In Vitro Studies of Prednisolone Loaded PLGA Nanoparticles-Surface Functionalized With Folic Acid on Glioma and Macrophage Cell Lines

2020 ◽  
Vol 27 (3) ◽  
pp. 407-417
Author(s):  
Sriprasad Acharya ◽  
Joyceline Praveena ◽  
Bharath Raja Guru
Keyword(s):  
Folic Acid ◽  
Block Copolymer ◽  
Cell Lines ◽  
Targeted Delivery ◽  
Inhibitory Effect ◽  
Free Drug ◽  
Growth Inhibitory Effect ◽  
Folate Receptors ◽  
Growth Inhibitory ◽  
Anti Inflammatory

Background: Glucocorticoids are employed for their anti-inflammatory effects in treatingglioma, whose cells are known to overexpress the folate receptors. Some glucocorticoids haveshown inhibitory effects, but the efficacy of prednisolone when delivered via folate receptormediateduptake, has not been attempted. The study aimed to assess the efficacy of targeteddelivery of prednisolone on glioma cell lines like C6 and U87 via the folate receptors. Methods: Targeted delivery of prednisolone was achieved by initially conjugating folic acid (FA)to the di-block copolymer of polylactic acid (PLA) – polyethylene glycol (PEG). This moietycarrying di-block copolymer was incorporated on the surface of the drug-loaded poly lactic-coglycolicacid (PLGA) nanoparticle (NP) by employing the Interfacial Activity Assisted SurfaceFunctionalization (IAASF) technique. The NPs were evaluated for size, zeta potential, and drugloading. It was characterized using particle size analyser, SEM, 1H-NMR, and XRD. cell uptake,cytotoxicity, and anti-inflammatory activities were studied for various formulations. Results: The cytotoxicity assay indicated a high cell growth inhibitory effect of drug encapsulatedNPs with FA moiety as compared to free drug and NPs without the moiety for an incubationperiod of three, five, and six days. The growth-inhibitory effect of the free drug was short-lived,whereas FA functionalized NPs showed higher uptake and sustained inhibitory effect, and werealso able to significantly control the release of pro-inflammatory cytokines like tumour necrosisfactor-alpha (TNF-α) and nitric oxide (NO). Conclusion: Uptake, attenuation of pro-inflammatory signals, and the inhibitory effect ofprednisolone on the cells were more effective when targeted with the FA moiety on the surfaceof NPs as compared to free drug and NPs without the moiety.

scholarly journals Norhierridin B, a New Hierridin B-Based Hydroquinone with Improved Antiproliferative Activity

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1578
Author(s):  
Pedro Brandão ◽  
Joana Moreira ◽  
Joana Almeida ◽  
Nair Nazareth ◽  
Ivo E. Sampaio-Dias ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Human Tumor ◽  
Colon Adenocarcinoma ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Protein Levels ◽  
Cycle Arrest ◽  
Growth Inhibitory ◽  
Potent Growth

Hierridin B (6), a methylated hydroquinone isolated from the marine picocyanobacterium Cyanobium sp. LEGE 06113, moderately inhibited the growth of colon adenocarcinoma HT-29 cells. Aiming to improve the potential antitumor activity of this natural product, the demethylated analogue, norhierridin B (10), as well as its structurally-related quinone (9), were synthesized and evaluated for their growth inhibitory effect on a panel of human tumor cell lines, including the triple-negative breast cancer (TNBC) cells MDA-MB-231, SKBR3, and MDA-MB-468. Norhierridin B (10) showed a potent growth inhibitory effect on all cancer cell lines. Moreover, the growth inhibitory effect of compound 10 on MDA-MB-231 cells was associated with cell cycle arrest and apoptosis. Norhierridin B (10) interfered with several p53 transcriptional targets, increasing p21, Bax, and MDM2, while decreasing Bcl-2 protein levels, which suggested the potential activation of a p53 pathway. Altogether, these results evidenced a great improvement of the antitumor activity of hydroquinone 10 when compared to 6 and its structurally-related quinone (9). Notably, hydroquinone 10 displayed a prominent growth inhibitory activity against TNBC cells, which are characterized by high therapeutic resistance.

Dual Inhibition of Canonical and Non-Canonical NF-KB Pathway Demonstrates Significant Anti-Tumor Activities in Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2902-2902
Author(s):  
Claire Fabre ◽  
Naoya Mimura ◽  
Kathryn Bobb ◽  
Gullu Gorgun ◽  
Diana D. Cirstea ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Cell Lines ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Advisory Committees ◽  
Growth Inhibitory ◽  
Canonical Pathways ◽  
Dual Inhibition

Abstract Abstract 2902 NF-kB plays a crucial role in the pathogenesis of multiple myeloma (MM). In MM cells, NF-kB pathway is constitutively activated and regulates transcription of genes whose protein products mediate proliferation, survival and drug resistance. In the context of the bone marrow (BM) microenvironment, NF-kB modulates the expression of cytokines (ie, IL6, TNFalpha) and adhesion molecules (ie, ICAM-1). Importantly, these cytokines and adhesion to BM stromal cells (BMSCs) further activate NF-kB pathway. Previous studies have shown that both canonical and non-canonical pathways contribute to total NF-kB activity in MM cells. Therefore inhibition of both pathways is necessary to target NF-kB. However, current therapeutic strategies can only inhibit the canonical, but not the non-canonical pathway. In this study, we examined the biologic impact of dual inhibition of both canonical and non-canonical pathways in MM cells using a novel small molecule inhibitor PBS-1086 (Profectus BioSciences) which selectively inhibits binding of Rel family member proteins to DNA. Importantly, the binding activity of all Rel family member proteins (RelA, RelB, NF-kB1, NF-kB2, cRel) to DNA was inhibited by PBS-1086, confirming that PBS-1086 blocks both canonical and non-canonical pathways in MM cell lines. We first investigated growth inhibitory effect of PBS-1086 in vitro. PBS-1086 potently inhibited the growth of MM cell lines (MM1S, MM1R, INA6, LR5, Dox40, KMS18, RPMI-8226 and U266) in a dose-dependent fashion with IC50 ranges of 0.15–5 μM. In contrast, PBS-1086 showed modest cytotoxicity on normal peripheral blood mononuclear cells from healthy volunteers. Similar growth inhibitory effect were observed in CD138+ primary tumor cells derived from MM patients. PBS-1086 induced apoptosis in MM1S cell line in a time-dependent manner, evidenced by annexin V-PI staining by flow cytometry and cleaved caspase 8, 9, 3 and PARP, suggesting that PBS-1086 activates both extrinsic and intrinsic apoptotic pathways. Importantly, PBS-1086 can overcome the proliferative and anti-apoptotic effects of BMSCs, associated with inhibition of NF-kB activity. We next examined the combination effect of PBS-1086 with other agents. PBS-1086 with bortezomib synergistically enhanced anti-MM activity even in bortezomib-resistant cell lines (Dox40, ANBL6-VR5) and primary tumor cells from MM patients. Finally, we investigated the effect of PBS-1086 in vivo in a murine xenograft model of human MM cells. Tumor-bearing mice were divided into 6 groups: non-treated, vehicle control, PBS-1086 (7.5 mg/kg ip daily), bortezomib (0.5 mg/kg IV, twice weekly) and the combination of PBS-1086 (either at 2.5 mg/kg or 7.5 mg/kg) with bortezomib. PBS-1086 showed significant anti-MM activity in combination (2.5 and 7.5 mg/kg) groups versus control group (p =0.00039 and p =0.00084, respectively). Combination groups also had significantly (p < 0.05) prolonged survival compared to single agent treatment group (PBS-1086 or bortezomib). In conclusion, our preclinical studies show that PBS-1086 is a promising novel therapeutic agent and our data supports further clinical evaluation of this agent in combination with bortezomib for the treatment of MM. Disclosures: Bobb: Profectus BioSciences: Employment; Rel-MD: Employment. Zhang:Profectus BioSciences: Employment; Rel-MD: Employment. Meshulam:Profectus BioSciences: Employment; Rel-MD: Employment. Mitsiades:Millennium: Consultancy, Honoraria. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Hideshima:Acetylon: Consultancy. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Curcumin Sensitizes Prolactinoma to Bromocriptine by Activating the ERK/EGR1 and Inhibiting AKT/GSK3β Signaling Pathway

2021 ◽  
Author(s):  
Chao Tang ◽  
Junhao Zhu ◽  
Feng Yuan ◽  
Jin Yang ◽  
Xiangming Cai ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Expression Profiles ◽  
Inhibitory Effect ◽  
Gh3 Cells ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
The Difference

Abstract Although bromocriptine (BRC) as first-line drugs are recommended for treating patients with prolactinoma, a minority of patients with prolactinoma resistance to BRC. Moreover, our previous study showed that the difference in drug sensitivity in BRC- treated rat prolactinoma cells, MMQ cells are more resistant to BRC, and GH3 cells are more sensitive to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to further investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. CCK-8 kit was used to test cell growth. Cell-cycle analysis and apoptosis was performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analysed using the Affymetrix Gene-Chip array. Western blotting was used to test protein expression. Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cell by inhibiting the AKT/GSK3β signaling pathway. The same results were confirmed in vivo study. Taken together, Cur sensitizes rat pituitary adenoma cell to BRC by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway.

Galectin-9 Overcomes Various Types of Treatment Resistance through ATF-3/Noxa Pathway-Mediated Apoptosis In Chronic Myelogenous Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4930-4930
Author(s):  
Junya Kuroda ◽  
Mio Yamamoto ◽  
Hisao Nagoshi ◽  
Tsutomu Kobayashi ◽  
Nasa Sasaki ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
Inhibitory Effect ◽  
Myelogenous Leukemia ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
Anti Cancer ◽  
New Treatment

Abstract Abstract 4930 Tyrosine kinase inhibitors (TKIs) against Bcr-Abl fusion oncoprotein, such as imatinib mesylate (IM), nilotinib, or dasatinib, are the first-line molecular targeted therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms, such as the acquisition of Abl mutation or the overexpression of Bcr-Abl, but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, a new treatment approach that induces an anti-leukemic effect via Bcr-Abl-unrelated molecular pathways is urgently needed for achievement of a complete cure and to overcome TKI resistance. Galectins are a family of animal lectins that show specific affinity for beta-galactosides. Among fourteen mammalian galectins, galectin-9 (Gal9) has been shown to possess the anti-cancer properties by regulating various cellular functions, such as cell adhesion, cell proliferation, or apoptosis. These prompted us to investigate whether Gal9 can have an anti-CML effect via signaling cascades distinct from the pathway utilized by Bcr-Abl TKIs or by other commonly utilized anti-cancer agents. Modified human Galectin-9 (hGal9) inhibits the proliferation of six CML-derived cell lines, BV173, KT-1, KCL22, K562, KBM5 and MYL, by inducing apoptosis at their IC50s from 17.5 to 164.9 nM, with the activation of caspases-3, -4, - 8 and -9. The addition of 25 mM lactose prevented the growth inhibitory effect by hGal9 in K562, indicating the essential role of beta-galactoside binding activity in the anti-CML activity of hGal9. Because hGal9 treatment caused upregulation of Noxa, a pro-apoptotic BH3-only protein of Bcl-2 family proteins, and Mcl-1, a member of anti-apoptotic Bcl-2 proteins, in CML cell lines, we next investigated the involvement of Bcl-2-regulated apoptosis pathway in cell death by hGal9. K562 sublines overexpressing Bcl-2, Bcl-XL, or Mcl-1, showed resistance to cell death induced by IM, but were as sensitive to hGal9-induced cell death as the parental cells, suggesting the involvement of a pathway which is independent of Bcl-2 family proteins. These results also indicate that the accumulation of Mcl-1 following hGal9 treatment does not hamper apoptotic induction by hGal9. Besides, the expression of dominant-negative FADD protein did not hamper the effect of hGal9, also indicating that the death receptor pathway was not responsible for apoptosis induced by hGal9. In contrast, our study revealed that hGal9 caused the upregulation of activating transcription factor 3 (ATF3), a member of the ATF/CREB family transcription factors, within 3 hour treatment, and the gene knockdown experiments using RNA interference (RNAi) technique revealed that ATF3 is the critical mediator for cell killing by hGal9. Moreover, RNAi experiments indicated that Noxa is one of the downstream effector molecules of ATF3, and that Noxa partly mediates cell death induction by hGal9. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. Considering that the activation of caspase-4 and caspase-8 is involved in ER stress-induced apoptosis, and that Noxa induction by ATF3 has been shown to be crucial in the cell death induced by inhibitors for ER-associated protein degradation, we suggest that hGal9-induced cell death may at least partly involve ER stress. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant AblT315I, or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth inhibitory effect with IM on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML, and suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics. Disclosures: No relevant conflicts of interest to declare.

Growth inhibitory effect of paradicsompaprika in cancer cell lines

2002 ◽  
Author(s):  
T. Mori ◽  
M. Ohnishi ◽  
M. Komiyama ◽  
A. Tsutsui ◽  
H. Yabushita ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory
Sign in / Sign up

Export Citation Format

Share Document