Determinação do mecanismo de ação citototóxica de alguns compostos extraídos de plantas do Nordeste brasileiro

• Ano de defesa: 2000
• Autor(a) principal: Pessoa, Cláudia do Ó
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Toxicidade; Antineoplásicos; Plantas medicinais; Medicina Herbária; Neoplasias
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/66037

Eleven phytochemicals derived from plants to Northeast Brazil were studied for their antiproliferative effects in the human tumor cell lines CEM (leukemia) and SW-1573 (lung tumor), and in the normal human fibroblast cell line CCD-922. Using the MTT microtiter assay, five compounds were found to have IC50 values less than 10 gg/mL in the tumor cell lines. Jatrophone showed non-specifíc cytotoxicity, with IC50 values less than 1 gg/mL for all three cell lines. Meanwhile, a diterpenoid and a flavanoid, both from Egletes viscosa (Compositae family) had moderate activity. The 12-acetoxy hautriwaic acid lactone (clerodane A) was cytotoxic, with IC50 values of 6, 6 and 10 gg/mL, while 4’5-dihydroxy- 3,3’,7,8-tetramethoxy-flavone (tematin) was growth-inhibitory, with IC50 values of 2, 2 and 10 gg/mL in CEM, SW-1573 and CCD-922, respectively. Those compounds showing more differential cytotoxicity were oncocalyxones A (re/-8a-hydroxy-5-hydroxymethyl-2- methoxy-8al3-mehtyl-7,8,8a,9-tetrahydro-l,4-anthracenodione) and C (re/-10a,HJ3-epoxy- 1 la.-ethoxy-8a-hydroxy-2-methoxy-8aP-methyl-5,6,7,8,8a,9,10,10aP-octahydro-l,4- anthracenodione), both derived from Auxemma oncocalyx (Boraginaceae family), with IC50 values of 0.8-2, 7-8 and 12-13 gg/mL in CEM, SW-1573 and CCD-922, respectively. These four latter compounds were examined for their DNA reactivity, with regard to inhibition of DNA synthesis (5-BrdU incorporation) and induction of apoptosis (TUNEL assay and annexin V binding). Except for tematin, these compounds caused DNA damage, marked inhibition of 5-BrdU incorporation, DNA strand breaks and strong induction of apoptosis. Derivatives of oncocalyxone A obtained by chlorination and acetylation were less cytotoxic relative to the parent compound when tested against human leukemia cells. The cytotoxicity of oncocalyxone A when compared with other anticancer drugs belonging to the anthroquinone group, showed a low potency. Nonetheless, in multidrug resistant tumor cells with 10 to 500 fold lower sensitivity to doxorubicin, oncocalyxone A cytotoxicity was only moderately reduced twofold. In vivo, studies showed substantial inhibition of tumor growth of approximately 42% and 50% in L1210 leukemia and Ehrlich carcinoma, respectively. Oncocalyxone A (1,4-anthracenedione) could be considered as a new benzoquinone, with therapeutic potential in câncer chemotherapy, that possibly involving DNA reactivity leading to apoptosis in the câncer cells.