3β-acetyl tormentic acid induces apoptosis of resistant leukemia cells independently of P-gp/ABCB1 activity or expression.
Chronic myeloid leukemia (CML) is a potentially fatal stem-cell cancer. P-glycoprotein (P-gp/ABCB1) activity has been described as a relevant factor in the chemotherapeutic failure and correlated to a poor prognosis in these malignancies. In the present study, we investigated the mechanism of the antineoplastic activity of 3β-acetyl tormentic acid (3ATA), a triterpene isolated from C. lyratiloba, on Lucena-1, an MDR leukemia cell line, that overexpressed P-gp/ABCB1. Results showing that this triterpene induced DNA-fragmentation, activation of caspase-3 and cytochrome c release indicated that its activity is mediated by the activation of the intrinsic pathway of apoptosis. Interestingly, this triterpene did not interfere with P-gp/ABCB1 expression or activity, indicating that induction of death is not mediated by any effect on this protein. Moreover, the results show that none of the others triterpenes from C. lyratiloba were able to modulate the activity of P-gp/ABCB1. Together these results suggest 3ATA and the other triterpenes as a promising material for the development of anti-neoplastic drugs for leukemia and other tumors independent of P-gp/ABCB1 activity or expression.
Rocha
Gleice da Graça
Gda G
Lab. de Imunologia Celular, Instituto de Biofísica Carlos Chagas Filho, CCS Bl G, UFRJ, Rio de Janeiro, RJ 21949-900, Brazil.
Simões
Marisol
M
Oliveira
Rodrigo Rodrigues
RR
Kaplan
Maria Auxiliadora Coelho
MA
Gattass
Cerli Rocha
CR
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D035702:Cecropia Plant / Q000737:chemistry; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014315:Triterpenes; C007695:euscaphic acid; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3
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