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Expert Opinion on Investigational Drugs Nov 2013Rigosertib (ON01910.Na), is a targeted therapeutic that inhibits multiple kinases, including PI3K and PIk-1. Rigosertib has been found to induce the proliferative arrest... (Review)
Review
INTRODUCTION
Rigosertib (ON01910.Na), is a targeted therapeutic that inhibits multiple kinases, including PI3K and PIk-1. Rigosertib has been found to induce the proliferative arrest and apoptosis of myeloblasts but not of other normal hematopoietic cells. Rigosertib has significant clinical activity as a therapy for patients with high-risk myelodysplastic syndrome who are otherwise refractory to DNA methyltransferase inhibitors. Moreover, rigosertib has potential clinical activity in a multitude of solid tumors.
AREAS COVERED
The objective of this review is to evaluate the mechanism of activity, efficacy and dosing of rigosertib. Furthermore, the challenge in the clinical development of rigosertib, to identify the specific patients that are most likely to benefit from this therapeutic agent, is discussed. A PubMed search was performed using the following key words: rigosertib and ON01910.Na.
EXPERT OPINION
We describe the application of a novel nanoscale proteomic assay, the nanoimmunoassay, a tractable approach for measuring the activity and predicting the efficacy of rigosertib, in real-time, using limited human clinical specimens. Our strategy suggests a possible paradigm where proteomic analysis during the pre-clinical and clinical development of a therapy can be used to uncover biomarkers for the analysis and prediction of efficacy in human patients.
Topics: Antineoplastic Agents; Biomarkers; Glycine; Humans; Myelodysplastic Syndromes; Nanotechnology; Neoplasms; Protein Kinase Inhibitors; Proteomics; Sulfones; Treatment Outcome
PubMed: 23937225
DOI: 10.1517/13543784.2013.829453 -
BioFactors (Oxford, England) 2023Human T lymphotropic virus type 1 (HTLV-1) infection can cause adult T-cell lymphoblastic leukemia (ATLL), an incurable, chemotherapy-resistant malignancy. In a quest...
Human T lymphotropic virus type 1 (HTLV-1) infection can cause adult T-cell lymphoblastic leukemia (ATLL), an incurable, chemotherapy-resistant malignancy. In a quest for new therapeutic targets, our study sought to determine the levels of AKT, mTOR, and PI3K in ATLL MT-2 cells, HTLV-1 infected NIH/3T3 cells (Inf-3T3), and HTLV-1 infected patients (Carrier, HAM/TSP, and ATLL). Furthermore, the effects of rigosertib, wortmannin, and rapamycin on the PI3K/Akt/mTOR pathway to inhibit the proliferation of ATLL cells were examined. The results showed that mRNA expression of Akt/PI3K/mTOR was down-regulated in carrier, HAM/TSP, and ATLL patients, as well as MT-2, and Inf-3T3 cells, compared to the healthy individuals and untreated MT-2 and Inf-3T3 as controls. However, western blotting revealed an increase in the phosphorylated and activated forms of AKT and mTOR. Treating the cells with rapamycin, wortmannin, and rigosertib decreased the phosphorylated forms of Akt and mTOR and restored their mRNA expression levels. Using these inhibitors also significantly boosted the expression of the pro-apoptotic genes, Bax/Bcl-2 ratio as well as the expression of the tumor suppressor gene p53 in the MT-2 and Inf-3T3cells. Rigosertib was more potent than wortmannin and rapamycin in inducing sub-G1 and G2-M cell cycle arrest, as well as late apoptosis in the Inf-3T3 and MT-2 cells. It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV-1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K-Akt-mTOR phosphorylation by HTLV-1. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.
Topics: Adult; Animals; Mice; Humans; Leukemia-Lymphoma, Adult T-Cell; Sirolimus; Wortmannin; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Human T-lymphotropic virus 1; HTLV-I Infections; TOR Serine-Threonine Kinases; RNA, Messenger
PubMed: 37345860
DOI: 10.1002/biof.1985 -
International Journal of Molecular... Jan 2023Rigosertib is a small molecule in preclinical development that, due to its characteristics as a dual PLK1 and PI3K inhibitor, is particularly effective in counteracting...
Rigosertib is a small molecule in preclinical development that, due to its characteristics as a dual PLK1 and PI3K inhibitor, is particularly effective in counteracting the advance of different types of tumors. In this work, we evaluated the efficacy of Rigosertib and the expression of p53 in five different human tumor cell lines in vitro, A549 (lung adenocarcinoma), MCF-7 and MDA-MB231 (breast cancer cells), RPMI 8226 (multiple myeloma), and U87-MG (glioblastoma). We demonstrated that in all cell lines, the effect was dose- and time-dependent, but A549 cells were the most sensible to the treatment while higher concentrations were required for the most resistant cell line U87-MG. Moreover, the highest and lowest p53 levels have been observed, respectively, in A459 and U87-MG cells. The alterations in the cell cycle and in cell-cycle-related proteins were observed in A549 at lower concentrations than U87-MG. In conclusion, with this article we have demonstrated that Rigosertib has different efficacy depending on the cell line considered and that it could be a potential antineoplastic agent against lung cancer in humans.
Topics: Humans; Phosphatidylinositol 3-Kinases; Tumor Suppressor Protein p53; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation
PubMed: 36675237
DOI: 10.3390/ijms24021721 -
International Journal of Molecular... Jul 2021Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for...
Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient's survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.
Topics: Antineoplastic Agents; Autophagy; Bile Duct Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Movement; Cholangiocarcinoma; Deoxycytidine; Fluorouracil; Glycine; Humans; Radiation-Sensitizing Agents; Sulfones; Gemcitabine
PubMed: 34360994
DOI: 10.3390/ijms22158230 -
Cancer Science Mar 2015A multi-kinase inhibitor, rigosertib (ON 01910.Na) has recently been highlighted as a novel type of anti-cancer agent for the treatment of the myelodysplastic syndromes...
A multi-kinase inhibitor, rigosertib (ON 01910.Na) has recently been highlighted as a novel type of anti-cancer agent for the treatment of the myelodysplastic syndromes (MDS), but its action mechanisms remain to be clarified. We investigated the in vitro effects of rigosertib on an MDS-derived cell line MDS-L and a myeloid leukemia cell line HL-60. Rigosertib suppressed the proliferation of both HL-60 and MDS-L cells and induced apoptosis by inhibition of the PI3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2AX and led to the DNA damage-induced G2/M arrest. In addition, an immunofluorescence staining study demonstrated the abnormal localization of aurora A kinase, suggesting that rigosertib causes perturbation of spindle assembly and deregulated mitotic patterns towards cell cycle arrest and apoptosis. We also found that rigosertib exerted growth inhibitory effects on two lymphoid cell lines, Jurkat and Ramos. We further examined the molecular pathways influenced by rigosertib from the gene expression profiling data of MDS-L cells and found a possible involvement of rigosertib treatment in the upregulation of the genes related to microtubule kinetics and the downregulation of the mRNA degradation system. The gene set enrichment analysis showed the suppression of "nonsense-mediated mRNA decay (NMD)" as the most significantly affected gene set. These data provide a new aspect and a potential utility of rigosertib for the treatment of refractory hematopoietic malignancies.
Topics: Antineoplastic Agents; Apoptosis; Aurora Kinase A; Cell Line, Tumor; Cell Proliferation; DNA Damage; Gene Expression Profiling; Glycine; HL-60 Cells; Histones; Humans; Leukemia, Myeloid; M Phase Cell Cycle Checkpoints; Microtubules; Myelodysplastic Syndromes; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; RNA, Messenger; Spindle Apparatus; Sulfones
PubMed: 25580850
DOI: 10.1111/cas.12605 -
Scientific Reports Dec 2014Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS...
Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS has not been thoroughly characterized. In this study, we found out that rigosertib induced apoptosis, blocked the cell cycle at the G2/M phase and subsequently inhibited the proliferation of CD34+ cells from MDS, while it minimally affected the normal CD34+ cells. Further studies showed that rigosertib acted via the activation of the P53 signaling pathway. Bioinformatics analysis based on gene expression profile and flow cytometry analysis revealed the abnormal activation of the Akt-PI3K, Jak-STAT and Wnt pathways in high-grade MDS, while the p38 MAPK, SAPK/JNK and P53 pathways were abnormally activated in low-grade MDS. Rigosertib could markedly inhibit the activation of the Akt-PI3K and Wnt pathways, whereas it activated the SAPK/JNK and P53 pathways in high-grade MDS. A receptor tyrosine kinase phosphorylation array demonstrated that rigosertib could increase the activation of RET and PDGFR-β while reducing the activation of Tie2 and VEGFR2 in MDS cells. Taken together, these data indicate that rigosertib is a selective and promising anti-tumor agent that could ameliorate multiple dysregulated signaling transduction pathways in high-grade MDS.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Cell Line; Female; G2 Phase Cell Cycle Checkpoints; Glycine; Humans; Janus Kinases; Male; Middle Aged; Myelodysplastic Syndromes; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; STAT Transcription Factors; Signal Transduction; Sulfones; Transcriptome; Tumor Suppressor Protein p53; p38 Mitogen-Activated Protein Kinases
PubMed: 25472472
DOI: 10.1038/srep07310 -
Clinical Cancer Research : An Official... Jun 2019Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic...
PURPOSE
Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC and .
RESULTS
ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib.
CONCLUSIONS
These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Proteins; Epidermolysis Bullosa Dystrophica; Gene Knockdown Techniques; Genes, Recessive; Glycine; Humans; Keratinocytes; Molecular Targeted Therapy; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Messenger; RNA, Small Interfering; Skin Neoplasms; Sulfones; Polo-Like Kinase 1
PubMed: 30846478
DOI: 10.1158/1078-0432.CCR-18-2661 -
International Journal of Radiation... Apr 2014To compare rigosertib versus cisplatin as an effective radiosensitizing agent for cervical malignancies. (Comparative Study)
Comparative Study
PURPOSE
To compare rigosertib versus cisplatin as an effective radiosensitizing agent for cervical malignancies.
METHODS AND MATERIALS
Rigosertib and cisplatin were tested in cervical cancer cell lines, HeLa and C33A. A 24-hour incubation with rigosertib and cisplatin, before irradiation (2-8 Gy), was used for clonogenic survival assays. Cell cycle analysis (propidium iodide staining) and DNA damage (γ-H2AX expression) were evaluated by fluorescence-activated cell sorter cytometry. Rigosertib was also tested in vivo in tumor growth experiments on cervical cancer xenografts.
RESULTS
Rigosertib was demonstrated to induce a G2/M block in cancer cells. Survival curve comparison revealed a dose modification factor, as index of radiosensitization effect, of 1.1-1.3 for cisplatin and 1.4-2.2 for rigosertib. With 6-Gy irradiation, an increase in DNA damage of 15%-25% was achieved in both HeLa and C33A cells with cisplatin pretreatment, and a 71-108% increase with rigosertib pretreatment. In vivo tumor growth studies demonstrated higher performance of rigosertib when compared with cisplatin, with 53% longer tumor growth delay.
CONCLUSIONS
Rigosertib was more effective than cisplatin when combined with radiation and caused minimal toxicity. These data support the need for clinical trials with rigosertib in combination therapy for patients with cervical carcinoma.
Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Separation; Cell Survival; Chemoradiotherapy; Cisplatin; DNA Damage; DNA Repair; Dose-Response Relationship, Radiation; Female; Flow Cytometry; Glycine; HeLa Cells; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Mitosis; Neoplasm Transplantation; Radiation-Sensitizing Agents; Sulfones; Time Factors; Uterine Cervical Neoplasms
PubMed: 24529717
DOI: 10.1016/j.ijrobp.2013.12.051 -
British Journal of Haematology Aug 2013The multi-kinase inhibitor rigosertib (ON 01910.Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to...
The multi-kinase inhibitor rigosertib (ON 01910.Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to determine the pharmacokinetic profile, maximum-tolerated dose (MTD), safety, and clinical activity of an oral formulation of rigosertib in patients with myelodysplastic syndromes (MDS). For pharmacokinetic studies, patients received rigosertib in single escalating weekly doses. To determine the MTD, patient cohorts received escalating doses of rigosertib twice daily for 14 d of a 21-d cycle. Overall, 37 patients were treated. Rigosertib exposure increased with escalating oral doses. Mean absolute oral bioavailability ranged from 13·9% (fed) to 34·8% (fasting) in 12 patients treated at the 560 mg b.i.d. dose level. Dose-limiting toxicity (grade 3 dysuria and shortness of breath) occurred at the 700 mg b.i.d. dose. Five patients experienced grade 3 non-haematological toxicity, including symptoms of urothelial inflammation, hypotension and syncope, fatigue and abdominal pain. Encouraging signs of clinical activity included two bone marrow complete remissions in refractory anaemia with excess blasts type 1 patients previously treated with azacitidine. In addition, four patients each achieved transfusion independence and haematological improvements. In conclusion, oral rigosertib is bioavailable and well tolerated, and has clinical activity in patients with MDS.
Topics: Administration, Oral; Aged; Aged, 80 and over; Biological Availability; Capsules; Disease Progression; Dose-Response Relationship, Drug; Dyspnea; Female; Food-Drug Interactions; Gastrointestinal Diseases; Glycine; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Protein Kinase Inhibitors; Remission Induction; Sulfones; Treatment Outcome; Urologic Diseases
PubMed: 23789936
DOI: 10.1111/bjh.12436 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Oct 2017To investigate the effects of rigosertib on the apoptosis, proliferation and cell cycle of HEL and K562 cells.
OBJECTIVE
To investigate the effects of rigosertib on the apoptosis, proliferation and cell cycle of HEL and K562 cells.
METHODS
The HEL and K562 cells were treated with different concentration of rigosertib at different time points, the cell apoptosis, proliferation and cycle were determined by using flow cytometry with Annexin V/PI double staining, WST-1 method and 7-AAD assay, respectively. Intracellular signaling proteins were detected by flow cytometry (FCM).
RESULTS
Rigosertib induced obvious apoptosis in HEL and K562 cells, and the apoptotic effect was both time-dependent and dose-dependent manner (P<0.05). The low dose of rigosertib inhibited obviously the proliferation of HEL and K562 cells after treatment from 6 to 54 h, Rigosertib arrested HEL and K562 cells into G/M phase. In addition, Rigosertib obviously increased the expression of apoptosis-related proteins such as cleaved caspase 3 and PARP, and reduced the proliferation-related proteins such as BCL-2 and Cyclin D1. Rigosetib inhibited the activation of AKT-GSK signaling through decreasing the expression of AKT, pAKT(Ser473) and GSK-3α/β (S21/9).
CONCLUSION
Rigosertib inhibites proliferation, induces apoptosis and cell cycle arrest in G/M phase of HEL and K562 cells. This agent may have potential application prospect in leukemia therapy.
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Glycine; Humans; K562 Cells; Leukemia, Erythroblastic, Acute; Sulfones
PubMed: 29070108
DOI: 10.7534/j.issn.1009-2137.2017.05.014