Doxorubicin and doxorubicin-loaded nanoliposome induce senescence by enhancing oxidative stress, hepatotoxicity, and in vivo genotoxicity in male Wistar rats.

The senescence phenomenon is historically considered as a tumor-suppressing mechanism that can permanently arrest the proliferation of damaged cells, and prevent tumor eradication by activating cell cycle regulatory pathways. Doxorubicin (DX) as an antineoplastic agent has been used for the treatment of solid and hematological malignancies for a long time, but its clinical use is limited due to irreversible toxicity on off-target tissues. Thereby, the encapsulation of plain drugs in a vehicle may decrease the side effects while increasing their permeability and availability in target cells. Here, we aimed to investigate and compare the effects of DX and DX-loaded nanoliposome (NLDX) on the induction of senescence via assessment of the occurrence of apoptosis/necrosis, genomic damage, oxidative stress, and liver pathologies. The study groups included DX (0.75, 0.5, 0.1 mg/kg/BW), NLDX groups (0.1, 0.05, 0.025 mg/kg/BW), and an untreated control group. The liver tissues were used to investigate the oxidative stress parameters and probable biochemical and histopathological alterations. Annexin V/PI staining was carried out to find the type of cellular death in the liver tissue of healthy rats exposed to different concentrations of DOX and LDOX. Data revealed that the highest dose of NLDX (0.1 mg/kg/BW) could significantly induce cellular senescence throughout significant increasing the level of genotoxic damage (p < 0.0001) and the oxidative stress (p < 0.001) compared with a similar dose of DX, in which the obtained results were further confirmed by flow cytometry and histopathological assessments of the liver tissue. This investigation provides sufficient evidence of improved therapeutic efficacy of NLDX compared with plain DX in male Wistar rats.