RESUMO
Phytochemicals have been suggested as an effective strategy for cancer prevention. Within this context, triterpene betulinic acid (BA) exhibits several biological properties but its chemopreventive effect has not been fully demonstrated. The present study investigated the antigenotoxic potential of BA against doxorubicin (DXR)-induced genotoxicity using the mouse peripheral blood micronucleus assay, as well as its anticarcinogenic activity against 1,2dimethylhydrazine (DMH)-induced colorectal lesions in rats. Micronuclei (MN) assay and aberrant crypt foci assay were used to assess the antigenotoxic and the anticarcinogenic potential, respectively. The molecular mechanisms underlying the anticarcinogenic activity of BA were evaluated by assessing anti-inflammatory (COX-2) and antiproliferative (PCNA) pathways. The results demonstrated that BA at the dose of 0.5 mg/kg bodyweight exerted antigenotoxic effects against DXR, with a reduction of 70.2% in the frequencies of chromosomal damage. Animals treated with BA showed a 64% reduction in the number of preneoplastic lesions when compared to those treated with the carcinogen alone. The levels of COX-2 and PCNA expression in the colon were significantly lower in animals treated with BA and DMH compared to those treated with the carcinogen alone. The chemopreventive effect of BA is related, at least in part, to its antiproliferative and anti-inflammatory activity, indicating a promising potential of this triterpene in anticancer therapies, especially for colorectal cancer.
Assuntos
Anticarcinógenos/farmacologia , Antimutagênicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Antígeno Nuclear de Célula em Proliferação/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/prevenção & controle , Ciclo-Oxigenase 2/metabolismo , Doxorrubicina/toxicidade , Inflamação/prevenção & controle , Masculino , Camundongos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Ácido BetulínicoRESUMO
Melanoma is the deadliest type of skin cancer. Treatments that directly address tumor survival are required. Indomethacin (IND) is a well-known drug used worldwide. Although widely used as a therapeutic agent, IND has undesirable gastrointestinal effects. PURPOSE: To investigate the antitumor efficacy of IND incorporated into mesoporous silica nanoparticles (MSNPs+IND), as well as its toxic potential in a syngeneic murine B16 melanoma model. METHODS: Antitumor activity was evaluated by measuring tumor size and weight and by histopathological analysis. Possible molecular signaling pathways involved in the antitumor activity were analyzed by Western blot in liver tissue and by immunohistochemistry in tumor tissue. The potential toxicity was evaluated by determining body and organ weights and by biochemical and genotoxic analysis. RESULTS: MSNPs+IND treatments inhibited tumor growth by up to 70.09% and decreased the frequency of mitosis in tumor tissues, which was up to 37.95% lower compared to the IND groups. In hepatic tissue, COX-2 levels decreased significantly after treatment with MSNPs+IND and IND. Additionally, MSNPs+IND and IND increased the levels of cleaved caspase-3 (156.25% and 137.50%, respectively), inducing tumor cell apoptosis. Genotoxicity was limited to the group treated with the higher concentration of IND, while MSNPs prevented IND-induced genotoxicity. CONCLUSIONS: MSNPs may be promising for future applications in cancer therapy.