Bypassing P-glycoprotein mediated efflux of afatinib by cyclodextrin complexation – Evaluation of intestinal absorption and anti-cancer activity

2020 ◽  
pp. 114866
Author(s):  
Vineela Parvathaneni ◽  
Rasha S. Elbatanony ◽  
Snehal K. Shukla ◽  
Nishant S. Kulkarni ◽  
Dipti D. Kanabar ◽  
...  
2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13162-13162 ◽  
Author(s):  
S. Hatakeyama ◽  
D. Tomioka ◽  
E. Kawahara ◽  
N. Matsuura ◽  
K. Masuya ◽  
...  

13162 Background: Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that regulates multiple cell functions. Elevated expression levels of FAK have been detected in various tumor samples and are closely correlated with invasive potential. Activation of integrins and the growth factor receptors result in FAK autophosphorylation at Y397 and the presentation of suitable binding sites for proteins containing either SH2 or phosphotyrosine binding domains. Recent evidences suggest that FAK plays important roles in cancer cell proliferation and survival. IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: In this study, anti-cancer activity of NVP-TAE226 that is identified as a potent and selective FAK inhibitor was evaluated in cancer cell lines panel and MIA PaCa-2 pancreatic carcinoma in vivo model. Results: Mean GI50 value of NVP-TAE226 against 37 cancer cell lines was 0.76 μmole/L. Inhibition of cancer cell proliferation was not affected by expression of P-glycoprotein, suggesting that NVP-TAE226 is not served as a substrate of P-glycoprotein. Oral administration of NVP-TAE226 efficiently inhibited MIA PaCa-2 human pancreatic tumor growth at all doses tested. Tumor stasis was observed at a dose of 30 mg/kg, qd for 7×/week and tumor regression was observed at a dose of 100 mg/kg, qd for 5×/week. All animals tolerated NVP-TAE226 treatment up to 100 mg/kg, 5×/wk, qd, po for 2 weeks with no body weight loss. Inhibition of downstream signaling such as phosphorylation of Akt at Serine473 was accompanied by inhibition of FAK phosphorylation in human pancreatic carcinoma cell lines. Conclusions: NVP-TAE226 is a novel class of selective and small molecule kinase inhibitors with a potent in vivo activity and potential therapeutic application. No significant financial relationships to disclose.


2014 ◽  
pp. 98-101
Author(s):  
Thi Bich Hien Le ◽  
Viet Duc Ho ◽  
Thi Hoai Nguyen

Nowadays, cancer treatment has been a big challenge to healthcare systems. Most of clinical anti-cancer therapies are toxic and cause adverse effects to human body. Therefore, current trend in science is seeking and screening of natural compounds which possess antineoplastic activities to utilize in treatment. Uvaria L. - Annonaceae includes approximately 175 species spreading over tropical areas of Asia, Australia, Africa and America. Studies on chemical compositions and pharmacological effects of Uvaria showed that several compound classes in this genus such as alkaloid, flavonoid, cyclohexen derivaties, acetogenin, steroid, terpenoid, etc. indicate considerable biological activities, for example anti-tumor, anti-cancer, antibacterial, antifungal, antioxidant, etc. Specifically, anti-cancer activity of fractions of extract and pure isolated compounds stands out for cytotoxicity against many cancer cell lines. This study provides an overview of anti-cancer activity of Uvaria and suggests a potential for further studies on seeking and developing novel anti-cancer compounds. Key words: Anti-cancer, Uvaria.


2018 ◽  
Vol 14 (6) ◽  
pp. 578-585
Author(s):  
Esen Sezen Karaoglan ◽  
Gulsah Gundogdu ◽  
Mucahit Secme ◽  
Onur Senol ◽  
Fatma Demirkaya Miloglu ◽  
...  

2019 ◽  
Vol 18 (11) ◽  
pp. 1639-1648 ◽  
Author(s):  
Daipeng Xiao ◽  
Fen He ◽  
Dongming Peng ◽  
Min Zou ◽  
Junying Peng ◽  
...  

Background: Berberine (BBR), an isoquinoline plant alkaloid isolated from plants such as Coptis chinensis and Hydrastis canadensis, own multiple pharmacological activities. Objective: In this study, seven BBR derivatives were synthesized and their anticancer activity against HeLa cervical and A549 human lung cancer cell lines were evaluated in vitro. Methods: The anti-cancer activity was measured by MTT assay, and apoptosis was demonstrated by the annexin V-FITC/PI staining assay. The intracellular oxidative stress was investigated through DCFH-DA assay. The molecular docking study was carried out in molecular operating environment (MOE). Results: Compound B3 and B5 showed enhanced anti-cancer activity compared with BBR, the IC50 for compound B3 and B5 were significantly lower than BBR, and compound B3 at the concentration of 64 or 128 µM induced apoptosis in HeLa and A549 cell lines. The reactive oxygen species (ROS) was generated in both cell lines when treated with 100 µM of all the compounds, and compound B3 and B5 induced higher activity in the generation of ROS, while compound B3 exhibited the highest activity, these results are in accordance with the cytotoxicity results, indicating the cytotoxicity were mostly generated from the oxidative stress. In addition, molecular docking analysis showed that compound B3 had the greatest affinity with Hsp90. Upon binding, the protective function of Hsp90 was lost, which might explain its higher cytotoxicity from molecular interaction aspect. Conclusion: All the results demonstrated that compound B3 and B5 showed significantly higher anti-cancer ability than BBR, and compound B3 is a promising anticancer drug candidate.


2015 ◽  
Vol 15 (5) ◽  
pp. 631-646 ◽  
Author(s):  
Kaalin Gopaul ◽  
Suhas Shintre ◽  
Neil Koorbanally

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