P04.26  The novel therapeutic curcumin enhances targeted bacteriophage mediated in-vitro cell death in primary human DIPG

Abstract The therapeutic outcome of glioblastomas (GBMs) is still very poor. Therefore, invention of novel therapeutic methods against GBM cases is considered urgent. The antitumor effects of naturally-derived compounds are attracting attention recently, and therapeutic efficacy of curcumin, a plant-derived compound previously used for multiple purpose, has been indicated in many cancer systems; however, clinical application of curcumin is considered difficult because of its poor bioavailability (under 1 %). Curcumin monoglucuronide (CMG), a water-soluble prodrug of curcumin recently developed for overcoming this weakness, has been demonstrated excellent antitumor effects for several malignancies in vitro and in vivo; therefore, we investigated the effects of CMG against GBM cells. CMG induced cell death of human GBM cells lines (T98G, U251MG, and U87MG) by dose dependent manner by triggering multiple forms of cell death such as apoptosis and perthanatos. Immunoblotting of CMG-treated GBM cell lysates demonstrated activation of multiple cell death signaling. Furthermore, immunodeficiency mice harboring intracerebral U87MG cell xenografts systemically treated by CMG showed significantly prolonged survival compared with control mice. These results suggest CMG would be a novel therapeutic agent against GBM cases.

Download Full-text

Inhibition of microRNA-21 via locked nucleic acid-anti-miR suppressed metastatic features of colorectal cancer cells through modulation of programmed cell death 4

Tumor Biology ◽

10.1177/1010428317692261 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769226 ◽

Cited By ~ 16

Author(s):

Reza Nedaeinia ◽

Mohammadreza Sharifi ◽

Amir Avan ◽

Mohammad Kazemi ◽

Abdolreza Nabinejad ◽

...

Keyword(s):

Colorectal Cancer ◽

Polymerase Chain Reaction ◽

Cell Death ◽

Nucleic Acid ◽

Locked Nucleic Acid ◽

Chain Reaction ◽

Programmed Cell Death 4 ◽

Polymerase Chain ◽

Novel Therapeutic

Colorectal cancer is among the most lethal of malignancies, due to its propensity to metastatic spread and multifactorial-chemoresistance. The latter property supports the need to identify novel therapeutic approaches for the treatment of colorectal cancer. MicroRNAs are endogenous non-coding small RNA molecules that function as post-transcriptional regulators of gene expression. Recently, programmed cell death 4 has been identified as a protein that increases during apoptosis. This gene is among the potential targets of miR-21 (OncomiR). Locked nucleic acid–modified oligonucleotides have recently emerged as a potential therapeutic option for targeting microRNAs. The aim of this study was to explore the functional role of locked nucleic acid-anti-miR-21 in the LS174T cell line in vitro and in vivo models. LS174T cells were treated with locked nucleic acid-anti-miR-21 for 24, 48, and 72 h in vitro. The expression of miR-21 and PDCD4 at messenger RNA (mRNA) level was evaluated by quantitative real-time polymerase chain reaction, while the protein level of PDCD4 was determined by Western blotting. Cell migratory behavior and the cluster-forming ability of cells were assessed before and after therapy. The disseminated tumor cells were assessed in the chick chorioallantoic membrane model by Alu quantitative polymerase chain reaction. Locked nucleic acid-anti-miR-21 was transfected successfully into the LS174T cells and inhibited the expression of miR-21. Locked nucleic acid-anti-miR-21 inhibited the migration and the number of cells forming clusters. Moreover, we found that locked nucleic acid-anti-miR-21 transfection was associated with a significant reduction in metastatic properties as assessed by the in ovo model. Our findings demonstrated the novel therapeutic potential of locked nucleic acid-anti-miR-21 in colon adenocarcinoma with high miR-21 expression.

Download Full-text

Synthesis of Two Novel Homologous Polyphosphoesters Containing Aminophosphonate Units and Cytotoxicity of Some Low-Molecular and Polymeric Aminophosphonate Derivatives

Advances in Materials Science and Engineering ◽

10.1155/2018/9565401 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8

Author(s):

Ivanka Kraicheva ◽

Georgi Momekov ◽

Rositsa Mihaylova ◽

Margarita Topashka-Ancheva ◽

Ivelina Tsacheva ◽

...

Keyword(s):

Cell Death ◽

Cell Lines ◽

Leukemic Cell ◽

The Novel ◽

Histological Subtype ◽

New Materials ◽

Antitumor Effects ◽

Cytotoxicity Assays ◽

Leukemic Cell Lines

Two novel polyphosphoesters containing anthracene- and furan-derived aminophosphonate moieties, namely, poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s P-12 and P-13, were synthesized through an addition of poly(oxyethylene H-phosphonate) to 9-anthrylidene-furfurylamine and characterized. The novel polyphosphoester P-12 and a series of previously described anthracene-derived compounds including Schiff bases S-1 and S-2, α-aminophosphonates A-3–A-6, bis-aminophosphonate B-6, two enantiomers A-5a and A-5b, and polyphosphoesters P-8–P-11 containing aminophosphonate units were screened for antitumor activity against a panel of human leukemic cell lines, using cisplatin as a reference cytotoxic agent. As concluded from the cytotoxicity assays, both precursors S-1 and S-2 presented similar cytotoxicity profiles that are cisplatin-like only in the REH cell line. Leader compound of the α-aminophosphonates is A-4 with cell death-inducing properties fully equaling those of the referent drug in all of the screened leukemic cell lines with the only exception being the AML histological subtype HL-60. Some of the polymeric analogues elicited moderate (P-10 and P-12) to low (P-11) cytotoxic activity, whereas the polyphosphoesters P-8 and P-9 produced in vitro antitumor effects largely surpassing cisplatin’s. The compounds P-8, P-9, and A-4 could be potential new materials for anticancer therapeutic purposed.

Download Full-text

The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1

Frontiers in Pharmacology ◽

10.3389/fphar.2021.752825 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yeting Hu ◽

Yucheng Qian ◽

Jingsun Wei ◽

Tian Jin ◽

Xiangxing Kong ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Therapeutic Strategy ◽

Whole Genome ◽

Library Screening ◽

Inhibit Tumor Growth ◽

Squamous Cells ◽

Novel Therapeutic

Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.

Download Full-text

Small Molecule Inhibition of Cdc7, a Key Cell Cycle Regulator and Novel Therapeutic Target, Successfully Inhibits Leukemia Cell Growth in Vitro and in Vivo

Blood ◽

10.1182/blood.v112.11.2668.2668 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2668-2668

Author(s):

Mark G. Frattini ◽

David Shum ◽

Kristen M O’Dwyer ◽

Renier J. Brentjens ◽

Ray Yeh ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Small Molecule ◽

Leukemia Cell ◽

Standard Cell ◽

Cdc7 Kinase ◽

Kinase Inhibitory Activity ◽

Novel Therapeutic

Abstract Cdc7 is a heterodimeric serine/threonine protein kinase that is a key regulator in the process of initiation of DNA replication and the G1 to S phase transition. Both the kinase and its known substrates are over-expressed in the majority of human cancers. As a result of the recent progress in the areas of pharmacogenetics and high throughput screening technology, identifying specific small molecule inhibitors of cell cycle regulated protein kinases has provided a means not only to study these signal transduction pathways but also to identify potential novel therapeutic agents. To this end, we have developed an assay for Cdc7 kinase inhibitory activity using a highthroughput screening (HTS) approach, screening over 250,000 natural and synthetic small molecules. As a result, we have identified and confirmed seventeen compounds, representing nine different chemical scaffolds, with Cdc7 kinase inhibitory activity. Based on potency, we selected the lead compound (CKI-7) which was further characterized using kinase profiling, microarray experiments, and standard cell based cytotoxicity assays. These latter studies demonstrated that CKI-7 induced cytotoxicity of established leukemia and lymphoma cell lines in culture with inhibitory concentrations (IC50s) in the low nanomolar range. Significantly, CKI-7 likewise induced cytotoxicity of MDR1 overexpressing cell lines with similar IC50s, demonstrating that this novel compound can overcome a major mechanism of chemotherapy resistence in human tumor cells. We additonally demonstrate that CKI-7 induces cytotoxicity of patient-derived primary acute leukemia tumor cells (both chemotherapy naïve and relapsed/refractory samples) in vitro at similarly low nanomolar concentrations. In vivo dose-dependent anti-tumor activity of CKI-7 was subsequently demonstrated in a SCID-Beige mouse systemic tumor model utilzing a recently isolated Philadelphia chromosome positive acute lymphoblastic leukemia cell line (PhALL3.1). Standard cell cycle synchronization studies established that exposure to CKI-7 results in cell cycle dependent caspase 3 activation and apoptotic cell death. This cell death is the direct result of Cdc7 kinase inhibition by CKI-7 as demonstrated using a substrate biomarker assay. In conclusion, our data confirm that Cdc7 is a new promising target for cancer therapy, and that CKI-7, a selective small molecule inhibitor of this enzyme, is an equally promising novel cancer therapeutic agent.

Download Full-text

Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo

Scientific Reports ◽

10.1038/srep18953 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 17

Author(s):

Christa A. Manton ◽

Blake Johnson ◽

Melissa Singh ◽

Cavan P. Bailey ◽

Lisa Bouchier-Hayes ◽

...

Keyword(s):

Cell Death ◽

Proteasome Inhibitor ◽

The Novel

Download Full-text

MINK1 modulates 5FU resistance in OSCC through AKT/MDM2 mediated regulation of p53

10.1101/2021.08.19.456939 ◽

2021 ◽

Author(s):

Sibasish Mohanty ◽

Pallavi Mohapatra ◽

Omprakash Shriwas ◽

Manashi Priyadarshini ◽

Shamima Azma Ansari ◽

...

Keyword(s):

Cell Death ◽

Clinical Investigation ◽

Tumor Burden ◽

Negative Regulator ◽

Clinical Samples ◽

The Novel ◽

Akt Phosphorylation ◽

Tumor Tissues ◽

Patients Experience

Cisplatin, 5FU and docetaxel (TPF) are the most common chemotherapy regimen used for advanced OSCC. However, many cancer patients experience relapse, continued tumor growth, and spread due to drug resistance, which leads to treatment failure and metastatic disease. Here, using a CRISPR/Cas9 based kinome knockout screening, Misshapen-like kinase 1 (MINK1) is identified as an important mediator of 5FU resistance in OSCC. Analysis of clinical samples demonstrated significantly higher MINK1 expression in the tumor tissues of chemotherapy non-responder as compared to chemotherapy responders. The in-vitro and xenograft experiments indicate that knocking out MINK1 restores 5FU mediated cell death in chemoresistant OSCC. An antibody based phosphorylation array screen revealed MINK1 as a negative regulator of p53. Mechanistically, MINK1 modulates AKT phosphorylation at Ser473, which enables p-MDM2 (Ser 166) mediated degradation of p53. We also identified lestaurtinib as a potent inhibitor of MINK1 kinase activity. Lestaurtinib significantly induces 5FU mediated cell death in chemoresistant OSCC lines. The patient derived chemoresistant cell based xenograft data suggest that lestaurtinib restores 5FU sensitivity and facilitates a significant reduction of tumor burden. Overall, our study suggests that MINK1 is a major driver of 5FU resistance in OSCC. The novel combination of MINK1 inhibitor lestaurtinib and 5FU needs further clinical investigation in advanced OSCC.

Download Full-text

The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro

PLoS ONE ◽

10.1371/journal.pone.0204271 ◽

2018 ◽

Vol 13 (9) ◽

pp. e0204271 ◽

Cited By ~ 17

Author(s):

Xuan Wang ◽

Andris Elksnis ◽

Per Wikström ◽

Erik Walum ◽

Nils Welsh ◽

...

Keyword(s):

Cell Death ◽

Nadph Oxidase ◽

Islet Cell ◽

Selective Inhibitor ◽

Human Islet ◽

The Novel ◽

Nadph Oxidase 4

Download Full-text

Milatuzumab immunoliposomes induce cell death in CLL by promoting accumulation of CD74 on the surface of B cells

Blood ◽

10.1182/blood-2009-11-253203 ◽

2010 ◽

Vol 116 (14) ◽

pp. 2554-2558 ◽

Cited By ~ 28

Author(s):

Erin Hertlein ◽

Georgia Triantafillou ◽

Ellen J. Sass ◽

Joshua D. Hessler ◽

Xiaoli Zhang ◽

...

Keyword(s):

Cell Death ◽

Monoclonal Antibodies ◽

B Cells ◽

Progressive Disease ◽

Therapeutic Agent ◽

Lymphocytic Leukemia ◽

Independent Manner ◽

Induce Cell Death ◽

Novel Therapeutic

Abstract Chronic lymphocytic leukemia (CLL) is an incurable progressive disease for which new therapies are required. Therapy with monoclonal antibodies (mAbs) has improved the outcome of patients with CLL, making further investigation of novel antibodies directed against alternative and specific targets on B cells an important area of translational research. We now describe functional properties of an antagonistic humanized mAb to CD74, milatuzumab, showing that milatuzumab combined with a crosslinking antibody induces cytotoxicity in vitro in CLL cells in a caspase- and stromal-independent manner associated with aggregation of CD74 on the cell surface. Furthermore, incorporation of milatuzumab into an immunoliposome induces even more of a cytotoxic response than in vitro crosslinking, representing a novel therapeutic formulation for this mAb. Based on these data, future development of the milatuzumab-immunoliposome formulation as a therapeutic agent for CLL is warranted.

Download Full-text