Doxorubicin and Doxorubicin-loaded Nanoliposome Triggers Hepatocyte Cells Senescence through Accumulation of Inflammatory Factors and Activation of P53

Abstract

Background and purpose: Induction of cellular senescence is indicative of new strategy to prevent abnormal proliferation of cancer cells. Doxorubicin (DOX) is gaining attention for its neoplasia suppressive and inhibitory properties, but its clinical utility is limited due to irreversible effects on non-target cells/tissues. In this way, nanoliposomal structures were developed in drug delivery systems with minimal systemic side effects. The biological role of doxorubicin-loaded nanoliposome (NLDX) in inflammation, a prerequisite for the onset of senescence, is unclear. This study was designed to evaluate the function of P53 and senescence-associated inflammatory markers during NLDX clearance in normal tissue of the liver. Materials and methods: This experimental study included three groups of Wistar rats; DOX (0.75, 0.5, and 0.1 mg/kg/BW) and LDOX (0.1, 0.05, 0.025 mg/kg/BW) groups, and a control group. Liver tissues were studied for inflammatory markers evaluation and Real-Time PCR was performed to investigate the level of P53 expression. Results: Data showed that NLDX at 0.1 mg/kg/BW could significantly induce senescence in rat liver tissue by remarkable increase in expression level of P53 (P<0.05) and senescence-related inflammatory markers, including TNF-α, NF-κB, interleukin -1, and interleukin-6 compared with a similar dose of DX (P<0.01). Conclusion: This research provides sufficient evidence of increased senescence in rat liver tissue caused by NLDX compared with DOX during liver excretion.

Keywords

• doxorubicin
• doxorubicin-loaded nanoliposome
• senescence
• hepatotoxicity
• inflammation
• p53