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Titanium nanostructure mitigating doxorubicin-induced testicular toxicity in rats via regulating major autophagy
Rehab M Abdel-Megeed1, Abdel-Hamid Z Abdel-Hamid1, Mai O Kadry1
1Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, El Buhouth St., Dokki, Cairo 12622, Egypt.
Abstract:
Doxorubicin (DOX) is a powerful antineoplastic FDA-approved anthracycline-derived antibiotic and is considered as the most suitable intervention for solid tumors and hematological cancers therapy. However, its therapeutic application is highly limited due to acute and chronic renal, hematological and testicular toxicity. Oxidative stress, lipid peroxidation and apoptosis in germ cells as well as low sperm count, motility and disturbing steroidogenesis are the principal machineries of DOX-induced testicular toxicity. Nevertheless, the comprehensive molecular pathways responsible for DOX-induced testicular damage are not yet fully understood. The current study aims to clarify the role of autophagy and apoptotic signaling pathways in testicular toxicity induced by DOX in the rat model. The study also investigates the potential role of both titanium dioxide nanoparticles (TiO2NP) loaded with DOX and Lactoferrin in combination with DOX in mitigating testicular toxicity induced by DOX the standard antitumor drug. In the present study, male Wister albino rats were intoxicated with a total cumulative dose of DOX (18 mg/kg) via intra-peritoneal injection and served as positive control group. The other two groups administered either TiO2NP-DOX or lactoferrin-DOX. Furthermore, biochemical and molecular analyses were then performed. DOX intoxication induced testicular toxicity, revealing mineral imbalance as indicated by an increase in both calcium and magnesium concentrations. Administration of either TiO2NP-DOX or lactoferrin-DOX resulted in a significant modulation of disrupted mineral concentrations, with TiO2NP-DOX showing superiority in modulating both magnesium and calcium concentrations. Acid Phosphatase level significantly increased upon DOX-induced testicular damage. Molecular analysis of EGFR and K-RAS gene expression showed significant overexpression, while p53 and JAK-2 gene expression was significantly reduced post-DOX intoxication. Protein expression of both AKT and PI3K significantly increased upon DOX administration. Results showed a remarkable modulation of all disrupted gene and protein expressions upon treatment with TiO2NP-DOX or Lactoferrin-DOX with the superiority of TiO2NP-DOX in modulating these parameters. In conclusion, TiO2NP-DOX could be a promising drug delivery system to improve bioavailability and drug release, as well as reducing DOX's adverse effects particularly on testicular function.
Insights
Doxorubicin (DOX) causes testicular toxicity by disrupting mineral balance and gene expression. Titanium dioxide nanoparticles loaded with DOX (TiO2NP-DOX) effectively mitigated these harmful effects, showing promise for safer cancer therapy.
Area of Science:
- Biochemistry
- Toxicology
- Nanomedicine
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug but causes significant testicular toxicity, limiting its use.
- Mechanisms of DOX-induced testicular damage, including oxidative stress and apoptosis, are not fully understood.
- Understanding these pathways is crucial for developing protective strategies.
Purpose of the Study:
- To investigate the roles of autophagy and apoptotic signaling in DOX-induced testicular toxicity in rats.
- To evaluate the protective effects of titanium dioxide nanoparticles loaded with DOX (TiO2NP-DOX) and Lactoferrin-DOX against DOX-induced testicular damage.
Main Methods:
- Male Wistar albino rats were administered DOX (18 mg/kg) to induce testicular toxicity.
- Experimental groups received either TiO2NP-DOX or Lactoferrin-DOX.
- Biochemical analyses (mineral levels, Acid Phosphatase) and molecular analyses (gene and protein expression of EGFR, K-RAS, p53, JAK-2, AKT, PI3K) were performed.
Main Results:
- DOX intoxication led to mineral imbalance (increased calcium and magnesium) and elevated Acid Phosphatase.
- DOX altered gene expression (overexpressed EGFR/K-RAS, reduced p53/JAK-2) and protein expression (increased AKT/PI3K).
- Both TiO2NP-DOX and Lactoferrin-DOX treatments modulated these disruptions, with TiO2NP-DOX demonstrating superior efficacy.
Conclusions:
- DOX-induced testicular toxicity involves significant mineral imbalance and alterations in key signaling pathways.
- TiO2NP-DOX represents a promising drug delivery system for improving DOX bioavailability and reducing its testicular side effects.
- Targeted delivery systems like TiO2NP-DOX can enhance cancer therapy safety and efficacy.
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