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Anticancer Research
J. G. Delinassios
Anticancer Research

J. G. Delinassios

0250-7005

Anticancer Research/Journal Anticancer ResearchSCIISTP
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    Adverse Events in Placebo Arms of Cancer Trials

    Wolff, Johannes E.Wolff, Birte J.Thielen, Marceal M.Hauch, Holger...
    8页
    查看更多>>摘要：Background/Aim: Adverse events (AEs) in cancer trials may be caused by the investigational agents or the underlying disease. Determining the causality is challenging, especially in early cancer drug development when a control arm is lacking. Materials and Methods: We carried out a systematic literature review of AE frequencies in placebo arms of randomized trials for malignant solid tumors and hematologic malignancies reported in PubMed from 2016 to January 2022. Results: Among 148 placebo arms, the AEs with the highest reported mean frequencies among all publications were: Fatigue (20.1%), nausea (16.3%), diarrhea (14.3%), abdominal pain (12.4%), and anemia (10.9%); AEs resulting in drug discontinuation were reported in 5.6% of placebo-treated patients and serious AEs in 18.7% of placebo patients. Conclusion: The data presented here may be used as a benchmark to help assess drug causality in early development cancer studies without a control arm.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    The Role of Toll-like Receptors in Esophageal Cancer

    Davakis, SpyridonKapelouzou, AlkistisLiakakos, TheodorosMpoura, Maria...
    6页
    查看更多>>摘要：Esophageal adenocarcinoma (AC) develops through Barrett's esophagus (BE) and columnar dysplasia, preceded by gastro-esophageal reflux disease (GERD). Incidence of esophageal squamous cell carcinoma (SCC) is increased with tobacco smoking and alcohol abuse. Toll-like receptors (TLRs) can act as prognostic factors and potential therapeutic targets of esophageal cancer. TLRs, an important family of pattern recognition receptors, allow immune cells to recognize pathogens triggering inflammation. TLR-signaling pathway activates signaling-elements, regulating inflammatory response, possibly correlating to carcinogenesis. In the normal esophagus, TLRs recognize molecular patterns on microorganisms and inflammatory response produced by tissue-damage. TLR3, TLR4, TLR5, and TLR9 are expressed at increasing levels from GERD to AC. TLR4 is a mediator of proliferation in AC, while TRL1 and TLR4 over-expression in AC is related to poor prognosis and metastasis. Additionally, TLR3, TLR4, and TLR9 expression in SCC has been associated with lymphatic metastasis, whereas increased expression of TLR7 and TLR9 has been also associated with advanced disease. It seems that TLR expression can indicate esophageal metaplasia, dysplasia, and cancer. Herein, we aimed to present all available data regarding the relation of TLRs and esophageal cancer. They may represent significant and valuable diagnostic or prognostic factors for esophageal cancer.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Cell Dissociation Enzymes Affect Annexin V/Flow-Cytometric Apoptotic Assay Outcomes After miRNA-based Transient Transfection

    Gobin, Christina M.Menefee, James N.Lattimore, Chayil C.Doty, Andria...
    7页
    查看更多>>摘要：Background/Aim: miRNA functional analysis involves transfection with miRNA-based oligos to identify gain of or loss-of function cellular phenotypes. Apoptosis is a common phenotypic endpoint for miRNA functional analysis. We report that four common cell dissociation enzymes, TrypLE, Accutase, Trypsin, and Accumax, can differentially impact cell viability and apoptosis in Annexin V flow cytometric analysis after miRNA-based transient transfection. Materials and Methods: We transiently transfected a nonsense oligo into an epithelial cancer cell line (UM-SCC-12) for 24 h. Cells were harvested with either TrypLE, Accutase, Accumax, or Trypsin after 5 min. The Annexin V/7-AAD assay via flow cytometry was employed. Studies were performed in triplicate. Significant effects were detected by ANOVA, followed by Tukey's Multiple Comparison tests. Results: Trypsin produced the lowest cell viability and lowest percentage of apoptotic cells, specifically when compared to TrypLE and Accutase, respectively (p<0.01). Importantly, transfected trypsinized cells had a significant difference in cell viability and necrosis (p<0.05) when compared with non-transfected trypsinized cells, highlighting the influence of miRNA-based transfection on Annexin V flow cytometric outcomes. Interassay variability was lowest with TrypLE (1.13 %). As such, TrypLE provided the greatest reproducibility and reliability in our cell line. Conclusion: Our study highlights the variable effects of cell dissociation enzymes on transfected cells. Overall, the variability may lead to errors in detection of apoptotic cells using the Annexin V assay after miRNA-based transfection. Before assay use, we recommend pretesting cell dissociation enzymes on transfected cells to ensure reliable and reproducible results.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Altered mRNA Expression Due to Rectal Perforation in a Porcine Model-A Pilot Study

    Oikonomakis, IoannisBrodin, DavidHorer, T. A. L. M.Skoog, P. E. R....
    7页
    查看更多>>摘要：Background: Anastomotic leakage is the most serious and unwelcome complication in rectal surgery. It has a great impact on postoperative morbidity and mortality. In this pilot study, changes of mRNA expression in blood were analyzed in an animal model designed to imitate anastomotic leakage. Materials and Methods: Twelve pigs were randomized into two groups: A sham-operated control group and an experimental group in which iatrogenic rectal perforation was performed. The changes in the mRNA expression at 4 hours after creating the perforation were studied. Microarray analysis was performed using Gene Chip whole porcine genome array. mRNA expression of 19,124 genes was investigated. Results: Significantly increased levels of genes with a fold change greater than 2 were found, including 276 coding for unknown proteins and 48 coding for known proteins. Eleven of those which coded for known proteins were up-regulated with a fold change >4. Conclusion: Eleven known genes were highly up-regulated after rectal perforation. These genes were mainly involved in inflammatory response, intracellular signaling and cell membrane regulation. Their corresponding proteins might potentially be clinical biomarkers of anastomotic leakage and should be evaluated in further clinical studies.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Isoprenylated Coumarin Exhibits Anti-proliferative Effects in Pancreatic Cancer Cells Under Nutrient Starvation by Inhibiting Autophagy

    Zhou, RonghaoKusaka, ErikaWang, YinZhang, Jing...
    11页
    查看更多>>摘要：Background/Aim: Due to the lack of early detection methods and effective treatments, pancreatic cancer has one of the lowest five-year survival rates among all cancers. We have previously identified novel isoprenylated coumarin compounds that exhibit preferential cytotoxicity against pancreatic adenocarcinoma cell line PANC-1 exclusively under glucose deprivation conditions. Materials and Methods: Using cell cytotoxicity assays, we investigated the anti-proliferative mechanism of our most potent isoprenylated coumarin compound of the series, DCM-MJ-I-21, with respect to time, against two other pancreatic cancer cell lines, BxPC-3 and Capan-2. We used western blotting to quantify the autophagic flux influenced by our compound, autophagy inducers (starvation and Rapamycin), and autophagy inhibitors (chloroquine and wortmannin). Results: We observed a clear dependence on glucose in DCM-MJ-I-21 in BxPC-3 and Capan-2 pancreatic cancer cell lines, suggesting that our compound targets a pathway shared by these cancer cell lines when glycolysis is not an option for survival. Our lead compound increased the conversion of LC3-I to LC3-II in PANC-1, similar to the effect of chloroquine, an autophagy inhibitor. In addition, Spautin-1, another autophagy inhibitor, showed almost the same anti-proliferative activities at the same concentration under nutrient-deprived conditions as our lead compound in both 2D and 3D cell cultures. Conclusion: Our lead isoprenylated coumarin compound induces selective pancreatic cancer cell death under nutrient-deprived conditions through inhibition of autophagy, potentially providing insights into new therapeutic options.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Preparation of Micelles Encapsulating Doxorubicin and Their Anticancer Effect in Combination With Tranilast in 3D Spheroids and In Vivo

    Nii, TerukiYoshikawa, KanjiTakeuchi, IsseiMakino, Kimiko...
    11页
    查看更多>>摘要：Background/Aim: The objective of this study was to prepare doxorubicin encapsulated in micelles (DOXmicelles) using poly(hexadecanyloxyethylene glycol-lactate phosphate), which we recently synthesized, and to evaluate the anticancer effect of DOX-micelles in vitro and in vivo. Materials and Methods: To evaluate the anticancer effect of DOX-micelles in vitro, three-dimensional spheroids composed of B16 mouse melanoma cells and fibroblasts were prepared by changing the ratio of cancer cells to fibroblasts. In addition, for efficient doxorubicin treatment of the cells present in the center of the spheroids, tranilast, an antifibrotic drug was added to the spheroids before treatment with DOX-micelles, then the amount of doxorubicin and cell viability of spheroids were evaluated. Moreover, to assess the effects of the combination of DOX-micelles with tranilast in vivo, relative tumor volume was investigated in a mouse model of melanoma. Results: The mean diameter and doxorubicin content of DOX-micelles were 93.3 nm and 3.5%, respectively. When the ratio of cancer cells to fibroblasts was 20:80, spheroids with spherical and rigid shapes were obtained. In addition, the amount of doxorubicin in the spheroids was increased by tranilast treatment, and an efficient anticancer effect was also observed. The anticancer effect of the combination of tranilast and DOX-micelles was confirmed in vivo. Conclusion: Micelles encapsulating doxorubicin are promising for cancer therapy, and their anticancer effect is improved by tranilast pretreatment in 3D spheroids in vivo.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Effect of Eribulin on Angiogenesis and the Expression of Endothelial Adhesion Molecules

    Abbona, AndreaPaccagnella, MatteoAstigiano, SimonettaMartini, Stefania...
    9页
    查看更多>>摘要：Background/Aim: Tumor vasculature is an important component of the tumor microenvironment and deeply affects anticancer immune response. Eribulin is a nontaxane inhibitor of the mitotic spindle. However, off-target effects interfering with the tumor vasculature have been reported. The mechanisms responsible of this effect are still unclear. Materials and Methods: We designed an in vitro study to investigate the effect of eribulin, with or without TGF-/3, on neo-angiogenesis, and on the expression of the adhesion molecules ICAM-1 and VCAM-1. We also investigated the effects of paclitaxel and vinorelbine under the same experimental conditions. Results: Eribulin up-regulated the epithelial markers VE-cadherin and CD-31 in HUVEC and inhibited tube formation in HUVEC cells cultured in Matrigel. The drug effectively arrested tube formation even in the presence of TGF-/3 and counteracted the TGF-/3-induced change in cell shape from the endothelial cobblestone-like morphology to an elongated spindle-shaped morphology. We also observed that eribulin was able to upregulate ICAM-1 and to counteract its down-regulation induced by TGF-/3. Conclusion: Eribulin exerts different off-label effects: increases vascular remodeling, counteracts the endothelial-tomesenchymal transition (EndMT) mediated by TGF-/3 and promotes tumor infiltration by immune cells via increasing the expression of ICAM-1 and transcription of CD31 and VE cadherin. Moreover, eribulin was able to inhibit vasculature remodeling and the induction of EndMT mediated by TGF-/3 better than vinorelbine and paclitaxel. The effects observed in this study might have important therapeutic consequence if the drug is combined with immunotherapy.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    PTPN3 Could Beta e a Therapeutic Target of Pancreatic Cancer

    Iwamoto, NaoyaSakanashi, KeitaKoga, SatokoOyama, Yasuhiro...
    6页
    查看更多>>摘要：Background/Aim: Recently, protein tyrosine phosphatase non-receptor type 3 (PTPN3) has gained attention. However, the role of PTPN3 in cancer has not been fully elucidated. In the present study, we analyzed the role of PTPN3 in pancreatic cancer and investigated whether PTPN3 could be a new therapeutic target for pancreatic cancer. Materials and Methods: Two pancreatic ductal adenocarcinoma (PDAC) cell lines were used as target cells. Cell proliferation was investigated using cell counting and a xenograft mouse model. Migration and invasion were analyzed using Transwell inserts. Activation-related signaling molecules were examined by western blotting. Results: PTPN3 contributes to the proliferation, migration, and invasion of PDAC cells in vitro. PTPN3 promotes tumor growth in a mouse xenograft model, an action mediated partially through the MAPK pathway. Conclusion: PTPN3 could be a new therapeutic target for pancreatic cancer.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Murine Double Minute 2 Antagonist Nutlin-3 Enhanced Chemosensitivity in Esophageal Squamous Cell Carcinoma

    Ito, KenIshida, HirotakaFujishima, FumiyoshiNakamura, Yasuhiro...
    8页
    查看更多>>摘要：Background/Aim: Murine double minute 2 (MDM2) is well known to inhibit p53 function and its over-expression is associated with poor prognosis in several human malignancies. Nutlin-3, a small-molecule inhibitor of MDM2, exerts antitumor effects on various solid tumors harboring wild-type p53. We aimed to clarify its effects on esophageal cancer. Materials and Methods: We first examined the potential antitumor effects of nutlin-3 according to MDM2 status using esophageal carcinoma cell lines (KYSE 170/180). We then immunolocalized MDM2 immunoreactivity in 62 surgical cases of esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy and correlated the findings with clinicopathological variables. Results: MDM2 mRNA expression in KYSE 170 was significantly higher than that in KYSE 180 cells. No significant changes were detected in both cell lines when nutlin-3 was added. However, cell proliferation was significantly decreased in KYSE 170 cells treated with nutlin-3 and cisplatin compared to cisplatin alone but not in KYSE 180. MDM2 immunoreactivity was also significantly associated with poor sensitivity to neoadjuvant chemotherapy in the cases examined. Conclusion: The combination of nutlin-3 with chemotherapeutic agents may become a novel therapeutic strategy in esophageal cancer over-expressing MDM2.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research

    Feasibility of Gastric Tumor Xenograft (GTX)-derived Cell Lines for Individualized Anti-cancer Drug Screening

    Oh, Sung EunOh, Mi YunKim, Sun YoungAn, Ji Yeong...
    9页
    查看更多>>摘要：Background/Aim: Because there are ongoing efforts to identify and develop novel drugs in the treatment of refractory gastric cancer, it is necessary to develop effective preclinical studies. Here, the preclinical efficacy of gastric tumor xenograft (GTX)-derived cell line models for the personalized treatment of gastric cancer was investigated. Materials and Methods: Anti-cancer drugs were scanned with high-throughput screening (HTS) using preestablished GTX-derived cell lines. The efficacy of a selected drug (afatinib) was re-confirmed in vivo and intracellular signaling pathways were investigated in xenograft tumor cell lysates using western blotting. Validation studies, such as cell proliferation and caspase activity assays, were also conducted in vitro with GTX-derived cell lines. Results: HTS indicated that afatinib was effective in one of the five GTXderived cell lines (GTX-087). A xenograft mouse model was established from GTX-087, and administration of afatinib at 1 mg/20 g body weight/day per oral resulted in tumor suppressive activity in vivo. The RAS-ERK pathway was inactivated by an increase in Bax and cleaved caspase-3 in this xenograft model. In vitro cell proliferation assay also revealed that afatinib was able to suppress the growth of the GTX-087 cell line. Caspase activity assay confirmed that afatinib had an apoptotic role on GTX-087 and showed that caspase-3/7 activity increased in a time dependent manner. Conclusion: The GTX-derived cell line model might be useful for estimating novel drug responses and could be an alternative to patient-derived xenograft animal models.
      原文链接:
    • NSTL
    • Int Inst Anticancer Research