional regulators regulate important physiological processes such as lipid metabolism, inflammation, and wound healing. Several reports point out that PPARs can also have an effect on the sensitivity of tumor cells to platinum-based chemotherapy drugs. However, the role of PPAR-target related genes (PPAR-TRGs) in chemotherapeutic resistance of OV remains unclear. The present study is aimed at optimizing candidate genes by integrating platinum-chemotherapy expression data and PPAR family genes with their targets. The gene expression profiles were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. A total of 4 genes (AP2A2, DOCK4, HSDL2, and PDK4) were the candidate differentially expressed genes (DEGs) of PPAR-TRGs with platinum chemosensitivity. After conducting numerous survival analyses using different cohorts, we found that only the upexpression of DOCK4 has important significance with the poor prognosis of OV patients. Meanwhile, DOCK4 is detected in plasma and enriched in neutrophil and monocyte cells of the blood. We further found that there were significant correlations between DOCK4 expression and the levels of CD4+ T cell infiltration, dendritic cell infiltration, and neutrophil infiltration in OV. In addition, we verified the expression level of DOCK4 in OV cell lines treated with platinum drugs and found that DOCK4 is potentially responsive to platinum drugs. In conclusion, DOCK4 is potentially associated with immune cell infiltration and represents a valuable prognostic biomarker in ovarian cancer patients.

Ототоксический эффект цитостатических препаратов, содержащих платину

Ototoxicity refers to the hearing impairment that results from the temporary or permanent inner ear dysfunction after treatment with an ototoxic drug. Other drug classes known to have ototoxic properties include aminoglycosides, loop diuretics, quinine, nonsteroidal anti-inflammatory drugs, and antiretroviral therapy. Platinum-based chemotherapy drugs are effective drugs used to treat many types of malignant neoplasms. However, its ototoxic potential puts cancer patients at risk of hearing loss. This, in turn, negatively affects the patient’s quality of life. It is essential for clinicians working with these patients to be aware of the ototoxic properties of platinum preparations and the clinical signs in order to identify patients at risk of developing hearing loss. The review identified peer-reviewed articles available from January 1975 to July 2019 on the monitoring of cytotopic toxicity and ototoxicity associated with cisplatin, and included only articles in English. The same researcher conducted a literature search and reviewed abstracts and articles for inclusion in the study. The studies were identified using a MeSH (Medical Subject Headings) keyword and term search in electronic databases. A manual search for relevant authors and journals was also completed. The links cited by each publication, review, or book chapter were reviewed to find additional potential publications. This article provides an updated review of the ototoxicity associated with platinum-based chemotherapy drugs.

A narrative review of progress in diagnosis and treatment of small cell lung cancer patients with hyponatremia

Small cell lung cancer (SCLC) is one of the malignant cancers of lung tumors, and hyponatremia, defined as serum sodium concentration (Na+) lower than 135 mmol/L, is the most common complication of solid tumors, with an incidence of up to 18.9% and a negative impact on quality of life in SCLC. As a prognostic index of SCLC, timely monitoring and correcting of hyponatremia is of great clinical significance for prolonging the survival period of patients. In the explore of new drugs for small cell lung cancer, it is necessary to include hyponatremia as an evaluation index in clinical studies. As the occurrence of hyponatremia is sometimes unavoidable owing to SCLC specific neurological characteristics, early monitoring to detect the presence of hyponatremia and timely correction are helpful to improve the prognosis of patients. There are many predisposing factors for hyponatremia, including heterotopia of antidiuretic hormone (ADH), use of platinum-based chemotherapy drugs, and intracranial metastasis, among others. Patients with small cell lung cancer are usually asymptomatic in the early stage, while it is of great significance to find a suitable clinical index to judge whether it is a malignant inducement or not. In the clinical setting, due to different electrolyte levels and therapeutic scheduling for the primary disease, an individualized plan is often made, mainly comprising water restriction, infusion, and medications. This review includes related clinical studies and describes the common symptoms and predisposing factors of hyponatremia in patients with SCLC, and their impact on quality of life and prognosis.

Super-selective intra-arterial platinum-based chemotherapy concurrent with low-dose-rate plaque brachytherapy in the treatment of retinoblastoma: A simulation study.

Retinoblastoma is the most common cancer among children under 5 years of age. The common conventional methods for the treatment of retinoblastoma include chemotherapy and brachytherapy (BT). This study investigated the concurrent use of BT with 125I and 103Pd sources and chemotherapy with platinum-based chemotherapy drugs for retinoblastoma. The absorbed doses in different parts of the eye were measured with and without platinum. Platinum concentrations of 5, 7.5, 10, and 15 mg/g were evaluated, and the dose enhancement factors (DEFs) were calculated for different cases. For the 125I source, the DEFs at the tumor apex were 1.49, 1.67, 1.81, and 1.97 at concentrations of 5, 7.5, 10, and 15 mg/g, respectively. The DEF decreased dramatically beyond the apex at 0.85 cm from tumor base and was 0.87, 0.82, 0.76, and 0.63 for the abovementioned concentrations, respectively. For the 103Pd source, the DEFs were 1.15, 1.24, 1.21, and 1.07, respectively, at the apex and 0.76, 0.65, 0.56, and 0.39, respectively, beyond the apex. Our results showed that the concurrent use of low-dose-rate plaque BT and platinum-based chemotherapy significantly increased the tumor-absorbed dose and decreased the absorbed dose in areas outside the tumor and the treatment time.

Meta-analysis of Banmao Capsules in adjuvant treatment for non-small cell lung cancer

To systemically evaluate the efficacy and safety of Banmao Capsules in the adjuvant treatment for non-small cell lung cancer(NSCLC). All of randomized controlled trials(RCT) about Banmao Capsules in adjuvant treatment for non-small cell lung cancer were retrieved in PubMed, EMbase, Cochrane Library, CNKI, VIP, CBM, WanFang database from database inception to August 2019. Two researchers extracted data and assessed literature quality separately, and made a Meta-analysis by RevMan 5.3 software. Thirteen trials involving 1 148 patients, including 595 in treatment group and 553 in control group, were enrolled in the review. The Meta-analysis showed that compared with conventional treatment, adjuvant treatment of NSCLC with Banmao Capsules can enhance the objective tumor response rate(RR=1.43,95%CI[1.30,1.58],P<0.01), and the disease control rate(RR=1.16,95%CI[1.11,1.22],P<0.01); improve the quality of life(RR=1.56,95%CI[1.27,1.92],P<0.01); reduce the incidence of myelosuppression(RR=0.41,95%CI[0.26,0.66],P<0.01), gastrointestinal reactions(RR=0.46,95%CI[0.33,0.65],P<0.01), liver and kidney dysfunction(RR=0.44,95%CI[0.29,0.66],P<0.01). The results showed that in the treatment of NSCLC, Banmao Capsules can increase the short-term efficacy, improve the quality of life of patients, and reduce the side effects of platinum-based chemotherapy drugs. More high-quality and large-scale randomized controlled trials are required in the future.

Novel Frog Skin-Derived Peptide Dermaseptin-PP for Lung Cancer Treatment: In vitro/vivo Evaluation and Anti-tumor Mechanisms Study.

Lung cancer is the major cause of cancer deaths worldwide, and it has the highest incidence and mortality rate of any cancer among men and women in China. The first-line therapy for lung cancer treatment is platinum-based chemotherapy drugs such as cisplatin. However, the application of present chemotherapies is limited by severe side effects, which stimulates the discovery of new drugs with new anti-tumor mechanisms and fewer side effects. Beneficially, many antimicrobial peptides (AMPs) from frog skin have been reported to exhibit potent anti-cancer activities with low toxicity, high selectivity and a low propensity to induce resistance. In this study, we first reported an AMP named Dermaseptin-PP, from a rarely studied frog species, Phyllomedusa palliata. Dermaseptin-PP exhibited selective cytotoxicity on H157, MCF-7, PC-3, and U251 MG cancer cells instead of normal HMEC-1 cells with low hemolytic effect. Furthermore, on subcutaneous H157 tumor model of nude mice, Dermaseptin-PP was found to display potent in vivo anti-tumor activity in a dose-related manner without obvious hepatopulmonary side effects. It is widely accepted that AMPs usually work through a membrane disruptive mode, and the confocal laser microscope observation confirmed that Dermaseptin-PP could destroy H157 cell membranes. Further investigation of mechanisms by flow cytometry assay and immunohistochemical analysis unraveled that Dermaseptin-PP also exerted its anti-tumor activity by inducing H157 cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway. Herein, we emphasize that the membrane disrupting and the apoptosis activation effects of Dermaseptin-PP both depend on its concentration. Overall, a novel frog skin-derived AMP, named Dermaseptin-PP, was identified for the first time. It possesses strong antimicrobial activity and effective anti-tumor activity by distinct mechanisms. This study revealed the possibility of Dermaseptin-PP for lung cancer treatment and provided a new perspective for designing novel AMP-based anti-tumor candidates with low risk of cytotoxicity.

Advances in the Treatment of Advanced Non-Small Cell Lung Cancer

In recent years, the incidence of lung adenocarcinoma has been increasing, and now it has become the largest type of non-small cell lung cancer (NSCLC). Currently, treatment of advanced NSCLC consists of several modalities: systemic chemotherapy, local radiation therapy, and targeted therapy (including most recently immunotherapy). In the past decade, the discovery of new molecular subtypes, the search for tumor driver gene mutations, the development of targeted molecular targeted drugs, or targeted therapy to suppress tumor angiogenesis and regulate tumor immune response have been the main directions of NSCLC research and clinical diagnosis and treatment. At present, platinum-based chemotherapy is widely used in NSCLC patients clinically. Platinum-based chemotherapy drugs can effectively prolong the survival time of patients and improve their quality of life, but the incidence of adverse reactions is still high. Therefore, it is necessary to find a drug that can improve the efficacy of patients and reduce the adverse reactions of platinum chemotherapy drugs to NSCLC patients.

Meta-analysis of Cinobufacini Injection combined with platinum-contained first-line chemotherapy in treatment of non-small cell lung cancer

To systemically evaluate the efficacy and safety of Cinobufacini Injection in combination with platinum-contained first-line chemotherapy for treatment of non-small cell lung cancer(NSCLC). The randomized controlled trials(RCT) about the Cinobufacini in combination with platinum-contained first-line chemotherapy(versus chemotherapy alone) were collected through PubMed,Cochrane library,CNKI,VIP,CBM,and Wan Fang Database from database inception to December 2018. Two researchers extracted data and assessed the literature quality separately,and made a Meta-analysis by using Rev Man 5. 3 software. Twenty-seven RCTs were included in the present review,involving 2 125 patients,1 082 in treatment group and 1 043 in control group. The Meta-analysis results showed that as compared with chemotherapy alone,the combination of Cinobufacini and platinum-contained first-line chemotherapy could enhance one year survival rate(RR = 1. 34,95%CI[1. 17,1. 55],P< 0. 01),two year survival rate(RR = 1. 84,95% CI[1. 31,2. 59],P<0. 01),objective tumor response rate(RR = 1. 47,95%CI[1. 33,1. 63],P<0. 01); improve the quality of life for patients(RR =1. 54,95%CI[1. 37,1. 72],P < 0. 01); and reduce the incidences of WBC toxicity(RR = 0. 63,95% CI[0. 49,0. 80],P < 0. 01),platelet toxicity(RR = 0. 54,95%CI[0. 35,0. 84],P<0. 01),gastrointestinal reactions(RR = 0. 60,95%CI[0. 45,0. 80],P<0. 05),pain(RR = 1. 68,95% CI[1. 38,2. 03],P< 0. 01),and hair loss reaction(RR = 0. 76,95% CI[0. 59,0. 98],P < 0. 05). The results showed that for the treatment of NSCLC,the addition of cinofacini to conventional platinum-contained chemotherapy can increase the long-term and short-term efficacy of chemotherapy,improve the quality of life for patients,and reduce the side effects of platinumbased chemotherapy drugs. However,more high quality and large-scale randomized controlled trials are required to verify this conclusion in the future.

Screening a library of approved drugs reveals that prednisolone synergizes with pitavastatin to induce ovarian cancer cell death

The survival rate for patients with ovarian cancer has changed little in the past three decades since the introduction of platinum-based chemotherapy and new drugs are needed. Statins are drugs used for the treatment and prevention of cardiovascular diseases. Recent work from our laboratory has shown that pitavastatin has potential as a treatment for ovarian cancer if dietary geranylgeraniol is controlled. However, relatively high doses of statins are required to induce apoptosis in cancer cells, increasing the risk of myopathy, the most common adverse effect associated with statins. This makes it desirable to identify drugs which reduce the dose of pitavastatin necessary to treat cancer. A drug-repositioning strategy was employed to identify suitable candidates. Screening a custom library of 100 off-patent drugs for synergistic activity with pitavastatin identified prednisolone as the most prominent hit. Prednisolone potentiated the activity of pitavastatin in several assays measuring the growth, survival or apoptosis in several ovarian cancer cells lines. Prednisolone, alone or in some cases in combination with pitavastatin, reduced the expression of genes encoding enzymes in the mevalonate pathway, providing a mechanistic explanation for the synergy.

Abstract 456: WR1065, the active metabolite of amifostine modulates chemistry and biology of cisplatin

Abstract WR-1065 [2-((aminopropyl)amino)ethanethiol] is metabolically active form of amifostine (also known as Ethyol, an agent used to mitigate side effects of chemo-radiotherapy in head and neck cancer). In vitro, WR-1065 was also found to decrease DNA damage caused by cisplatin. In some human studies, amifostine was found to be effective against chemotherapy-induced peripheral neuropathy (CIPN). While this effect was not dramatic in all such studies, it was notable in patients who received cisplatin alone. Because CIPN is the most common and longest lasting side effect of chemotherapy we decided to explore possible biological and chemical basis of amifostine mediated protection against platinum (II). Two human cell lines were used in this study: SK-N-SH neuroblastoma cells and NT2/D1 embryonal carcinoma cells. Importantly, their response to cisplatin treatment corresponded to their differentiation. In both cases, differentiated cells survived exposure to cisplatin better than their non-differentiated counterparts; cisplatin IC50 doses in differentiated cells were regularly two times higher. Addition of WR-1065 to cisplatin treated differentiated cells increased their viability regardless of whether that treatment was done, before, during or after cisplatin treatment. Similar approach was used to prepare samples for chemical studies using X-ray absorption near edge structure (XANES) spectroscopy. XANES can be used to investigate oxidation-reduction changes of Pt in biological samples. This was used by others to follow gradual reduction of Pt(IV) into Pt(II) inside cells. In this work, XANES was used to estimate Pt (II) to Pt (IV) ratio in samples of cisplatin treated cells and cisplatin mixed with cellular components such as DNA. Comparisons were done between such samples and their counterparts additionally exposed to WR-1065. In all cases, presence of WR-1065 changed the ratio of two forms of Pt, suggesting that chemistry of this interaction may be a possible mechanism of WR-1065 protection against cisplatin. At the moment, amifostine is not used in clinical practice in combination with platinum based chemotherapy drugs. Reasons for that may lay in the fact that there remains a concern that Amifostine could possibly protect cancer cells from therapy and not only normal tissues. This work shows that the mechanisms underlying ability of amifostine to decrease detrimental effects of platinum (II) are compatible with delayed CIPN treatment. This means that amifostine could be used to reduce CIPN symptoms significantly after cancer treatment, in patients who are cured from cancer but suffer treatment complications. Citation Format: Tatjana Paunesku, Jelena Popovic, Andrijana Klajn, Natasa Kovacevic-Grujicic, Qing Ma, Milena Stevanovic, Gayle E. Woloschak. WR1065, the active metabolite of amifostine modulates chemistry and biology of cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 456.