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Oncotarget Jan 2018Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for...
Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo-like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling. A recently developed small molecule inhibitor, ON-01910 ("rigosertib", RGS), was shown to interfere with both RAS- and PLK1-signaling. The aim of this study was to analyze the effects of RGS in HCC and to assess PLK1 and HRAS expression in HCC. RGS treatment reduced cell proliferation and induced cell cycle arrest in human HCC cell lines . Moreover, RGS strongly inhibited both ERK- and AKT-activation in HCC cells, indicating disruption of RAS-signaling. Analysis of HCC patient data showed that PLK1 and HRAS expression levels are upregulated during HCC development and in advanced HCC, respectively. High expression levels of PLK1 significantly correlated with poor patient survival. Moreover, high expression of both PLK1 and HRAS revealed combined effects on patient outcome. This underscores the importance of these genes and associated pathways in HCC. We newly demonstrate the therapeutic potential of RGS in HCC by inhibition of both PLK1 activation and major RAS-pathways, revealing a novel therapeutic "dual-hit" approach for HCC.
PubMed: 29423069
DOI: 10.18632/oncotarget.23188 -
Archives of Gynecology and Obstetrics May 2011Ovarian cancer is a difficult to treat cancer entity with a high relapse rate. After initial surgery and chemotherapy, only a few options for therapeutic treatment... (Review)
Review
INTRODUCTION
Ovarian cancer is a difficult to treat cancer entity with a high relapse rate. After initial surgery and chemotherapy, only a few options for therapeutic treatment remain in case of cancer recurrence. New treatment options with improved efficacies to circumvent acquired or pre-existing drug resistance are needed.
MATERIALS
This survey focuses on new prospective drugs for ovarian cancer treatment that either cause direct damage to the nuclear DNA or inhibit chromosome segregation by acting as mitotic spindle inhibitors.
RESULTS
Among a plethora of currently tested and proposed new drugs for ovarian cancer treatment, only a few appear to meet the criteria of sufficient and reliable efficacy with tolerable toxicity. These include the naturally occurring DNA-alkylating alkaloid trabectedin, the nitrogen mustard prodrug canfosfamide, and the synthetic kinase inhibitor ON-01910. The latter inhibits mitotic spindle formation without a direct tubulin interaction, avoiding adverse neurotoxic reactions common to the taxanes. Further, epothilones and oxaliplatin, already approved drugs for other cancer entities, show promising activity against ovarian cancer; they are even of interest as a first-line treatment option.
DISCUSSION
Although the current focus and interest of modern cancer drug design tends to be more specific and targeted therapies, including therapeutic antibodies and specific small molecules to inhibit growth-, apoptosis-, and angiogenesis-regulating signalling cascades, the main target for ovarian cancer treatment appears to remain its basic, though uncontrolled working proliferation machinery. This includes the current gold standard for ovarian cancer chemotherapy, carboplatin, and taxanes, as well as the few remaining alternatives, such as topotecan, doxorubicin, and gemcitabine, which all rely on their ability to bind to or to modify the DNA or the chromosome-separating spindle apparatus. Thus, the genomic integrity and replication machinery of ovarian cancer cells prove to represent an established, and obviously still effective target to be tackled for ovarian cancer treatment.
Topics: Antineoplastic Agents, Alkylating; Cell Division; DNA; Drugs, Investigational; Female; Humans; Microtubules; Ovarian Neoplasms
PubMed: 21082186
DOI: 10.1007/s00404-010-1757-x -
The Oncologist Jun 2009Polo-like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint... (Review)
Review
Polo-like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint regulation of mitosis. About 80% of human tumors, of various origins, express high levels of PLK transcripts. However, PLK mRNA is mostly absent in surrounding healthy tissues. Overexpression of PLK is associated with a poor prognosis in several tumor types and a lower overall survival rate. The overexpression of PLKs in human tumors, but not in healthy nondividing cells, makes them an attractive, selective target for cancer drug development. PLK inhibitors interfere with different stages of mitosis, such as centrosome maturation, spindle formation, chromosome separation, and cytokinesis. They induce mitotic chaos and severely perturb cell cycle progression, eventually leading to cancer cell death. Several PLK inhibitors are in development and are undergoing evaluations as potential cancer treatments. This review includes an overview of PLK inhibitors in early clinical development (i.e., BI 2536, BI 6727, GSK461364, ON 019190.Na, and HMN-214) and in advanced preclinical development (i.e., ZK-thiazolidinone, NMS-1, CYC-800, DAP-81, and LC-445). If proof of principle is confirmed in large studies, PLK inhibitors will offer a new targeted antitumor therapy for cancer patients.
Topics: Aniline Compounds; Animals; Cell Cycle Proteins; Clinical Trials as Topic; Cyclic N-Oxides; Drug Evaluation, Preclinical; Glycine; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Pyridines; Sulfonamides; Sulfones; Thiazolidines; Polo-Like Kinase 1
PubMed: 19474163
DOI: 10.1634/theoncologist.2009-0010 -
Leukemia Research Dec 2012While MDS was only recently viewed as an orphan disease without any FDA approved therapeutic options, the landscape has changed dramatically with a promise for... (Review)
Review
While MDS was only recently viewed as an orphan disease without any FDA approved therapeutic options, the landscape has changed dramatically with a promise for development of exciting new therapeutics that parallels our growing understanding of the pathobiology of the disease. An array of new agents is entering clinical development, many of which were not discussed in this review. Nevertheless, our paradigm for the approach to treatment of MDS can be expected to evolve with our ever expanding insight into the disease biology, targeting not only the MDS clone, but also the surrounding microenvironment while at the same time considering the context of the dynamics of disease pathogenesis.
Topics: Antineoplastic Agents; Azacitidine; Bone Marrow; Chromosomes, Human, Pair 5; Glycine; Humans; Hydroxamic Acids; Lenalidomide; Myelodysplastic Syndromes; Neoplastic Stem Cells; Sequence Deletion; Sulfones; Thalidomide; Transforming Growth Factor beta; Tumor Microenvironment; p38 Mitogen-Activated Protein Kinases
PubMed: 22959510
DOI: 10.1016/j.leukres.2012.08.010 -
IUBMB Life Oct 2005Prostate cancer (PCa) is the most commonly occurring cancer in American men, next to skin cancer. Existing treatment options and surgical intervention are unable to... (Review)
Review
Prostate cancer (PCa) is the most commonly occurring cancer in American men, next to skin cancer. Existing treatment options and surgical intervention are unable to effectively manage this cancer. Therefore, continuing efforts are ongoing to establish novel mechanism-based targets and strategies for its management. The serine/threonine kinases Polo-like kinase (Plk) 1 plays a key role in mitotic entry of proliferating cells and regulates many aspects of mitosis which are necessary for successful cytokinesis. Plk1 is over-expressed in many tumor types with aberrant elevation frequently constituting a prognostic indicator of poor disease outcome. This review discusses the studies which indicate that Plk1 could be an excellent target for the treatment as well as chemoprevention of prostate cancer.
Topics: Animals; Antibodies; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemoprevention; Female; Glycine; Humans; Male; Mice; Mitosis; NIH 3T3 Cells; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Sulfones; Polo-Like Kinase 1
PubMed: 16223707
DOI: 10.1080/15216540500305910 -
Experimental Hematology Apr 2016Mammalian erythroblasts undergo enucleation through a process thought to be similar to cytokinesis. Microtubule-organizing centers (MTOCs) mediate organization of the...
Mammalian erythroblasts undergo enucleation through a process thought to be similar to cytokinesis. Microtubule-organizing centers (MTOCs) mediate organization of the mitotic spindle apparatus that separates the chromosomes during mitosis and are known to be crucial for proper cytokinesis. However, the role of MTOCs in erythroblast enucleation remains unknown. We therefore investigated the effect of various MTOC inhibitors on cytokinesis and enucleation using human colony-forming units-erythroid (CFU-Es) and mature erythroblasts generated from purified CD34(+) cells. We found that erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA), a dynein inhibitor, and monastrol, a kinesin Eg5 inhibitor, as well as various inhibitors of MTOC regulators, including ON-01910 (Plk-1), MLN8237 (aurora A), hesperadin (aurora B), and LY294002 (PI3K), all inhibited CFU-E cytokinesis. Among these inhibitors, however, only EHNA blocked enucleation. Moreover, terminally differentiated erythroblasts expressed only dynein; little or none of the other tested proteins was detected. Over the course of the terminal differentiation of human erythroblasts, the fraction of cells with nuclei at the cell center declined, whereas the fraction of polarized cells, with nuclei shifted to a position near the plasma membrane, increased. Dynein inhibition impaired nuclear polarization, thereby blocking enucleation. These data indicate that dynein plays an essential role not only in cytokinesis but also in enucleation. We therefore conclude that human erythroblast enucleation is a process largely independent of MTOCs, but dependent on dynein.
Topics: Cell Differentiation; Cell Division; Cell Proliferation; Cells, Cultured; Dyneins; Erythroblasts; Erythroid Precursor Cells; Erythropoiesis; Gene Expression; Glycine; Humans; Microtubule-Organizing Center; Molecular Motor Proteins; Sulfones; Tubulin
PubMed: 26724640
DOI: 10.1016/j.exphem.2015.12.003 -
Leukemia Research Aug 2012
Topics: Cyclin D1; Female; Glycine; Humans; Male; Molecular Targeted Therapy; Myelodysplastic Syndromes; Sulfones
PubMed: 22607960
DOI: 10.1016/j.leukres.2012.04.023 -
Molecular Pharmacology Jan 2015ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage...
ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910.Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide (TL-77)] which has shown improved oral bioavailability compared with ON01910.Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910.Na. TL-77 displays potent growth inhibitory activity in vitro (GI50 < 1μM against HCT-116 cells), demonstrating 3- to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation.
Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glycine; HCT116 Cells; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; MCF-7 Cells; Neoplasms; Signal Transduction; Spindle Apparatus; Styrenes; Sulfonamides; Sulfones; Tubulin
PubMed: 25316768
DOI: 10.1124/mol.114.093245 -
Cancer Discovery Jun 2016Rigosertib acts as a RAS mimetic, binding to the RAS-binding domain of multiple RAS effector proteins.
Rigosertib acts as a RAS mimetic, binding to the RAS-binding domain of multiple RAS effector proteins.
Topics: Animals; Antineoplastic Agents; Glycine; Humans; Molecular Mimicry; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors; Signal Transduction; Sulfones; ras Proteins
PubMed: 27150538
DOI: 10.1158/2159-8290.CD-RW2016-085 -
Journal of Medicinal Chemistry Feb 2024In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors...
In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, and , not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.
Topics: Humans; Animals; Mice; Histone Deacetylase Inhibitors; Hydroxamic Acids; Cell Line, Tumor; Cell Proliferation; Vorinostat; Apoptosis; Antineoplastic Agents; Glycine; Sulfones
PubMed: 38261411
DOI: 10.1021/acs.jmedchem.3c01941