Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma

Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their use in pediatric brain cancers is lacking. Here we investigated the potential role for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in medulloblastoma and ependymoma. Dose-dependent cytotoxicity of medulloblastoma and ependymoma cells was induced by THC and CBD in vitro, and a synergistic reduction in viability was observed when both drugs were combined. Mechanistically, cannabinoids induced cell cycle arrest, in part by the production of reactive oxygen species, autophagy, and apoptosis; however, this did not translate to increased survival in orthotopic transplant models despite being well tolerated. We also tested the combination of cannabinoids with the medulloblastoma drug cyclophosphamide, and despite some in vitro synergism, no survival advantage was observed in vivo. Consequently, clinical benefit from the use of cannabinoids in the treatment of high-grade medulloblastoma and ependymoma is expected to be limited. This study emphasizes the importance of preclinical models in validating therapeutic agent efficacy prior to clinical trials, ensuring that enrolled patients are afforded the most promising therapies available.

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Schisandrol A Suppresses Catabolic Factor Expression by Blocking NF-κB Signaling in Osteoarthritis

Pharmaceuticals ◽

10.3390/ph14030241 ◽

2021 ◽

Vol 14 (3) ◽

pp. 241

Author(s):

Seong Jae Han ◽

Jimoon Jun ◽

Seong-il Eyun ◽

Choong-Gu Lee ◽

Jimin Jeon ◽

...

Keyword(s):

Therapeutic Agent ◽

Cartilage Destruction ◽

Dependent Manner ◽

Oral Gavage ◽

Osteoarthritic Cartilage ◽

Surgical Model ◽

Dose Dependent ◽

Cox2 Expression

Schisandrol A possesses pharmacological properties and is used to treat various diseases; however, its effects on osteoarthritis (OA) progression remain unclear. Here, we investigated Schisandrol A as a potential therapeutic agent for OA. In vitro, Schisandrol A effects were confirmed based on the levels of expression of catabolic factors (MMPs, ADAMTS5, and Cox2) induced by IL-1β or Schisandrol A treatment in chondrocytes. In vivo, experimental OA in mice was induced using a destabilized medial meniscus (DMM) surgical model or oral gavage of Schisandrol A in a dose-dependent manner, and demonstrated using histological analysis. In vitro and in vivo analyses demonstrated that Schisandrol A inhibition attenuated osteoarthritic cartilage destruction via the regulation of Mmp3, Mmp13, Adamts5, and Cox2 expression. In the NF-κB signaling pathway, Schisandrol A suppressed the degradation of IκB and the phosphorylation of p65 induced by IL-1β. Overall, and Schisandrol A reduced the expression of catabolic factors by blocking NF-κB signaling and prevented cartilage destruction. Therefore, Schisandrol A attenuated OA progression, and can be used to develop novel OA drug therapies.

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A Hopeful Natural Product, Pristimerin, Induces Apoptosis, Cell Cycle Arrest, and Autophagy in Esophageal Cancer Cells

Analytical Cellular Pathology ◽

10.1155/2019/6127169 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Peng Huang ◽

Li-Ying Sun ◽

Yan-Qiao Zhang

Keyword(s):

Esophageal Cancer ◽

Therapeutic Agent ◽

Quinone Methide ◽

Cycle Arrest ◽

Digestive Diseases ◽

Cancer Tumor ◽

Esophageal Cancer Cells

Esophageal cancer is one of the most common malignant digestive diseases worldwide. Although many approaches have been established for the treatment of esophageal cancer, the survival outcome has not improved. Pristimerin is a quinone methide triterpenoid with anticancer, antiangiogenic, anti-inflammatory, and antiprotozoal activities. However, the role of pristimerin in cancers such as esophageal cancer is unclear. In this study, we investigated the role and mechanisms of action of pristimerin in esophageal cancer. First, we found that pristimerin can induce apoptosis in esophageal cancer in vivo and in vitro. CCK-8 and clonogenic assays showed that pristimerin decreased the growth of Eca109 cells. In addition, we found that pristimerin decreased the protein expression of CDK2, CDK4, cyclin E, and BCL-2 and increased the expression of CDKN1B. Meanwhile, pristimerin elevated the ratio of LC3-II/LC3-I. Otherwise, downregulation of CDKN1B can reduce the esophageal cancer tumor growth induced by pristimerin. In conclusion, our findings revealed an important role of pristimerin in esophageal cancer and suggest that pristimerin might be a potential therapeutic agent for this cancer.

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Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook

Cancers ◽

10.3390/cancers13102317 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2317

Author(s):

Kevin Zhai ◽

Manaal Siddiqui ◽

Basma Abdellatif ◽

Alena Liskova ◽

Peter Kubatka ◽

...

Keyword(s):

Survival Rates ◽

Chemotherapeutic Agents ◽

Surgical Interventions ◽

Beneficial Effects ◽

Natural Substances ◽

Cycle Arrest ◽

Brain Barrier Permeability ◽

The Central Nervous System

Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances—an integral component of the lifestyle medicine approach to chronic diseases—are examined as potential chemotherapeutic agents. These heterogenous substances exert anti-GBM effects by upregulating apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural substances’ efficacy in GBM is constrained by their bioavailability and blood–brain barrier permeability; various chemical formulations are proposed to improve their pharmacological properties. Many of the reviewed substances are available as over-the-counter dietary supplements, underscoring their viability as lifestyle interventions. However, clinical trials remain necessary to substantiate the in vitro and in vivo properties of natural substances.

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Honokiol, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells

Pharmacological Research ◽

10.1016/j.phrs.2016.11.038 ◽

2017 ◽

Vol 115 ◽

pp. 288-298 ◽

Cited By ~ 28

Author(s):

Chieh-Hsiang Lu ◽

Shu-Hsin Chen ◽

Yi-Sheng Chang ◽

Yi-Wen Liu ◽

Jin-Yi Wu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Thyroid Cancer ◽

Therapeutic Agent ◽

Human Thyroid ◽

Cycle Arrest ◽

Thyroid Cancer Cells ◽

Program Cell Death

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Targeting Dopamine Receptor D2 by Imipridone Suppresses Uterine Serous Cancer Malignant Phenotype

Cancers ◽

10.3390/cancers12092436 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2436 ◽

Cited By ~ 1

Author(s):

Wen Hu ◽

Li Zhang ◽

Sammy Ferri-Borgogno ◽

Suet-Ying Kwan ◽

Kelsey E. Lewis ◽

...

Keyword(s):

Therapeutic Agent ◽

Survival Rates ◽

Metabolic Reprogramming ◽

Recurrence Rates ◽

Poor Overall Survival ◽

Orally Bioavailable ◽

Induced Apoptosis ◽

Promising Therapeutic Agent

Uterine serous cancer (USC) is an aggressive subtype of endometrial cancer, with poor survival and high recurrence rates. The development of novel and effective therapies specific to USC would aid in its management. However, few studies have focused solely on this rare subtype. The current study demonstrated that the orally bioavailable, investigational new drug and novel imipridone ONC206 suppressed USC cell proliferation and induced apoptosis both in vitro and in vivo. Disruption of the DRD2-mediated p38MAPK/ERK/PGC-1α network by ONC206 led to metabolic reprogramming and suppression of both glycolysis and oxidative phosphorylation. ONC206 also synergized with paclitaxel in reducing USC cell viability. In addition, DRD2 overexpression correlated with poor overall survival in patients. This study provides the first evidence that ONC206 induced metabolic reprogramming in USC cells and is a promising therapeutic agent for USC treatment. These findings support further development of ONC206 as a promising therapeutic agent and improves survival rates in patients with USC.

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Surface functionalized drug loaded spinel ferrite MFe2O4 (M = Fe, Co, Ni, Zn) nanoparticles, their biocompatibility and cytotoxicity in vitro: A comparison

10.3762/bxiv.2021.56.v1 ◽

2021 ◽

Author(s):

Sadaf Mushtaq ◽

Khuram Shahzad ◽

Tariq Saeed ◽

Anwar Ul-Hamid ◽

Bilal Haider Abbasi ◽

...

Keyword(s):

Cell Lines ◽

Anticancer Drugs ◽

Spinel Ferrite ◽

Cycle Arrest ◽

Elevated Expression ◽

Tumor Specificity ◽

Dose Dependent ◽

3D Spheroids

In this study, polymer coated biocompatible MFe2O4 (M=Fe, Co, Ni, Zn) NPs were developed as carriers of anticancer drugs. Synthesized NPs were characterized via XRD, TEM, EDS and PPMS which confirmed formation of pure cubic structures (14 - 22 nm) with magnetic properties. The anticancer drugs: doxorubicin (DOX) and methotrexate (MTX) loaded NPs exhibited tumor specificity with significantly higher (p<0.005) drug release in acidic pH 5.5. NPs were highly colloidal in deionized water, PBS and SBB (-35 to -26 mV). They showed elevated and dose dependent cytotoxicity in vitro compared to free drug controls. IC50 values ranged from 0.81 - 3.97 mg/ml against HepG2 and HT144 cells. On the contrary, IC50 values for normal lymphocytes were 10 to 35 times higher (18.35 - 43.04 mg/ml). CFO and ZFO nanocarriers were highly genotoxic (p<0.05) against both cancer cell lines. NPs caused cytotoxicity via oxidative stress, causing DNA damage and activation of p53 (significantly elevated expression, p<0.005) mediated cell cycle arrest (majorly G1 and G2/M arrest) and apoptosis. When tested for cytotoxicity in 3D spheroids, they showed significant (p<0.05) reduction in spheroid diameter and upto 74 ± 8.9% cell death after 2 weeks. In addition, they also inhibited MDR pump activity in both cell lines suggesting their potential to combat multidrug resistance in cancers. Among tested MFe2O4 NPs, CFO nanocarriers were most favorable for targeted cancer therapy due to excellent magnetic, colloidal, cytotoxic, and biocompatible aspects. However, detailed investigations of molecular pathways involved, in vivo cytotoxicity and magnetic field assisted experiments are needed to fully exploit them in therapeutic domains.

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Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653872 ◽

1995 ◽

Vol 73 (05) ◽

pp. 805-811 ◽

Cited By ~ 12

Author(s):

Yasuo Takahashi ◽

Yoshitaka Hosaka ◽

Hiromi Niina ◽

Katsuaki Nagasawa ◽

Masaaki Naotsuka ◽

...

Keyword(s):

Human Urine ◽

Specific Activity ◽

Anticoagulant Activity ◽

Rabbit Lung ◽

Soluble Thrombomodulin ◽

Molecular Weights ◽

Dose Dependent Fashion ◽

Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

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Cruciferous Vegetables as Antioxidative, Chemopreventive and Antineoplasic Functional Foods: Preclinical and Clinical Evidences of Sulforaphane Against Prostate Cancers

Current Pharmaceutical Design ◽

10.2174/1381612825666190116124233 ◽

2019 ◽

Vol 24 (40) ◽

pp. 4779-4793 ◽

Cited By ~ 4

Author(s):

Paulo M.P. Ferreira ◽

Lays A.R.L. Rodrigues ◽

Lunna Paula de Alencar Carnib ◽

Paulo Víctor de Lima Sousa ◽

Luis Michel Nolasco Lugo ◽

...

Keyword(s):

Histone Deacetylases ◽

Cruciferous Vegetables ◽

Tumor Cell Death ◽

Antitumor Effects ◽

Antiapoptotic Proteins ◽

Cycle Arrest ◽

Government Documents ◽

Prostate Cancers

Background: Sulforaphane (SF, 1-isothiocyanato-4-(methyl-sulfinyl)-butane) is found in broccoli, cabbage and cauliflower. Methods: we performed a critical review on the antioxidative, chemopreventive and antitumor effects of SF from cruciferous vegetables against prostate cancers and molecular pathways. For a complete and reliable review, primary and secondary resources were used, including original and review articles, books and government documents published until March 2018. Articles that are in duplicity and disconnected are not considered for review. SF is derived from glucoraphanin (4-methyl-sulfinyl-butyl-glucosinate), being one of the most commonly found isothiocyanates in vegetables from Brassica spp., especially in broccoli samples. In vitro studies indicate that SF induces apoptosis in a dependent or non-dependent method of androgens by transcription of tumor suppressor genes, oxidation response and higher expression of phase II enzymes in prostate cancer cells. Sulforaphane also decreases transcription of the nuclear factor kB and antiapoptotic proteins, expression of cyclin D2 and survivin and DNA synthesis, increases Nrf2 gene activity, interferes with genome compacting by inhibition of histone deacetylases and disrupts Hsp90 complexes, which cause cell cycle arrest, mitosis interruption, activation of caspases and mitochondria depolarization. Conclusion: SF and cruciferous vegetables play antioxidative and chemopreventive role, delaying or blocking in vivo carcinogenesis, causing biochemical and epigenetic changes, preventing, delaying, or reversing preneoplastic or advanced prostate lesions, and frequently activating tumor cell death by intrinsic methods of apoptosis. These outcomes encourage the consumption of Brassica specimens, which could be easily achieved by the incorporation of food and vegetables rich in cruciferous isothiocyanates in the diet.

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Pleiotropic Effect of Mahanine and Girinimbine Analogs: Anticancer Mechanism and its Therapeutic Versatility

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180830151720 ◽

2019 ◽

Vol 18 (14) ◽

pp. 1983-1990 ◽

Cited By ~ 2

Author(s):

V. Lenin Maruthanila ◽

Ramakrishnan Elancheran ◽

Ajaikumar B. Kunnumakkar ◽

Senthamaraikannan Kabilan ◽

Jibon Kotoky

Keyword(s):

Biological Effects ◽

Pleiotropic Effect ◽

In Vivo Evaluation ◽

Chemopreventive Agents ◽

Cycle Arrest ◽

Wide Range ◽

Anticancer Mechanism ◽

Metastasis Development

Emerging evidence present credible support in favour of the potential role of mahanine and girinimbine. Non-toxic herbal carbazole alkaloids occur in the edible part of Murraya koenigii, Micromelum minutum, M. zeylanicum, and M. euchrestiolia. Mahanine and girinimbine are the major potent compounds from these species. In fact, they interfered with tumour expansion and metastasis development through down-regulation of apoptotic and antiapoptotic protein, also involved in the stimulation of cell cycle arrest. Consequently, these compounds were well proven for the in-vitro and in vivo evaluation that could be developed as novel agents either alone or as an adjuvant to conventional therapeutics. Therefore, mahanine and girinimbine analogs have the potential to be the promising chemopreventive agents for the tumour recurrence and the treatment of human malignancies. In this review, an updated wide-range of pleiotropic anticancer and biological effects induction by mahanine and girinimbine against cancer cells were deeply summarized.

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A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666181207102037 ◽

2019 ◽

Vol 19 (3) ◽

pp. 365-374 ◽

Cited By ~ 1

Author(s):

Yang Liu ◽

Jingyin Zhang ◽

Shuyun Feng ◽

Tingli Zhao ◽

Zhengzheng Li ◽

...

Keyword(s):

Cell Cycle ◽

Flow Cytometry ◽

Dna Damage ◽

Cyclin D ◽

Dna Relaxation ◽

Cycle Arrest ◽

H460 Cell ◽

H1975 Cell

Objective: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. Background: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. Methods: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. Results: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. Conclusion: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

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