Liposomal simvastatin sensitizes C26 murine colon carcinoma to the antitumor effects of liposomal 5‐fluorouracil in vivo

Autor: Lavinia Luput, Emilia Licarete, Laura Patras, Alina Sesarman, Laurian Vlase, Manuela Banciu, Vlad Alexandru Toma, Ioan Tomuta, Valentin Florian Rauca, Tibor Casian, Alina Porfire, Nicolae Dragoş, Ioana Stejerean, Marcela Achim, Dana Muntean, Denise Minerva Drotar
Rok vydání: 2020
Předmět:
liposomes
0301 basic medicine
CD31
Simvastatin
Cancer Research
Colorectal cancer
Apoptosis
medicine.disease_cause
resistance
Mice
03 medical and health sciences
combined therapy
0302 clinical medicine
Western blot
In vivo
Cell Line
Tumor
medicine
Animals
Humans
Cell Proliferation
bcl-2-Associated X Protein
Neovascularization
Pathologic
medicine.diagnostic_test
Chemistry
Carcinoma
NF-kappa B
Cancer
Original Articles
General Medicine
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation
Neoplastic
Platelet Endothelial Cell Adhesion Molecule-1
5‐fluorouracil
Drug Discovery and Delivery
030104 developmental biology
Proto-Oncogene Proteins c-bcl-2
Oncology
Drug Resistance
Neoplasm
Fluorouracil
030220 oncology & carcinogenesis
Cancer research
Original Article
Colorectal Neoplasms
Oxidative stress
medicine.drug
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: 5‐Fluorouracil‐based therapy remains the main approach in colorectal cancer, even though there are still some drawbacks, such as chemoresistance. In this study we combined 5‐fluorouracil encapsulated in long‐circulating liposomes with simvastatin, also encapsulated in long‐circulating liposomes, that was previously proved to exert antitumor actions on the same tumor model. The production of angiogenic/inflammatory proteins was assessed by protein array and the production of markers for tumor aggressiveness (Bcl‐2, Bax, and nuclear factor [NF]‐κB) were determined by western blot analysis. Intratumor oxidative stress was evaluated through measurement of malondialdehyde level by HPLC, and through spectrophotometric analysis of catalytic activity of catalase and of total antioxidant capacity. Immunohistochemical analysis of tumors for CD31 expression was assessed. Intratumor activity of MMP‐2 by gelatin zymography was also carried out. Our results revealed that combined therapies based on liposomal formulations exerted enhanced antitumor activities compared with combined treatment with free drugs. Sequential treatment with liposomal simvastatin and liposomal 5‐fluorouracil showed the strongest antitumor activity in C26 colon carcinoma in vivo, mainly through inhibition of tumor angiogenesis. Important markers for cancer progression (Bcl‐2, Bax, NF‐κB, and intratumor antioxidants) showed that liposomal simvastatin might sensitize C26 cells to liposomal 5‐fluorouracil treatment in both regimens tested. The outcome of simultaneous treatment with liposomal formulations was superior to sequential treatment with both liposomal types as the invasive capacity of C26 tumors was strongly increased after the latest treatment. The antitumor efficacy of combined therapy in C26 colon carcinoma might be linked to the restorative effects on proteins balance involved in tumor angiogenesis.
Liposomal simvastatin sensitizes C26 cells to liposomal 5‐fluorouracil treatment. The combination therapy based on the administration of liposomal simvastatin and 5‐fluorouracil has the potential to become a successful cancer‐targeted therapy, mainly due to the inhibitory effects on the intratumor angiogenesis.
Databáze: OpenAIRE
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