ONC201 Depletes Cancer Stem Cells in Refractory Cancer Patient Samples

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5219-5219 ◽  
Author(s):  
Varun Vijay Prabhu ◽  
Jo Ishizawa ◽  
Dan Zhao ◽  
Joshua E. Allen ◽  
Tracy T. Batchelor ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Hematological Malignancies ◽  
Therapeutic Potential ◽  
Tumor Initiation ◽  
Preclinical Models ◽  
Antitumor Effects ◽  
Equity Ownership ◽  
Sw480 Cells

Abstract ONC201 is a small molecule that is being developed as a novel anticancer drug based on its strong anti-tumor efficacy in preclinical models of advanced cancer (Allen et al, Sci Transl Med, 2013). ONC201 has demonstrated strong antitumor effects in vitro and in vivo in a variety of solid and liquid tumors. Cancer stem cells (CSCs) are known to be responsible for tumor propagation and maintenance as well as driving resistance to many cancer therapies. Based on the potent efficacy of ONC201 in preclinical models, we investigated the therapeutic impact of ONC201 on CSCs to rationalize its strong antitumor effects and realize the extent of its therapeutic potential. In primary refractory AML patient samples, ONC201 induced very high levels of apoptosis in leukemia stem/progenitor cells (CD45 dim+/ CD34+/ CD38-) to a similar extent observed in the bulk tumor population. In addition to this effect in hematological malignancies, ONC201 has also exhibited strong anti-CSC efficacy in solid tumors such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). ONC201 eradicated CSC-enriched 3-dimensional neurosphere culture models of primary GBM samples, including newly diagnosed and recurrent samples. ONC201 potently inhibited in vitro cell proliferation of all 5 neurosphere lines tested, with IC50 values of 433 nM (MGG18), 1.46 µM (MGG4), 1.09 µM (MGG8), 3.97 µM (MGG67R) and 688 nM (MGG152). In CRC, ONC201 significantly depleted CD133, CD44 and Aldefluor positive CSCs in HCT116, DLD1 and SW480 cells. ONC201 significantly inhibited colonosphere formation of unsorted and sorted Aldefluor positive 5-Fluorouracil-resistant DLD1 and SW480 cells. ONC201 significantly reduced tumor growth of CSC-initiated tumors and prevented the passage of these tumors. CD44 and CD133 expression was reduced in ONC201-treated tumors. ONC201-treatment decreased tumor initiation relative to 5-Fluorouracil treatment in a limiting dilution tumor initiation assay. The ONC201-mediated anti-CSC effect was significantly blocked by the TRAIL sequestering antibody RIK-2. ONC201-mediated TRAIL-induction was also observed in CSC-initiated tumors. ONC201 inhibited Akt and ERK leading to Foxo3a activation and surface TRAIL induction in sorted CSCs and non-CSCs. Overexpression of myristoylated Akt significantly reduced the induction of surface TRAIL by ONC201 in CSCs and prevented ONC201-mediated depletion of CSCs and colonosphere inhibition. In conclusion, ONC201 cytotoxicity is extended to CSCs in hematological and solid malignancies as well as the bulk tumor population. The ability of ONC201 to deplete CSCs suggests the clinical potential for ONC201 to reduce the incidence of disease relapse, which is frequently a fatal event in hematological malignancies, in addition to its immediately apparent antitumor effects. Disclosures Allen: Oncoceutics: Employment, Equity Ownership, Patents & Royalties. Andreeff:Oncoceutics: Membership on an entity's Board of Directors or advisory committees. El-Deiry:Oncoceutics: Equity Ownership, Patents & Royalties.

scholarly journals Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1–JNK axis

2020 ◽  
Vol 295 (52) ◽  
pp. 18328-18342
Author(s):  
Shuhei Suzuki ◽  
Masashi Okada ◽  
Tomomi Sanomachi ◽  
Keita Togashi ◽  
Shizuka Seino ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Residual Disease ◽  
Xenograft Model ◽  
Postoperative Recurrence ◽  
Receptor Activation ◽  
Tumor Formation ◽  
Tumor Initiation

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

scholarly journals The Efficacy of PI3Kγ and EGFR Inhibitors on the Suppression of the Characteristics of Cancer Stem Cells

2021 ◽  
Author(s):  
Yanning Xu ◽  
Said M. Afify ◽  
Juan Du ◽  
Bingbing Liu ◽  
Qing Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Recurrence ◽  
Significant Inhibition ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Self Renewal ◽  
Egfr Signaling Pathway

Abstract Cancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3Kγ inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3Kγ, might be a promising therapeutic strategy against CSCs defeating cancer in the near future

scholarly journals Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 560 ◽  
Author(s):  
Julie Giraud ◽  
Damien Bouriez ◽  
Lornella Seeneevassen ◽  
Benoit Rousseau ◽  
Elodie Sifré ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Mouse Models ◽  
Distant Metastases ◽  
Preclinical Models ◽  
Immunocompromised Mice ◽  
Orthotopic Xenografts

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice; gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells’ phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies.

scholarly journals The efficacy of PI3Kγ and EGFR inhibitors on the suppression of the characteristics of cancer stem cells

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yanning Xu ◽  
Said M. Afify ◽  
Juan Du ◽  
Bingbing Liu ◽  
Ghmkin Hassan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Recurrence ◽  
Significant Inhibition ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Self Renewal ◽  
Egfr Signaling Pathway

AbstractCancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3Kγ inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3Kγ, might be a promising therapeutic strategy against CSCs defeating cancer in the near future.

Stem Cells Derived from Human Exfoliated Deciduous teeth [shed] in Neuronal Disorders: A Review

2020 ◽  
Vol 16 ◽  
Author(s):  
Minu Anoop ◽  
Indrani Datta
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Dental Pulp ◽  
Therapeutic Potential ◽  
Permanent Teeth ◽  
Deciduous Teeth ◽  
Proliferative Potential ◽  
Pulp Tissue ◽  
Human Exfoliated Deciduous Teeth

: Most conventional treatments for neurodegenerative diseases fail due to their focus on neuroprotection rather than neurorestoration. Stem cell‐based therapies are becoming a potential treatment option for neurodegenerative diseases as they can home in, engraft, differentiate and produce factors for CNS recovery. Stem cells derived from human dental pulp tissue differ from other sources of mesenchymal stem cells due to their embryonic neural crest origin and neurotrophic property. These include both dental pulp stem cells [DPSCs] from dental pulp tissues of human permanent teeth and stem cells from human exfoliated deciduous teeth [SHED]. SHED offer many advantages over other types of MSCs such as good proliferative potential, minimal invasive procurement, neuronal differentiation and neurotrophic capacity, and negligible ethical concerns. The therapeutic potential of SHED is attributed to the paracrine action of extracellularly released secreted factors, specifically the secretome, of which exosomes is a key component. SHED and its conditioned media can be effective in neurodegeneration through multiple mechanisms, including cell replacement, paracrine effects, angiogenesis, synaptogenesis, immunomodulation, and apoptosis inhibition, and SHED exosomes offer an ideal refined bed-to-bench formulation in neurodegenerative disorders. However, in spite of these advantages, there are still some limitations of SHED exosome therapy, such as the effectiveness of long-term storage of SHED and their exosomes, the development of a robust GMP-grade manufacturing protocol, optimization of the route of administration, and evaluation of the efficacy and safety in humans. In this review, we have addressed the isolation, collection and properties of SHED along with its therapeutic potential on in vitro and in vivo neuronal disorder models as evident from the published literature.

scholarly journals STEM-26. SMALL MOLECULE DRUG CBL0137 INHIBITS THE FACT COMPLEX AND SENSITIZES GLIOBLASTOMA CANCER STEM CELLS TO RADIOTHERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii201-ii202
Author(s):  
Miranda Tallman ◽  
Abigail Zalenski ◽  
Amanda Deighen ◽  
Morgan Schrock ◽  
Sherry Mortach ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
High Rate ◽  
Orthotopic Model ◽  
In Vivo Models ◽  
Specific Cytotoxicity ◽  
Treatment Paradigm ◽  
Cancer Agent

Abstract Glioblastoma (GBM) is a malignant brain tumor with nearly universal recurrence. GBM cancer stem cells (CSCs), a subpopulation of radio- and chemo-resistant cancer cells capable of self-renewal, contribute to the high rate of recurrence. The anti-cancer agent, CBL0137, inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy using both in vitro and in vivo models. Treatment of CBL0137 combined with radiotherapy led to increased DNA damage in GBM patient specimens and failure to resolve the damage led to decreased cell viability. Using clonogenic assays, we confirmed that CBL0137 radiosensitized the CSCs. To validate that combination therapy impacted CSCs, we used an in vivo subcutaneous model and showed a decrease in the frequency of cancer stem cells present in tumors as well as decreased tumor volume. Using an orthotopic model of GBM, we confirmed that treatment with CBL0137 followed by radiotherapy led to significantly increased survival compared to either treatment alone. Radiotherapy remains a critical component of patient care for GBM, even though there exists a resistant subpopulation. Radio-sensitizing agents, including CBL0137, pose an exciting treatment paradigm to increase the efficacy of irradiation, especially by inclusively targeting CSCs.

scholarly journals Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells

2021 ◽  
Author(s):  
Zhigeng Zou ◽  
Wei Zheng ◽  
Hongjun Fan ◽  
Guodong Deng ◽  
Shih-Hsin Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Squamous Cell Carcinoma ◽  
Cancer Stem Cells ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
High Throughput Sequencing ◽  
Combined Treatment ◽  
Oesophageal Squamous Cell Carcinoma

Abstract Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

scholarly journals Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
HuiYa Li ◽  
DanQing Hu ◽  
Guilin Chen ◽  
DeDong Zheng ◽  
ShuMei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Paracrine Factors ◽  
Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

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