Estudo da interferência do álcool perílico na atividade antitumoral da doxorrubicina em camundongos com sarcoma 180

Abstract

The therapeutic management of sarcomas remains a clinical challenge due to the high heterogeneity and complexity of these neoplasms. Therefore, the combination of antineoplastic agents is fundamental to increase antitumor efficacy and mitigate toxic effects. Doxorubicin, the drug of choice in the treatment of sarcomas, has broad clinical efficacy; however, it can cause a risk of cardiotoxicity, as well as hepatotoxicity and hematological toxicity mediated by oxidative stress and inflammation. Perillyl alcohol, a monoterpene with anticancer, antioxidant, and anti-inflammatory properties, could potentiate the antitumor effect of doxorubicin and attenuate its toxic effects. Therefore, the aim of this study was to evaluate the interference of perillyl alcohol on the antitumor activity of doxorubicin in mice with sarcoma 180. For this, 56 male Swiss mice, transplanted with Sarcoma 180 cells, were distributed into 8 groups (n=7), namely: Saline [tween 80 0.2%, orally, on consecutive days + sodium chloride 0.9%, on alternate days, intraperitoneally (ip.)]; DOX (doxorubicin 2 mg/kg, on alternate days, i.p.); POH 50 (perillyl alcohol 50 mg/kg/day, orally), POH 100 (perillyl alcohol 100 mg/kg/day, orally), POH 200 (perillyl alcohol 200 mg/kg/day, orally), POH 50 + DOX (perillyl alcohol 50 mg/kg/day, orally + doxorubicin 2 mg/kg, every other day, intraperitoneally), POH 100 + DOX (perillyl alcohol 100 mg/kg/day, orally + doxorubicin 2 mg/kg, every other day, intraperitoneally), and POH 200 + DOX (perillyl alcohol 200 mg/kg/day, orally + doxorubicin 2 mg/kg, every other day, intraperitoneally). These treatments were administered for 9 days. Following the experiment, parameters of tumor inhibition, body and organ mass, biochemical markers of cardiac and hepatic injury, oxidative stress in cardiac and hepatic tissue – through levels of malondialdehyde (MDA), total sulfhydryls, and activity of glutathione peroxidase (GPX) and superoxide dismutase (SOD) – and hematological analysis were evaluated. Data were processed using the Shapiro-Wilk test, analysis of variance (one-way or two-way), and Tukey's post-hoc test. The results showed that the combined treatment did not present a significant antitumor effect. In toxicological parameters, the combined treatment led to loss of body mass and heart and liver mass, as well as elevation of levels of biochemical markers of cardiac and hepatic injury, especially in the POH 50 + DOX and POH 100 + DOX groups. In oxidative stress of cardiac tissue, the POH 100 + DOX and POH 200 + DOX groups showed elevated MDA levels, with increased SOD activity in the latter group. In liver tissue, MDA levels decreased in both combined treatment groups, and GPX activity increased. Hematological analysis showed that the alterations induced by doxorubicin persisted in the combined treatment. Therefore, perillyl alcohol combined with doxorubicin did not show promise in the treatment of sarcoma 180.