In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118
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Cancer is a malignancy of worldwide prevalence, and although new therapeutic strategies are under investigation, patients still resort to reductive or palliative chemotherapy. Side effects are a great concern, since treatment can render patients susceptible to infections or secondary cancers. Thus, design of safer chemotherapeutic drugs must consider the risk of immunotoxicity. Pterocarpans are natural isoflavones that possess immunomodulatory and antineoplastic properties. Ubiquitous in nature, quinones are present in chemotherapeutic drugs such as doxorubicin and mitoxantrone. Our group has patented a hybrid molecule, the pterocarpanquinone LQB-118, and demonstrated its antineoplastic effect in vitro. In this report we describe its antineoplastic effect in vivo and assess its toxicity toward the immune system. Treated mice presented no changes in weight of primary and secondary organs of the immune system nor their cellular composition. Immunophenotyping showed that treatment increased CD4+ thymocytes and proportionally reduced the CD4+CD8+ subpopulation in the thymus. No significant changes were observed in T CD8+ peripheral lymphocytes nor was the activation of fresh T cells affected after treatment. LQB-118 induced apoptosis in murine tumor cells in vitro, being synergistic with the autophagy promoter rapamycin. Furthermore, treatment significantly reduced ascites or solid Ehrlich and B16F10 melanoma growth in vivo, and ameliorated side effects such as cachexia. Based on its favorable preclinical profile and considering previous results obtained in vitro, this drug emerges as a promising candidate for further development.
KeywordsPterocarpan Naphthoquinone Autophagy Immunotoxicity Ehrlich tumor Melanoma
Authors are grateful to Prof. Alcides José Monteiro da Silva and Prof. Camilla Djenne Buarque Müller for participating in discussions and the preparing of LQB-118. We would also like to thank Dr. Ottilia Rodrigues Affonso-Mitidieri for useful suggestions in chemistry, Prof. Martha Meriwether Sorenson for reviewing the manuscript and Prof. Claudio Akio Masuda for his kind rapamycin donation. Research was supported by grants from: Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq; Financiadora de Estudos e Projetos – FINEP; Programa de Oncobiologia; Fundação do Câncer; Instituto Nacional de Ciência e Tecnologia para Controle do Câncer – INCT-Câncer, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES.
Compliance with ethical standards
Conflict of interest
LQB-118, compounds of the pterocarpanquinone family, methods for preparing the same, pharmaceutical compositions containing new compounds of the pterocarpanquinone family, uses and therapeutic methods are protected under patent number US8835489B2, assigned to the Federal University of Rio de Janeiro and granted by USPTO in 16–09-2014 . Eduardo J. Salustiano, Chaquip D. Netto, Paulo R. Costa and Vivian M. Rumjanek are listed as inventors. Patent was not outlicenced and inventors did not receive money from private companies but grants from public agencies stated in Acknowledgments. Funding agencies had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. Procedures for animal experimentation were approved by the Centro de Ciências da Saúde Ethics Committee for Animal Use (CEUA-CCS, UFRJ) under protocol number IBQM082.
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