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1.
Med Oncol ; 40(11): 331, 2023 Oct 14.
Article in English | MEDLINE | ID: mdl-37838642

ABSTRACT

The most common primary brain malignancy, glioblastoma multiforme, is tremendously resistant to conventional treatments due to its potency for metastasis to surrounding brain tissue. Temozolomide is a chemotherapeutic agent that currently is administrated during the treatment procedure. Studies have attempted to investigate new agents with higher effectiveness and fewer side effects. Combretastatin A-4 (CA-4), a natural compound derived from Combretum caffrum, has been recently considered for its potent antitumor activities in a wide variety of preclinical solid tumor models. Our findings have shown that CA-4 exerts potent anti-proliferative and apoptotic effects on glioma cells, and ROS generation may be involved in these cellular events. CA-4 has imposed G2 arrest in U-87 cells. We also observed that CA-4 significantly reduced the migration and invasion capability of U-87 cells. Furthermore, the gene expression and enzyme activity of MMP-2 and MMP-9 were significantly inhibited in the presence of CA-4. We also observed a considerable decrease in PI3K and Akt protein expression following treatment with CA-4. In conclusion, our findings showed significant apoptogenic and anti-metastatic effects of CA-4 on glioma cells and also suggested that the PI3K/Akt/MMP-2/-9 and also ROS pathway might play roles in these cellular events.


Subject(s)
Brain Neoplasms , Glioma , Humans , Matrix Metalloproteinase 2/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Phosphatidylinositol 3-Kinases/metabolism , Reactive Oxygen Species , Cell Proliferation , Glioma/pathology , Apoptosis , Brain Neoplasms/pathology , Cell Line, Tumor
2.
Int J Pharm ; 613: 121396, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-34942328

ABSTRACT

Combretastatin A4 (CA4), a vascular disrupting agent has been recently proposed as an anticancer agent. However, its low water solubility and low bioavailability limited its clinical efficacy. Overcomingthis issue requires developing new delivery strategies to enhance its anticancer effects. Here, we prepared various PEGylated liposomal formulations containing CA4 composed of different molar ratios of HSPC/DSPE-mPEG2000/Cholesterol/CA4 (F1: 80:5:10:5; F2: 75:5:15:5; F3: 70:5:20:5; F4: 60:5:30:5 and F5: 50:5:40:5) by the thin-film hydration method plus sonication and extrusion. All formulations had a particle diameter of 100-150 nm, a monomodal distribution with low polydispersity index and a negative zeta potential. Among the formulations only F1, F2, and F3 showed a high CA4 encapsulation efficiency; so their anticancer effects on triple-negative breast cancer (TNBC) were investigated in vitro and in vivo. The release study showed that F3 liposomes had significantly lower CA4 release compared to the F1 and F2 liposomes in different pH of 5.5, 6.5, and 7.4. We found that, CA4-loaded liposomes effectively inhibited both proliferation and migration of 4T1 and MDA-MB-231 TNBC cell lines by inducing cell cycle arrest at the G2/M phase and decreasing MMP-2 and MMP-9 expression and activity. In vivo studies revealed that F3 liposomes were highly accumulated at the tumor site and more effectively delayed tumor growth andprolonged the overall survival than other groups in 4T1 breast tumor-bearing mice. Taken together, encapsulation of CA4 in PEGylated F3 liposomes enhances its anti-tumor activity and may be serve as a promising approach for TNBC treatment and merits further investigation.


Subject(s)
Stilbenes , Triple Negative Breast Neoplasms , Animals , Humans , Liposomes , Mice , Polyethylene Glycols , Triple Negative Breast Neoplasms/drug therapy
3.
Curr Med Chem ; 28(2): 377-400, 2021.
Article in English | MEDLINE | ID: mdl-32000638

ABSTRACT

In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.


Subject(s)
Brain Neoplasms , Glioblastoma , Apoptosis , Biological Products/pharmacology , Biological Products/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Humans , Nitric Oxide , Signal Transduction
4.
Pharmacol Rep ; 72(2): 285-295, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32152926

ABSTRACT

BACKGROUND: Glioblastoma multiforme (GBM), as the broadest cerebrum tumor, is resistant to current medical interventions, particularly chemo/radiation. Hence, it necessitates further therapeutic options that could enhance the efficacy of existing modalities. METHODS: A comprehensive and systematic review of literature on the NF-κB signaling pathway-contributed in the pathogenesis of GBM with a focus on natural products was carried out. RESULTS: Several examinations have shown that nuclear factor (NF)-κB is participated in apoptosis, cellular proliferation, angiogenesis, metastasis, invasion, and many other processes implicated in GBM pathobiology. Recent studies have provided that NF-κB regulation is the primary pharmacological target for GBM therapy. Specific natural products are involved in several signaling pathways implicated in tumor growth and apoptosis of GBM cells. CONCLUSION: In the current review, we elaborate on the role of NF-κB as a promising target in GBM and discuss some natural products affecting the NF-κB signaling pathway.


Subject(s)
Antineoplastic Agents/therapeutic use , Biological Products/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , NF-kappa B/antagonists & inhibitors , Apoptosis/drug effects , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Humans , Molecular Targeted Therapy , Signal Transduction
5.
Drug Res (Stuttg) ; 69(12): 665-670, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31499542

ABSTRACT

Glioblastoma multiforme (GBM) is the fatal type of astrocytic tumors with a survival rate of 12 months. The present study, for the first time, evaluated the cytotoxic impacts of Ferula latisecta (F. latisecta) hydroalcoholic extract on U87 GBM cell line. The MTT assay measured the cellular toxicity following 24- and 48 h treatment with various doses of F. latisecta (0-800 µg/mL). Apoptosis was evaluated by an Annexin V/propidium iodide (PI) staining 24 h after treatment by F. latisecta. Moreover, to determine the cellular metastasis of U87 cells, we used a gelatin zymography assay (matrix metalloproteinase [MMP]-2/-9 enzymatic activity). The outcomes showed that F. latisecta mitigated the viability of U87 cells in a concentration- and time-dependent manner with IC50 values of 145.3 and 192.3 µg/mL obtained for 24- and 48 h treatments, respectively. F. latisecta induced apoptosis in a concentration-dependent manner after 24 h. Also, MMP-9 activity was significantly decreased following 24 h after treatment concentration-dependently with no change in MMP-2 enzymatic activity. This study showed that F. latisecta induced cytotoxicity and apoptosis, and mitigated metastasis of U87 GBM cells. Hence, F. latisecta could be beneficial as a promising natural herb against GBM after further studies.


Subject(s)
Antineoplastic Agents/pharmacology , Ferula/chemistry , Glioma/drug therapy , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Glioblastoma/drug therapy , Glioma/metabolism , Humans , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism
6.
Res Pharm Sci ; 13(4): 343-352, 2018 Aug.
Article in English | MEDLINE | ID: mdl-30065767

ABSTRACT

The role of angiogenesis in tumor progression and metastasis formation has been well recognized. Recent studies have reported that Trigonella foenum-graecum L. (fenugreek) seed extracts have potential anticancer properties. The current study was planned to investigate the anti-angiogenic activity of hydroalcoholic extract of fenugreek (HAEF) in vitro and in vivo. Effect of HAEF (50-3000 µg/mL) and thalidomide (200-3000 µmol/L), as a positive control, on the viability of human umbilical vein endothelial cells (HUVECs) and 3T3 fibroblast cells was assessed by thiazolyl blue tetrazolium bromide (MTT) assay. Effect of HAEF on vessel-like tube formation by HUVECs was examined in the matrigel-based assay. Furthermore, the chick chorioallantoic membrane (CAM) was used as in vivo model to study the anti-angiogenic effect of HAEF. HAEF, similar to thalidomide, significantly inhibited the viability of HUVECs and 3T3 cells dose-dependently after 24 h. Moreover, both HAEF and thalidomide significantly reduced tube formation by HUVECs in cell culture condition. In CAM model, HAEF and thalidomide caused a significant decline in the number of neovascular points and in the amount of grades 1 and 2 vessels. These findings revealed that fenugreek has cytotoxic and anti-angiogenic effects in vitro and in vivo. Therefore, this medicinal plant can be subjected to further investigations as antitumor agents.

7.
J Cell Physiol ; 233(6): 4783-4790, 2018 06.
Article in English | MEDLINE | ID: mdl-29165795

ABSTRACT

Mammalian target of rapamycin (mTOR) signaling pathway controls cell energy metabolism. There is an interplay between mTOR and proinflammatory signaling pathways, supporting the role of the pathway in the pathogenesis of inflammatory diseases. Inhibition of mTOR signaling using specific pharmacological inhibitors could offer therapeutic promise in several inflammatory-associated diseases. In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis, and rheumatoid arthritis for a better understanding and hence a better management of these diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Inflammation Mediators/antagonists & inhibitors , Inflammation/drug therapy , Protein Kinase Inhibitors/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/enzymology , Arthritis, Rheumatoid/immunology , Atherosclerosis/drug therapy , Atherosclerosis/enzymology , Atherosclerosis/immunology , Humans , Inflammation/enzymology , Inflammation/immunology , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/immunology , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/enzymology , Neurodegenerative Diseases/immunology , Sepsis/drug therapy , Sepsis/enzymology , Sepsis/immunology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism
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