https://orcid.org/0000-0001-8887-3727
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Abstract
Background: Cancer stem cells' (CSCs) resistance to 5-fluorouracil (Fu), which is the main obstacle in treating colon cancer (CC), can be overcome by ferroptosis. The latter, herein, can be triggered by FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate-inhibited glutathione system and aldehyde dehydrogenase (ALDH1A1-maintained stemness, therapeutic resistance and metastasis). Materials & methods: Nanocomplex of FeO nanoparticles and diethyldithiocarbamate (FD) was used in combination with Fu to investigate its potential synergistic anti-CSC influence using CC spheroid models. Results: In Fu + FD-treated spheroids, the strongest growth inhibition, the highest cell death percentage, and the lowest CD133+-CSCs percentage and stemness gene expressions (e.g., drug efflux transporter), and the strongest antimetastatic effect were recorded with high synergistic indexes. Conclusion: Fu + FD represents effective combination therapy for chemoresistant CC cells.
Resistance of colon cancer stem cells (CSCs) to traditional chemotherapeutic drugs (e.g., 5-fluorouracil [Fu]) is a key challenge in the success of colon cancer therapy.
Ferroptosis, a new nonapoptosis and non-necrosis iron accumulation-dependent cell death, can suppress CSCs' therapeutic resistance.
The prepared nanocomplex (FD) consisting of FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate (inhibitor of ALDH1A1 and glutathione system) was used as a combined treatment with Fu to synergistically augment the anti-CSC influence using 3D spheroid models of Caco-2 and HCT-116.
After treating spheroids with Fu (resistance dose) + FD (maximum safe dose on normal colonocytes), the strongest growth inhibition with high synergistic indexes and the highest percentages of apoptotic, necrotic and late-death stage cell populations were recorded.
The cotreated spheroids exhibited the lowest percentage of CD133+-CSCs and stemness gene expressions (CSC transcription factors, drug-efflux transporter [ABCG2], HIF-1A, ALDH1A1 and ZEB1).
This synergistic anti-CSC activity is mainly related to inhibiting ALDH1A1 activity that was associated with ferroptosis induction, as evidenced by the lowest glutathione system level and the maximum elevation of ROS and lipid peroxidation in cotreated spheroids.
Fu + FD had the strongest antimetastatic effect, as illustrated by synergistic inhibition of MMP9 activity and lowering invasion area in cotreated spheroid.
Consequently, Fu + FD represents an effective combination therapy for tackling the chemoresistance of colon cancer cells.
Financial disclosure
The author has no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Competing interests disclosure
The author has no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The author states the current animal experiment was performed according to the principles outlined in the Declaration of Helsinki for all animal experimental investigations and the guidelines of Alexandria University Institutional Care and Use Committee (IACUC) for Laboratory Animal Science (ICLAS) with approval code AU-01222101531.