Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED₃₀, von Frey testing) and thermal hyperalgesia (ED₅₀, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED₃₀ and ED₅₀ for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.

Breast cancer is associated with systemic inflammation and increased cardiovascular risk, and anthracycline chemotherapy may contribute to persistent myocardial injury. This study aimed to evaluate acute changes in inflammatory cytokines and plasma redox status after the first anthracycline cycle and to assess long-term ventricular function after 10 years in women with breast cancer. We conducted a prospective study of 17 patients with breast cancer treated with anthracycline-based chemotherapy at Salvador Hospital, Santiago, Chile. Plasma cytokines were measured at baseline (day −7) and on day +3 after the first cycle using a MILLIPLEX Luminex^® assay. Echocardiographic assessment of left ventricular systolic and diastolic function, together with oxidative stress parameters, was performed at baseline and after 10 years of follow-up. Anthracycline exposure was associated with an acute increase in several cytokines related to inflammatory and vascular remodeling, including EGF, eotaxin, MCP-1, and VEGF. In addition, markers of redox imbalance suggested an acute pro-oxidant response after treatment. At long-term follow-up (10 years), left ventricular ejection fraction (LVEF) remained within the normal range in all patients. However, integrative echocardiographic assessment revealed impaired left ventricular relaxation, evidenced by significant reductions in the mitral inflow E/A ratio, and septal and lateral e′ velocities with respect to baseline, despite preserved estimated filling pressures. These alterations were accompanied by persistent oxidative stress, reflected by persistently elevated levels of lipid peroxidation markers, such as in vivo 8-isoprostanes. In this pilot cohort, anthracycline chemotherapy induced an early inflammatory and oxidative response that was not associated with overt long-term systolic dysfunction but was accompanied by persistent biochemical and diastolic alterations. These findings support the concept of a long-term subclinical cardiotoxic phenotype and highlight the potential value of combining echocardiographic assessment with circulating redox and inflammatory biomarkers to improve long-term cardiovascular surveillance in breast cancer survivors.