Ahmed A Abd-Rabou1, Dhruba J Bharali2, Shaker A Mousa3. 1. Hormones Department, Medical Research Division, National Research Center, Cairo, 12622, Egypt. 2. The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, New York, 12144, USA. 3. The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, New York, 12144, USA. shaker.mousa@acphs.edu.
Abstract
PURPOSE: Breast cancer is the second most common cause of mortality in women in the United States. Targeted delivery of antitumor breast cancer drugs as a drug-delivery strategy may allow direct delivery into the tumor. Currently, chemotherapy is one of the principle strategies for cancer treatment, but it can have toxic side effects. Nanotechnology attempts to resolve these challenges by loading drugs in nanoparticles, such as solid lipid nanoparticles (SLN). In response to the breast cancer drug 5-fluorouracil (5-FU), p38MAPK signaling has been investigated since the 1990s. Ribavirin, a nucleotide derivative, inhibits p38MAPK in infected hepatocytes. A ribavirin prodrug, taribavirin (TBV), was recently synthesized to concentrate in the liver and have minimal concentration in red blood cells. METHODS: In this study, TBV and 5-FU-pegylated SLNs were prepared and characterized. The in vitro cytotoxicity was evaluated against MCF-7 breast cancer cells. Using molecular docking experiments, 5-FU and TBV were docked on p38MAPK protein. RESULTS: The TBV nanoformulation had the highest cytotoxic effects, achieving IC50 = 0.690 μM after 24 h, compared with free TBV, which also achieved a good cytotoxic effect (IC50 = 0.756 μM). However, there was a detectable cytotoxic effect and an undetectable IC50 of 5-FU nanoparticles and free 5-FU on MCF-7 cells. CONCLUSIONS: The effect of TBV nanoparticles on MCF-7 cells may be due to its inhibitory effect against p38MAPK protein, where it fits inside the active pocket site of the p38 protein molecular surface, with a minimum binding affinity of -5.5 kcal/mol (rmsd of 1.07), and it formed strong hydrogen bonds with amino acids ASP'168, ILE'166, HIS'148, and ILE'147. Further studies are warranted to investigate the mechanistic details of the proposed approach.
PURPOSE:Breast cancer is the second most common cause of mortality in women in the United States. Targeted delivery of antitumor breast cancer drugs as a drug-delivery strategy may allow direct delivery into the tumor. Currently, chemotherapy is one of the principle strategies for cancer treatment, but it can have toxic side effects. Nanotechnology attempts to resolve these challenges by loading drugs in nanoparticles, such as solid lipid nanoparticles (SLN). In response to the breast cancer drug 5-fluorouracil (5-FU), p38MAPK signaling has been investigated since the 1990s. Ribavirin, a nucleotide derivative, inhibits p38MAPK in infected hepatocytes. A ribavirin prodrug, taribavirin (TBV), was recently synthesized to concentrate in the liver and have minimal concentration in red blood cells. METHODS: In this study, TBV and 5-FU-pegylated SLNs were prepared and characterized. The in vitro cytotoxicity was evaluated against MCF-7 breast cancer cells. Using molecular docking experiments, 5-FU and TBV were docked on p38MAPK protein. RESULTS: The TBV nanoformulation had the highest cytotoxic effects, achieving IC50 = 0.690 μM after 24 h, compared with free TBV, which also achieved a good cytotoxic effect (IC50 = 0.756 μM). However, there was a detectable cytotoxic effect and an undetectable IC50 of 5-FU nanoparticles and free 5-FU on MCF-7 cells. CONCLUSIONS: The effect of TBV nanoparticles on MCF-7 cells may be due to its inhibitory effect against p38MAPK protein, where it fits inside the active pocket site of the p38 protein molecular surface, with a minimum binding affinity of -5.5 kcal/mol (rmsd of 1.07), and it formed strong hydrogen bonds with amino acids ASP'168, ILE'166, HIS'148, and ILE'147. Further studies are warranted to investigate the mechanistic details of the proposed approach.
Entities:
Keywords:
5-fluorouracil; breast cancer; solid lipid nanoparticles; taribavirin