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Oncology 2017The multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC).... (Review)
Review
The multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC). However, as with other drugs, sorafenib has its limitations, and various clinical trials have been conducted to develop novel molecular targeted agents for use alone or in combination with existing locoregional therapies. Despite this, clinical trials of molecular targeted agents combined with transarterial chemoembolization (TACE) have not reported major treatment outcomes to date. In this review, we describe previous clinical trials of combination therapy with TACE and a molecular targeted agent in patients with unresectable HCC.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Liver Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sorafenib
PubMed: 29258086
DOI: 10.1159/000481243 -
International Journal of Oncology May 2017Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although...
Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although diagnosis modalities for primary prostate cancer have markedly improved, there are still no effective therapies for metastatic prostate cancer. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2, PDGFRβ and FGFR1. There is strong experimental evidence that SU6668 can induce growth inhibition of various primary tumors. However, the function and molecular mechanism of SU6668 in prostate cancer has not been fully elucidated. In the present study, we found that SU6668 inhibited the proliferation and invasion of prostate cancer cells. Functional studies also demonstrated that SU6668 inhibited epithelial-mesenchymal transition in DU145 and LNCap cells. After treatment with SU6668, MTDH protein, which has been reported to be significantly overexpressed in many human tumor tissues, was downregulated in DU145 and LNCap cells. siRNA-mediated silencing of MTDH in prostate cancer cells decreased their proliferation and invasive capabilities, suggesting that SU6668 may inhibit cell proliferation and invasion of prostate cancer cells partly through downstream targeting of MTDH. Mechanistic investigations showed that AKT signaling pathway was inhibited after SU6668 treatment in prostate cancer cells. Moreover, a combination of SU6668 and PI3K-AKT pathway inhibitor LY29004 resulted in increased inhibition of cell proliferation and invasion in DU145 cells. Taken together, our findings revealed that SU6668 suppressed prostate cancer progression by downregulating MTDH/AKT signaling pathway and identified a promising therapeutic strategy for prostate cancer.
Topics: Angiogenesis Inhibitors; Cell Adhesion Molecules; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Indoles; Male; Membrane Proteins; Neoplasm Invasiveness; Oxindoles; Propionates; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrroles; RNA-Binding Proteins; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2
PubMed: 28339027
DOI: 10.3892/ijo.2017.3926 -
Anticancer Research Mar 2015TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the...
BACKGROUND
TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the tumor-microenvironment interaction in hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
HCC and fibroblast cell lines (HuH7, Hep3B, HuH1 and WI-38) were used to evaluate their interactions. Cancer characteristics were evaluated by spheroid formation and tumorigenicity in immunodeficient mice. Time-lapse image analysis was performed to monitor cell motility.
RESULTS
Although PDGFA was abundantly expressed, PDGFR-α was predominantly located in the cytoplasm and was not functional in HuH7 cells. Co-culture experiments demonstrated that HCC cells induced phosphorylation of PDGFR-α in WI-38 fibroblasts and that stimulated fibroblasts, in turn, boosted the spheroid formation capacity of HCC cells. TSU-68 inhibited phosphorylation of PDGFR-α in WI-38 cells and suppressed the growth of subcutaneously co-injected HuH7/WI-38 tumor xenografts.
CONCLUSION
TSU-68 inhibits stromal PDGF signaling activated by cancer cells and suppresses HCC growth.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Liver Neoplasms; Mice; Oxindoles; Platelet-Derived Growth Factor; Propionates; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Transforming Growth Factor beta1
PubMed: 25750293
DOI: No ID Found -
Biochemistry Sep 2018Serine/threonine protein kinase ULK3 is implicated in a variety of cellular processes, including autophagy, cell division, and execution of the Sonic hedgehog pathway....
Serine/threonine protein kinase ULK3 is implicated in a variety of cellular processes, including autophagy, cell division, and execution of the Sonic hedgehog pathway. However, very little about how its biological activity could be controlled is known. This study focuses on unraveling biochemical insights into the mechanism of inhibition and activation of ULK3. We identify novel phosphorylation sites in ULK3 and show that autophosphorylation has no impact on the kinase activity of the protein. We further demonstrate that phosphorylation of two residues in the kinase domain of ULK3 by an as yet unidentified kinase may completely abolishes its catalytic activity. We show that a low-molecular weight inhibitor SU6668, designed as an ATP competitive inhibitor for tyrosine kinases, binds in the ATP pocket of ULK3 yet inhibits ULK3 kinase activity in a partially ATP noncompetitive manner. Finally, we demonstrate that the ULK3 kinase domain, annotated in silico, is not sufficient for its kinase activity, and additional amino acids in the 271-300 region are required.
Topics: Amino Acid Sequence; Catalytic Domain; Gene Expression Regulation, Enzymologic; Humans; Indoles; Models, Molecular; Mutagenesis, Site-Directed; Mutation; Oxindoles; Phosphorylation; Propionates; Protein Conformation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrroles; Sequence Homology; Signal Transduction
PubMed: 30096229
DOI: 10.1021/acs.biochem.8b00356 -
Cellular Physiology and Biochemistry :... 2017Recently, some small-molecule compounds that were designed for cancer therapy have acquired new roles in the treatment of pulmonary diseases. However, drug screening...
BACKGROUND/AIMS
Recently, some small-molecule compounds that were designed for cancer therapy have acquired new roles in the treatment of pulmonary diseases. However, drug screening aimed at abnormal muscle contraction is still limited. TSU-68 is a potent, orally administered, small-molecule agent that can reduce the vascular endothelial growth factor (VEGF)-induced Ca2+ increase in endothelial cells. We questioned whether TSU-68 could also affect calcium influx and relax airway smooth muscle (ASM) cells. The current study aimed to investigate these effects and to explore the underlying mechanisms.
METHODS
The effects of TSU-68 on ASM cells were studied in mice using a series of biophysiological techniques, including force measurement and patch-clamp experiments.
RESULTS
TSU-68 inhibited high K+ or acetylcholine chloride (ACh)-induced pre-contracted mouse tracheal rings in a concentration-dependent manner. Further research demonstrated that the TSU-68-induced ASM relaxation was mediated by calcium, which was decreased by blocking voltage-dependent Ca2+ channels (VDCCs) and non-selective cation channels (NSCCs).
CONCLUSION
Our data indicated that TSU-68 relaxes tense ASM by reducing the intracellular Ca2+ concentration through blocking VDCCs and NSCCs, which suggested that this small molecule might be useful in the treatment of abnormal smooth muscle.
Topics: Acetylcholine; Angiogenesis Inhibitors; Animals; Calcium; Calcium Channels; Cells, Cultured; Indoles; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle Relaxation; Myocytes, Smooth Muscle; Oxindoles; Patch-Clamp Techniques; Potassium; Propionates; Pyrroles
PubMed: 28478457
DOI: 10.1159/000475653 -
Investigational New Drugs Oct 2014We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor...
Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.
PURPOSE
We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment.
PATIENTS AND METHODS
Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed.
RESULTS
Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively.
CONCLUSION
The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.
Topics: Administration, Oral; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Oxindoles; Oxonic Acid; Propionates; Pyrroles; Tegafur; Treatment Outcome
PubMed: 24829073
DOI: 10.1007/s10637-014-0109-2 -
Asia-Pacific Journal of Clinical... Dec 2017The aim of this study is to investigate whether the addition of TSU-68 would affect on the quality of life (QOL) of Korean metastatic breast cancer patients treated with...
Quality of life on TSU-68: Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline.
AIM
The aim of this study is to investigate whether the addition of TSU-68 would affect on the quality of life (QOL) of Korean metastatic breast cancer patients treated with docetaxel.
METHODS
Sixty-three of 78 patients completed the baseline QOL questionnaires and at least one follow-up questionnaire comprising questions from the Korean Functional Assessment of Cancer Therapy-Breast (FACT-B), hospital anxiety and depression scale (HAD), the shortened form of the profile of mood states (BPOMS), and anticipation and anxiety for treatment scale. Changes in QOL scores from baseline were compared by analysis of covariance at each time point (6, 12 weeks, 9, 12 and 18 months) and at the end of treatment (EOT), and the longitudinal changes over time were evaluated by repeated measure analysis.
RESULTS
The two-treatment groups (TSU-68 plus docetaxel [A] vs docetaxel alone [B]) were well balanced regarding sociodemographic characteristics, including age (P = 0.450), religion (P = 1.000), education (P = 0.257), ECOG performance status (P = 0.261), and employment status (P = 0.325). The return rate at EOT was 61.9%. In analyses at each QOL measuring time, A group showed a higher FACT-B total score and FACT-G score than B at 12 months (P = 0.031 and P = 0.024, respectively). The anticipation and anxiety for treatment scale of A group was higher than that of B at 12 weeks and EOT (P = 0.046 and P = 0.022, respectively). However, repeated measure analysis for longitudinal changes over time showed no significant group wise differences.
CONCLUSIONS
The combination of TSU-68 with docetaxel showed no additional adverse effects on patient QOL during the study period, as compared with docetaxel monotherapy.
Topics: Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Humans; Indoles; Middle Aged; Neoplasm Metastasis; Oxindoles; Propionates; Pyrroles; Quality of Life; Taxoids
PubMed: 28303646
DOI: 10.1111/ajco.12681 -
Investigational New Drugs Aug 2014The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline: randomized phase II multicenter trial.
The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer were randomly assigned to receive either TSU-68 400 mg twice daily on days 1-21 plus docetaxel 60 mg/m(2) on day 1 every 3 weeks, or docetaxel 60 mg/m(2) on day 1 every 3 weeks. The primary endpoint was progression-free survival. Between November 2006 and December 2007, 81 patients were included in this study (41 for TSU-68 plus docetaxel and 40 for docetaxel alone). Median progression-free survival was 6.8 months (95 % confidence interval [CI] = 5.4-12.5 months) in the TSU-68 plus docetaxel group and 8.1 months (95 % CI = 4.0-13.7 months) in the docetaxel-alone group (hazard ratio [HR] = 1.0; 95 % CI = 0.6-1.8; p = 0.95). There were no significant differences in the overall response rates and overall survival between groups (p = 0.29 and p = 0.42, respectively). In subgroup analysis, TSU-68 plus docetaxel was associated with better overall survival than docetaxel alone in anthracycline-resistant patients (HR = 0.3; 95 % CI = 0.1-0.8; p = 0.02). The most frequent adverse events were neutropenia and anorexia in both arms. Although both regimens were well tolerated, grade 3/4 non-hematologic toxicity was more frequently observed in the TSU-68 plus docetaxel group. Combination of TSU-68 and docetaxel is well tolerated but failed to demonstrate superior efficacy over docetaxel alone in anthracycline-pretreated breast cancer patients. As TSU-68 was associated with better survival in the anthracycline-resistant subgroup, it should be further explored in this subgroup.
Topics: Adult; Aged; Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Docetaxel; Female; Humans; Indoles; Middle Aged; Oxindoles; Propionates; Pyrroles; Taxoids
PubMed: 24715580
DOI: 10.1007/s10637-014-0093-6 -
Cancer Research and Treatment Apr 2016This study analyzed the role of plasma biomarkers for TSU-68 in a previous phase II trial comparing TSU-68 plus docetaxel and docetaxel alone in patients with metastatic...
PURPOSE
This study analyzed the role of plasma biomarkers for TSU-68 in a previous phase II trial comparing TSU-68 plus docetaxel and docetaxel alone in patients with metastatic breast cancer.
MATERIALS AND METHODS
A total of 77 patients were eligible for this study (38 in the TSU-68 plus docetaxel arm and 39 in the docetaxel alone arm). Blood samples were collected prior to the start of each cycle, and vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-AA, -AB, -BB, fibroblast growth factor, M30, C-reactive protein (CRP), and interleukin 6 (IL-6) levels were measured using enzyme linked immunosorbent assay. The primary endpoint was progression-free survival (PFS).
RESULTS
In patients with baseline PDGF-AA ≥ median, median PFS was significantly worse in the TSU-68 plus docetaxel group than in the docetaxel alone group (5.4 months vs. 13.7 months, p=0.049), while a trend toward a PFS benefit was observed in those with baseline PDGF-AA < median (9.7 months vs. 4.0 months, p=0.18; p for interaction=0.03). In the TSU-68 plus docetaxel group, PFS showed significant association with fold changes in CRP (p=0.001), IL-6 (p < .001), PDGF-BB (p=0.02), and VEGF (p=0.047) following the first treatment cycle.
CONCLUSION
Baseline PDGF-AA levels and dynamics of VEGF, PDGF-BB, CRP, and IL-6 levels were predictive for the efficacy of TSU-68.
Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Docetaxel; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factors; Humans; Indoles; Interleukin-6; Middle Aged; Neoplasm Metastasis; Oxindoles; Propionates; Pyrroles; Taxoids; Vascular Endothelial Growth Factor A
PubMed: 26194374
DOI: 10.4143/crt.2015.089