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Investigational New Drugs

, Volume 29, Issue 6, pp 1143–1155 | Cite as

LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells

  • Raquel C. Maia
  • Flavia C. Vasconcelos
  • Thiago de Sá Bacelar
  • Eduardo J. Salustiano
  • Luis Felipe R. da Silva
  • Débora L. Pereira
  • Arthur Moellman-Coelho
  • Chaquip D. Netto
  • Alcides J. da Silva
  • Vivian M. Rumjanek
  • Paulo R. R. Costa
PRECLINICAL STUDIES

Summary

Despite the relevant therapeutic progresses obtained with imatinib, clinical resistance to this drug has emerged and reemerged after cytogenetic remission in a group of patients with chronic myeloid leukemia (CML). Therefore, novel treatment strategies are needed. In this study, we evaluated the anti-CML activity and mechanisms of action of LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]. LQB-118 treatment resulted in an important reduction of cell viability in cell lines derived from CML, both the vincristine-sensitive K562 cell line, and the resistant K562-Lucena (a cell line overexpressing P-glycoprotein). In agreement with these results, the induction of caspase-3 activation by this compound indicated that a significant rate of apoptosis was taking place. In these cell lines, apoptosis induced by LQB-118 was accompanied by a reduction of P-glycoprotein, survivin, and XIAP expression. Moreover, this effect was not restricted to cell lines as LQB-118 produced significant apoptosis rate in cells from CML patients exhibiting multifactorial drug resistance phenotype such as P-glycoprotein, MRP1 and p53 overexpression. The data suggest that LQB-118 has a potent anti-CML activity that can overcome multifactorial drug resistance mechanisms, making this compound a promising new anti-CML agent.

Keywords

Chronic myeloid leukemia Pterocarpanquinone LQB-118 Multidrug resistance IAPs ABC transporter proteins 

Notes

Acknowledgements

This work was supported by grants from FINEP, FAPERJ-PensaRio, INCT, CNPq and Swissbridge Foundation.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Raquel C. Maia
    • 1
    • 2
    • 6
  • Flavia C. Vasconcelos
    • 1
    • 2
  • Thiago de Sá Bacelar
    • 3
  • Eduardo J. Salustiano
    • 3
  • Luis Felipe R. da Silva
    • 1
    • 2
  • Débora L. Pereira
    • 1
    • 2
  • Arthur Moellman-Coelho
    • 2
  • Chaquip D. Netto
    • 4
  • Alcides J. da Silva
    • 5
  • Vivian M. Rumjanek
    • 3
  • Paulo R. R. Costa
    • 5
  1. 1.Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia MolecularInstituto Nacional de Câncer (INCA)Rio de JaneiroBrazil
  2. 2.Serviço de Hematologia, Hospital do Câncer IINCARio de JaneiroBrazil
  3. 3.Laboratório de Imunologia Tumoral, Instituto de Bioquímica MédicaUniversidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
  4. 4.Laboratório de Química Orgânica, Instituto de QuímicaUFRJ, CampusMacaéBrazil
  5. 5.Laboratório de Química Bioorgânica (LQB), Núcleo de Pesquisas de Produtos Naturais (NPPN), Centro de Ciências da SaúdeUFRJRio de JaneiroBrazil
  6. 6.Laboratório de Hemato-Oncologia Celular e Molecular, Hospital do Câncer IInstituto Nacional de CâncerRio de JaneiroBrazil

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