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

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2436 ◽  
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.

scholarly journals DCTPP1, an Oncogene Regulated by miR-378a-3p, Promotes Proliferation of Breast Cancer via DNA Repair Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Ming Niu ◽  
Ming Shan ◽  
Yang Liu ◽  
Yanni Song ◽  
Ji-guang Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Dna Repair ◽  
Survival Rates ◽  
The Other ◽  
Poor Survival ◽  
Induced Apoptosis ◽  
Cell Growth And Proliferation

Breast cancer (BRCA) is one of the most deadly cancers worldwide, with poor survival rates that could be due to its high proliferation. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is implicated in numerous diseases, including cancers. However, its role in BRCA is unclear. In this study, we used bioinformatic analyses of the ONCOMINE, UALCAN, and GEPIA databases to determine the expression pattern of DCTPP1 in BRCA. We found that elevated DCTPP1 levels correlate with poor BRCA prognosis. DCTPP1 silencing inhibited BRCA cell proliferation and induced apoptosis in vitro, as well as in vivo. Our data show that this tumorigenic effect depends on DNA repair signaling. Moreover, we found that DCTPP1 is directly modulated by miR-378a-3p, whose downregulation is linked to BRCA progression. Our results showed down-regulation of miR-378a-3p in BRCA. Upregulation of miR-378a-3p, on the other hand, can inhibit BRCA cell growth and proliferation. This study shows that reduced miR-378a-3p level enhances DCTPP1 expression in BRCA, which promotes proliferation by activating DNA repair signaling in BRCA.

scholarly journals Pharmacological Activity of Garcinia indica (Kokum): An Updated Review

2021 ◽  
Vol 14 (12) ◽  
pp. 1338
Author(s):  
Sung Ho Lim ◽  
Ho Seon Lee ◽  
Chang Hoon Lee ◽  
Chang-Ik Choi
Keyword(s):  
Traditional Medicine ◽  
Pharmacological Activity ◽  
Therapeutic Agent ◽  
Industrial Applications ◽  
Pharmacological Activities ◽  
Garcinia Indica ◽  
Hydroxycitric Acid ◽  
Promising Therapeutic Agent

Garcinia indica (commonly known as kokum), belonging to the Clusiaceae family (mangosteen family), is a tropical evergreen tree distributed in certain regions of India. It has been used in culinary and industrial applications for a variety of purposes, including acidulant in curries, pickles, health drinks, wine, and butter. In particular, G. indica has been used in traditional medicine to treat inflammation, dermatitis, and diarrhea, and to promote digestion. According to several studies, various phytochemicals such as garcinol, hydroxycitric acid (HCA), cyanidin-3-sambubioside, and cyanidin-3-glucoside were isolated from G. indica, and their pharmacological activities were published. This review highlights recent updates on the various pharmacological activities of G. indica. These studies reported that G. indica has antioxidant, anti-obesity, anti-arthritic, anti-inflammatory, antibacterial, hepatoprotective, cardioprotective, antidepressant and anxiolytic effects both in vitro and in vivo. These findings, together with previously published reports of pharmacological activity of various components isolated from G. indica, suggest its potential as a promising therapeutic agent to prevent various diseases.

scholarly journals A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Motoo Saito ◽  
Kohei Nishitani ◽  
Hanako O. Ikeda ◽  
Shigeo Yoshida ◽  
Sachiko Iwai ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Therapeutic Agent ◽  
Articular Chondrocytes ◽  
Cartilage Explants ◽  
Chondrocyte Death ◽  
Post Traumatic ◽  
Promising Therapeutic Agent

AbstractPost-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.

scholarly journals PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chengcheng Shi ◽  
Huapeng Zhang ◽  
Penglei Wang ◽  
Kai Wang ◽  
Denghui Xu ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Osteosarcoma Cell ◽  
Human Osteosarcoma ◽  
Bet Inhibitors ◽  
Oncogenic Protein ◽  
Bet Protein ◽  
Massive Apoptosis ◽  
Promising Therapeutic Agent

Abstract Targeting oncogenic proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer research. Bromodomain and extra-terminal (BET) family proteins are newly identified cancer-related epigenetic regulators, which have a role in the pathogenesis and progression of osteosarcoma. In this study, we investigated the in vitro and in vivo anti-osteosarcoma activity by targeting BET with a PROTAC molecule BETd-260. The results showed that BETd-260 completely depletes BET proteins and potently suppresses cell viability in MNNG/HOS, Saos-2, MG-63, and SJSA-1 osteosarcoma cell lines. Compared with BET inhibitors HJB-97 and JQ1, the activity of BETd-260 increased over 1000 times. Moreover, BETd-260 substantially inhibited the expression of anti-apoptotic Mcl-1, Bcl-xl while increased the expression of pro-apoptotic Noxa, which resulted in massive apoptosis in osteosarcoma cells within hours. In addition, pro-oncogenic protein c-Myc also was substantially inhibited by BETd-260 in the OS cells. Of note, BETd-260 induced degradation of BET proteins, triggered apoptosis in xenograft osteosarcoma tumor tissue, and profoundly inhibited the growth of cell-derived and patient-derived osteosarcoma xenografts in mice. Our findings indicate that BET PROTACs represent a promising therapeutic agent for human osteosarcoma.

In vivo efficacy of olorofim against systemic scedosporiosis and lomentosporiosis

2021 ◽  
Author(s):  
S. Seyedmousavi ◽  
Y. C. Chang ◽  
J. H. Youn ◽  
D. Law ◽  
M. Birch ◽  
...  
Keyword(s):  
Post Infection ◽  
Therapeutic Agent ◽  
Intraperitoneal Administration ◽  
Scedosporium Apiospermum ◽  
Pseudallescheria Boydii ◽  
Target Organs ◽  
Fungal Dna ◽  
Promising Therapeutic Agent

Clinically relevant members of the Scedosporium / Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro and the infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent olorofim (formerly F901318) against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide immunosuppressed CD-1 mice infected by Scedosporium apiospermum , Pseudallescheria boydii ( Scedosporium boydii ) and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days post infection, levels of serum (1-3)-β-d-glucan (BG), histopathology, and fungal burden of kidneys 3 days post infection. Olorofim therapy significantly improved survival compared to the untreated controls; 80%, 100% and 100% of treated mice survived infection by Scedosporium apiospermum , Pseudallescheria boydii , and Lomentospora prolificans, respectively while less than 20% of the control mice (PBS-treated) survived at 10 days post infection. In the olorofim-treated neutropenic CD-1 mice infected with all three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than controls. Furthermore, histopathology of kidneys revealed no or only few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, a devastating emerging fungal infection difficult to treat with currently available antifungals.

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

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 330
Author(s):  
Clara Andradas ◽  
Jacob Byrne ◽  
Mani Kuchibhotla ◽  
Mathew Ancliffe ◽  
Anya C. Jones ◽  
...  
Keyword(s):  
Multidisciplinary Approach ◽  
Potential Role ◽  
Therapeutic Agent ◽  
Survival Rates ◽  
Cycle Arrest ◽  
High Risk Disease ◽  
Dose Dependent ◽  
Pediatric Brain

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.

scholarly journals Zuo Jin Wan Reverses DDP Resistance in Gastric Cancer through ROCK/PTEN/PI3K Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Meng-Yao Sun ◽  
Jian Sun ◽  
Jie Tao ◽  
Yu-Xia Yuan ◽  
Zhen-Hua Ni ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chemotherapy Resistance ◽  
Underlying Mechanism ◽  
Pi3k Signaling ◽  
Gastric Cancer Cells ◽  
Poor Overall Survival ◽  
Mitochondrial Translocation ◽  
Induced Apoptosis

Gastric cancer (GC) is the third leading cause of cancer-related death. Chemotherapy resistance remains the major reason for GC treatment failure and poor overall survival of patients. Our previous studies have proved that Zuo Jin Wan (ZJW), a traditional Chinese medicine (TCM) formula, could significantly enhance the sensitivity of cisplatin (DDP)-resistant gastric cancer cells to DDP by inducing apoptosis via mitochondrial translocation of cofilin-1. However, the underlying mechanism remains poorly understood. This study aimed to evaluate the effects of ROCK/PTEN/PI3K on ZJW-induced apoptosis in vitro and in vivo. We found that ZJW could significantly activate the ROCK/PTEN pathway, inhibit PI3K/Akt, and promote the apoptosis of SGC-7901/DDP cells. Inhibition of ROCK obviously attenuated ZJW-induced apoptosis as well as cofilin-1 mitochondrial translocation, while inhibition of PI3K had the opposite effects. In vivo, combination treatment of DDP and ZJW (2000 mg/kg) significantly reduced tumor growth compared with DDP alone. Moreover, the combined administration of ZJW and DDP increased the expression of cleaved ROCK and p-PTEN while it decreased p-PI3K and p-cofilin-1, which was consistent with our in vitro results. These findings indicated that ZJW could effectively inhibit DDP resistance in GC by regulating ROCK/PTEN/PI3K signaling and provide a promising treatment strategy for gastric cancer.

scholarly journals Mitochondrial Genome Regulator TFAM Modulates Head and Neck Tumorigenesis Through Activation of Intracellular Metabolic Reprogramming and Oncogenic Effectors

2020 ◽  
Author(s):  
Yi-Ta Hsieh ◽  
Hsi-Feng Tu ◽  
Muh-Hwa Yang ◽  
Yi-Fen Chen ◽  
Chien-Ling Huang ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Head And Neck ◽  
Aerobic Glycolysis ◽  
Survival Rates ◽  
Cellular Level ◽  
Metabolic Reprogramming ◽  
Clinical Databases

Abstract Background: Mitochondrial defect is often observed in cancers while, in comparison with other metabolic cues, mitochondria mediated regulations in controlling tumorigenesis are less emphasized. Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory factor to control mitochondrial DNA (mtDNA) replication and packing; the role of TFAM in modulating carcinogenesis, however, is controversial. Current study therefore aims to define TFAM mediated regulations in head and neck cancer (HNC) development. Methods: Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical correlations of TFAM and its downstream Electron Transport Chain (ETC) associated factors in regulating HNC progression were also examined in HNC specimens and different clinical databasesResults: At the cellular level, it was demonstrated that shRNA mediated TFAM silencing resulted in an enhanced cell proliferation, both in vitro and in vivo; in contrast, TFAM overexpression suppressed cell growth. Moreover, TFAM loss also facilitated cell migration and chemodrug resistance. At the molecular basis, TFAM mediated phenotypic changes could be resulting from metabolic reprogramming by directing HNC metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater extracellular acidification in response to TFAM loss. Interestingly, it was also found that TFAM loss upregulated ERK1/2 and Akt-mTORC-S6 signaling activity, revealing a potential "mitochondrion-to-cytoplasm" retrograde regulatory cue in controlling HNC malignancy. Clinical impact of TFAM and its downstream targets was further examined in clinical HNC tissues while the results showed that TFAM expression and mtDNA copy numbers were significant dropped in HNC tissues compared with their normal counterparts. By using clinical databases, HNC subjects with higher TFAM expression and less genetic alteration(s) exhibited better survival rates. Conclusion: Collectively, Current study uncovered a tumor suppressing role of TFAM and mitochondrial genome in determining HNC oncogenicity. This TFAM mediated regualtions are through intracellular metabolic reprogramming and mitochondria-to-cytoplasm cross-talk to activate oncogenic signals.

scholarly journals The Protective Effect of Cordycepin on D-Galactosamine/Lipopolysaccharide-Induced Acute Liver Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jin Li ◽  
Liping Zhong ◽  
Haibo Zhu ◽  
Fengzhong Wang
Keyword(s):  
Protective Effect ◽  
Therapeutic Agent ◽  
Cytokine Production ◽  
Hepatocyte Apoptosis ◽  
Apoptosis And Necrosis ◽  
And Oxidative Stress ◽  
Lps Treatment ◽  
Promising Therapeutic Agent

As the major active ingredient ofCordyceps militaris, cordycepin (3′-deoxyadenosine) has been well documented to alleviate inflammation and oxidative stress both in vitro and in vivo. To explore the potential protective effect of cordycepin in fulminant hepatic failure, mice were pretreated with cordycepin for 3 weeks followed by D-galactosamine (GalN)/lipopolysaccharide (LPS) injection. Then we found cordycepin (200 mg/kg) administration elevated survival rate, improved liver function, and suppressed hepatocyte apoptosis and necrosis in mice with severe hepatic damage by GalN/LPS treatment. Further, cordycepin inhibited hepatic neutrophil and macrophage infiltration and prevented proinflammatory cytokine production possibly through suppressing TLR4 and NF-κB signaling transduction. The blockade of reactive oxygen species (ROS) and lipid peroxidation production by cordycepin was associated with the decrease of NAD(P)H oxidase (NOX) activity. Besides, cordycepin significantly prevented excessive autophagy induced by GalN/LPS in the liver. These data suggested that cordycepin could be a promising therapeutic agent for GalN/LPS-induced hepatotoxicity.

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