Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer

Abstract

Existing treatments are frequently ineffective in combating liver cancer (LC) due to its rapid growth, high metastatic potential, and chemoresistance. Thus, inducing ferroptosis, a new non-apoptotic regulated cell death-dependent massive iron overload-mediated lipid peroxidation, is an alternative effective approach for treating LC. The efficient trigger of ferroptosis requires blocking cellular antioxidant (anti-ferroptosis) response and selectivity to avoid harming other healthy tissues. In this study, green chemically synthesized ferrous oxide nanoparticles (F(II) NPs) were used for enhancing selective iron accumulation in tumor tissue, while diethyldithiocarbamate (DE) was for inhibiting the antioxidant system (glutathione and aldehyde dehydrogenase (ALDH) 2) which protects the tumor from damage-dependent lipid peroxides. Thus, F(II) NPs were used with DE as nanocomplex (DF(II) NPs) and its anti-LC activity compared to ferrous oxide DF(II). DF(II) NPs outperformed the typical complex of DF(II) in eradicating metastatic LC cells in HepG2 cells and a chemically induced metastatic LC animal model, as evidenced by flow cytometry, histological and immunohistochemical analyses, and α-fetoprotein depletion. The superior therapeutic potency-dependent ferroptotic activity of DF(II) NPs, attributed to their higher selective accumulation (∼77%) than DF(II) in tumor tissues (liver and lung), resulted in a strong elevation of cellular lipid peroxidation with extreme suppression of nuclear related factor 2 (Nrf2) transcriptional activity, glutathione (GSH), glutathione peroxidase 4, and ALDH2. Subsequently, a severe inhibition in the expression of oncogenes and metastatic cancer stem cell genes was recorded in DF(II) NPs-treated LC animal group. In contrast to DF(II), DF(II) NPs were able to normalize liver functions and did not show any variations in hematological and histological parameters in the blood and tissues of DF(II) NPs-treated normal mouse group. These findings validate the potency and safety of DF(II) nanocomplex as a promising nanodrug for combating metastatic LC.

Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction

“…This efficiency was potentiated when disulfiram was combined with copper, generating DE/Cu complex ( Wang et al, 2022 ), with a more potent inactivation of proteasome, resulting in toxic protein accumulation, and subsequently improving sensitivity to TMZ and radiation ( Hothi et al, 2012 ; Lun et al, 2016 ; Zhuo et al, 2022 ). The thiol affinity of DE also inactivates the antioxidant glutathione system (GPX4 and GSH), promoting ferroptosis that is triggered by accumulation of FeO NPs ( Abu-Serie, 2023 ; Abu-Serie and Abdelfattah, 2023 ). Iron (Fe +2 ) not only initiates lipid peroxidation by reacting with hydrogen peroxides, forming hydroxyl radicals, but also mediates its autopropagation by converting lipid peroxides into peroxyl and alkoxyl radicals ( Luo et al, 2022 ).…”

“…GSH level was quantified using Ellman (5,5′-dithio-bis-2(nitro benzoic acid) reagent as previously reported ( Ellman, 1959 ; Abu-Serie and Abdelfattah, 2022 ). GPX4 activity was detected as described in previous studies ( Kernstock and Girotti, 2008 ; Abu-Serie, 2023 ). Then, GPX4 inhibition percentage in the treated spheres was estimated relative to the untreated spheres.…”

“…Recent studies reported that nanocomplexes of diethyldithiocarbamate (DE, a metabolite of the FDA-approved drug disulfiram) with metal oxide nanoparticles (NPs) exhibited potent anticancer impact against human cancer cell lines and tumor animal models ( Abu-Serie and Eltarahony, 2021 ; Abu-Serie and Abdelfattah, 2022 ; Abu-Serie, 2023 ; Abu-Serie and Abdelfattah, 2023 ; Abu-Serie, 2024 ). As cancer stem cells (CSCs) can resist apoptosis-dependent cell death ( Safa, 2022 ), these efficient nanocomplexes of DE and green chemically synthesized metal oxide (Cu 4 O 3 , Cu 2 O, and FeO) NPs were able to mediated cancer cell death by inducing new nonapoptotic pathways.…”

“…As cancer stem cells (CSCs) can resist apoptosis-dependent cell death ( Safa, 2022 ), these efficient nanocomplexes of DE and green chemically synthesized metal oxide (Cu 4 O 3 , Cu 2 O, and FeO) NPs were able to mediated cancer cell death by inducing new nonapoptotic pathways. These novel cell death pathways including the accumulated copper-mediated cuproptosis and iron-mediated ferroptosis, lead to mitochondrial dysfunction and uncontrolled lipid peroxidation, respectively ( Tang et al, 2021 ; Abu-Serie, 2023 ; Abu-Serie and Abdelfattah, 2023 ). Ferroptosis inducers can thus improve sensitivity of GBM to chemotherapeutic drugs (e.g., TMZ), radiation, and immunotherapy as well as targeted therapy (e.g., epidermal growth factor receptor inhibitors) and inhibit metastasis ( Zhuo et al, 2022 ; Bo et al, 2024 ; Wang et al, 2024 ).…”

“…This glutathione system suppression can be mediated by DE, which is a potent inhibitor of ALDH1A1 ( Abu-Serie and Abdelfattah, 2023 ). Previous studies found that ALDH1A1 inhibitors prevented hypoxia and stemness expression, while increasing reactive oxygen species (ROS) and CSCs’ drug sensitivity ( Vassalli, 2019 ; Abu-Serie and Eltarahony, 2021 ; Abu-Serie and Abdelfattah, 2022 ; Abu-Serie, 2023 ; Abu-Serie and Abdelfattah, 2023 ; Abu-Serie, 2024 ).…”