Anti-glioma Effects of Caffeic Acid Phenethyl Ester and Dasatinib Combination Therapy in an in vivo Rat Glioma Model

Background: Caffeic acid phenethyl ester and Dasatinib in combination, when used incongruous proportions and durations, present an antitumor potential for glioma in vitro, suggesting a high therapeutic potential for glioma treatment. Objective: In the present study, we addressed the question whether CAPE and Dasatinib target multiple pathways involved in tumor growth, proliferation and development on an in vivo rat model of glioma. Method: Expression analysis of proteins thought to be mediating proliferation, cell motility, angiogenesis, and invasion was carried out to delineate the antineoplastic action of CAPE and Dasatinib. Results: CAPE and Dasatinib modulate the expression of proteins having potential interactive crosstalk with major oncogenic pathways involved in glioma progression. Our results showed that combination treatment modulates the expression of p53 in group co-administered with CAPE and Dasatinib after glioma induction in comparison to the group induced with glioma only. EGFR and PCNA expression were significantly altered in the co-treated group in comparison with the glioma-induced group. The effects of CAPE and Dasatinib treatment were further evaluated on the AKT pathway by Western blot analysis. The co-treated group showed a significant reduction in the expression of AKT. The histopathological analysis further backed the antiproliferative and anti invasive effects of CAPE and Dasatinib. Conclusion: This study in totality suggests that the combinational therapy remarkably reduces the proliferation of glioma cells in vivo, suggesting that CAPE and Dasatinib therapy could be exploited for the management of gliomas without showing drug-related resistances and side effects, suggesting a high therapeutic potential of the therapy in glioma.

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Novel Caffeic Acid Phenethyl Ester-Mortalin Antibody Nanoparticles Offer Enhanced Selective Cytotoxicity to Cancer Cells

Cancers ◽

10.3390/cancers12092370 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2370

Author(s):

Jia Wang ◽

Priyanshu Bhargava ◽

Yue Yu ◽

Anissa Nofita Sari ◽

Huayue Zhang ◽

...

Keyword(s):

Tumor Growth ◽

Anticancer Activity ◽

Cancer Cells ◽

Caffeic Acid ◽

Treated Group ◽

Caffeic Acid Phenethyl Ester ◽

Caspase Cleavage ◽

Unique Cell

Caffeic acid phenethyl ester (CAPE) is a key bioactive ingredient of honeybee propolis and is claimed to have anticancer activity. Since mortalin, a hsp70 chaperone, is enriched in a cancerous cell surface, we recruited a unique cell internalizing anti-mortalin antibody (MotAb) to generate mortalin-targeting CAPE nanoparticles (CAPE-MotAb). Biophysical and biomolecular analyses revealed enhanced anticancer activity of CAPE-MotAb both in in vitro and in vivo assays. We demonstrate that CAPE-MotAb cause a stronger dose-dependent growth arrest/apoptosis of cancer cells through the downregulation of Cyclin D1-CDK4, phospho-Rb, PARP-1, and anti-apoptotic protein Bcl2. Concomitantly, a significant increase in the expression of p53, p21WAF1, and caspase cleavage was obtained only in CAPE-MotAb treated cells. We also demonstrate that CAPE-MotAb caused a remarkably enhanced downregulation of proteins critically involved in cell migration. In vivo tumor growth assays for subcutaneous xenografts in nude mice also revealed a significantly enhanced suppression of tumor growth in the treated group suggesting that these novel CAPE-MotAb nanoparticles may serve as a potent anticancer nanomedicine.

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Formulation development of folic acid conjugated PLGA nanoparticles for improved cytotoxicity of Caffeic acid phenethyl ester

Pharmaceutical Nanotechnology ◽

10.2174/2211738509666210111160528 ◽

2021 ◽

Vol 09 ◽

Author(s):

Harshad S Kapare ◽

Sathiyanarayanan L ◽

Arulmozhi S ◽

Kakasaheb Mahadik

Keyword(s):

Folic Acid ◽

Drug Release ◽

Caffeic Acid ◽

Caffeic Acid Phenethyl Ester ◽

Therapeutic Effects ◽

Formulation Development ◽

Sustained Drug Release ◽

Active Constituent

Background: Honey bee propolis is one of the natural product reported in various traditional systems of medicines including Ayurveda. Caffeic acid phenethyl ester (CAPE) is an active constituent of propolis which is well known for its anticancer potential. The therapeutic effects of CAPE are restricted owing to its less aqueous solubility and low bioavailability. Objective: In this study CAPE loaded folic acid conjugated nanoparticle system (CLFPN) was investigated to enhance solubility, achieve sustained drug release and improved cytotoxicity of CAPE. Methods: Formulation development, characterization and optimization were carried out by design of experiment approach. In vitro and in vivo cytotoxicity study was carried out for optimized formulations. Results: Developed nanoparticles showed particle size and encapsulation efficiency of 170 ± 2 - 195 ± 3 nm and 75.66 ± 1.52 - 78.80 ± 1.25 % respectively. Optimized formulation CLFPN showed sustained drug release over a period of 42 h. GI50 concentration was decreased by 46.09% for formulation as compared to CAPE in MCF-7 cells indicating targeting effect of CLFPN. An improved in vitro cytotoxic effect was reflected in in-vivo Daltons Ascites Lymphoma model by reducing tumor cells count. Conclusion: The desired nanoparticle characteristic with improved in vivo and in vitro cytotoxicity was shown by developed formulation. Thus it can be further investigated for biomedical applications.

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Iminoflavones Combat 1,2-Dimethyl Hydrazine-Induced Aberrant Crypt Foci Development in Colon Cancer

BioMed Research International ◽

10.1155/2014/569130 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

V. Ganga Prasad ◽

Shishir Kawade ◽

B. S. Jayashree ◽

Neetinkumar D. Reddy ◽

Albi Francis ◽

...

Keyword(s):

Colon Cancer ◽

Treated Group ◽

Aberrant Crypt Foci ◽

Colonic Crypts ◽

Antitumor Potential ◽

Histopathological Images ◽

Nuclear Changes ◽

The Imf

The aim of the present study was to evaluate the antitumor potential of iminoflavones inin vitroandin vivoanticancer models. Preliminary screening in various cancer cell lines revealed four potential iminoflavones out of which IMF-8 was taken based on its activity against colon cancer cells. This was further confirmed by observing the nuclear changes in the cells by AO/EB and Hoechst 33342 staining studies.In vivoactivity was assessed by dimethyl hydrazine-(DMH-) induced colon cancer model in rats. Animals were administered DMH (20 mg/kg, b.w. for 10 weeks and 30 mg/kg b.w.,i.p.for 10 weeks) and were supplemented with (IMF-8) iminoflavone-8 (200 mg/kg,p.o.for 14 days). Results showed that DMH induced 100% aberrant crypt foci (ACF) and polyps which were significantly reduced in the IMF-8 treated group. IMF-8 significantly increased the catalase and GSH levels whereas it reduced the TNF-αand IL-6 levels markedly which suggests the antioxidative and anti-inflammatory actions of flavonoids present in IMF-8. The histopathological images of the IMF-8 treated colon showed no signs of mucosal crypt abscess. These findings suggest that the semi-synthetic iminoflavones, IMF-8, effectively inhibit DMH-induced ACFs and colonic crypts by alleviating the oxidative stress and suppressing the inflammation.

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In Vivo and In Vitro Antıneoplastic Actions of Caffeic Acid Phenethyl Ester (CAPE): Therapeutic Perspectives

Nutrition and Cancer ◽

10.1080/01635581.2013.776693 ◽

2013 ◽

Vol 65 (4) ◽

pp. 515-526 ◽

Cited By ~ 56

Author(s):

Sumeyya Akyol ◽

Gulfer Ozturk ◽

Zeynep Ginis ◽

Ferah Armutcu ◽

M. Ramazan Yigitoglu ◽

...

Keyword(s):

Caffeic Acid ◽

Caffeic Acid Phenethyl Ester

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In Vitro and in Vivo Stability of Caffeic Acid Phenethyl Ester, a Bioactive Compound of Propolis

Journal of Agricultural and Food Chemistry ◽

10.1021/jf063477o ◽

2007 ◽

Vol 55 (9) ◽

pp. 3398-3407 ◽

Cited By ~ 51

Author(s):

Nicola Celli ◽

Luana K. Dragani ◽

Stefania Murzilli ◽

Tommaso Pagliani ◽

Andreina Poggi

Keyword(s):

Caffeic Acid ◽

Bioactive Compound ◽

Caffeic Acid Phenethyl Ester

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Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling

AJP Renal Physiology ◽

10.1152/ajprenal.90285.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. F672-F679 ◽

Cited By ~ 7

Author(s):

Shuang Wang ◽

Jifu Jiang ◽

Qiunong Guan ◽

Hao Wang ◽

Christopher Y. C. Nguan ◽

...

Keyword(s):

Transforming Growth Factor ◽

Therapeutic Potential ◽

Mek Inhibitor ◽

Treated Group ◽

Chronic Allograft Nephropathy ◽

Beneficial Effects ◽

Extracellular Signal ◽

Vehicle Treated Group

Chronic allograft nephropathy (CAN), the most common cause of late kidney allograft failure, is not effectively prevented by immunosuppressive regimens. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) via MEK mediates actions of various growth factors, including transforming growth factor (TGF)-β1, which plays a key role in CAN. Hence, we tested the therapeutic potential of MEK-ERK1/2 signaling disruption to prevent CAN. Kidneys from C57BL/6J (H-2b) mice were transplanted to bilaterally nephrectomized BALB/c (H-2d) mice. At 14 days after transplantation, the recipients were subjected to 28 days of treatment with the MEK inhibitor CI-1040. All six CI-1040-treated allografts survived, while two of seven grafts in the vehicle-treated group were lost. At the end of the experiment, the function and structure of grafts in the CI-1040-treated group were significantly preserved, as indicated by lower levels of serum creatinine or blood urea nitrogen than in the vehicle-treated group [30 ± 6 vs. 94 ± 39 μM creatinine ( P = 0.0015) and 22 ± 8 vs. 56 ± 25 mM BUN ( P = 0.0054)] and reduced CAN in the CI-1040-treated group compared with vehicle controls (CAN score = 4.2 vs. 10.3, P = 0.0119). The beneficial effects induced by CI-1040 were associated with reduction of ERK1/2 phosphorylation and TGFβ1 levels in grafts. Also, CI-1040 potently suppressed not only TGFβ biosynthesis in kidney cell cultures but also antiallograft immune responses in vitro and in vivo. Our data suggest that interference of MEK-ERK1/2 signaling with a pharmacological agent (e.g., CI-1040) has therapeutic potential to prevent CAN in kidney transplantation.

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Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms23010126 ◽

2021 ◽

Vol 23 (1) ◽

pp. 126

Author(s):

Alasdair G. Kay ◽

Kane Treadwell ◽

Paul Roach ◽

Rebecca Morgan ◽

Rhys Lodge ◽

...

Keyword(s):

T Cell ◽

Extracellular Vesicles ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Histopathological Analysis ◽

Therapeutic Effects ◽

Synovial Joint ◽

Paracrine Signalling

Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.

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