MitoTEMPO Mitigates Chemotherapy-Induced Inflammasome Activation: Implications for Neuroprotection in Canine Oncology

Background: Canine mammary tumors represent ۴۰-۵۰% of neoplasms in intact female dogs, sharing molecular similarities with human and murine breast cancer models. Vincristine-induced peripheral neuropathy due to inflammasome activation remains a dose-limiting toxicity in canine chemotherapy, preventing treatment completion. molecular mechanisms underlying chemotherapy-induced inflammasome activation in veterinary oncology remain unexplored. The NLRP۳-ROS pathway mediates tumor progression and chemotherapy-induced toxicity. This pilot study investigated MitoTEMPO’s potential to intercept vincristine-induced inflammasome activation, providing evidence for neuroprotective strategies in canine protocols Methods: Twenty female BALB/c mice (۶-۸ weeks, ۲۲.۵g) received subcutaneous ۴T۱ mammary carcinoma cells (۳۰۰,۰۰۰ cells/۰.۱ mL), selected for molecular similarity to canine mammary tumors. Following tumor establishment, mice were randomized into five groups: positive control (tumor only), vincristine monotherapy (liposome-encapsulated, ۱ mg/kg IP), MitoTEMPO monotherapy (۱.۲۵ mg/kg IP), and combination therapy, in addition to negative controls (PBS). Weekly treatments continued ۲۸ days with hematological monitoring. Blood samples were collected for inflammatory analysis. Quantitative RT-PCR targeted NLRP۳ with GAPDH normalization using ΔΔCt methodology. Statistical analysis utilized one-way ANOVA with Tukey’s post-hoc testing (P < ۰.۰۵). Results: All mice developed tumors, confirming model establishment. Vincristine significantly upregulated NLRP۳ (P = ۰.۰۰۱) expression, establishing chemotherapy-induced inflammasome activation. combination therapy with MitoTEMPO demonstrated significant inflammasome suppression: NLRP۳ expression was reduced compared to vincristine monotherapy (P = ۰.۰۰۰۱). Conclusion: This pilot study establishes proof-of-concept for MitoTEMPO-mediated suppression of vincristine-induced inflammasome activation in mammary carcinoma models. The demonstrated NLRP۳-ROS pathway modulation provides mechanistic foundation for systematic dose-escalation studies in canine patients, supporting development of evidence-based neuroprotective strategies in veterinary chemotherapy protocols.

کلیدواژه ها:

canine mammary tumor ، ۴T۱ ، NLRP۳ ، MitoTEMPO ، vincristine