In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118
- 404 Downloads
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.
- 9.Derenzini E, Casadei B, Broccoli A, Gandolfi L, Pellegrini C, Zinzani PL (2014) Sequential therapy with alternating short courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and R-FM (rituximab, fludarabine, mitoxantrone) followed by autologous stem cell transplantation results in long term remission in advanced follicular lymphoma. Br J Haematol 166:625–628. doi: 10.1111/bjh.12894 CrossRefPubMedGoogle Scholar
- 10.Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A, Vonhof S, Bickeboller H, Toliat MR, Suk EK, Tzvetkov M, Kruger A, Seifert S, Kloess M, Hahn H, Loeffler M, Nurnberg P, Pfreundschuh M, Trumper L, Brockmoller J, Hasenfuss G (2005) NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112:3754–3762. doi: 10.1161/CIRCULATIONAHA.105.576850 CrossRefPubMedGoogle Scholar
- 11.da Cunha-Junior EF, Pacienza-Lima W, Ribeiro GA, Netto CD, do Canto-Cavalheiro MM, da Silva AJ, Costa PR, Rossi-Bergmann B, Torres-Santos EC (2011) Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis. J Antimicrob Chemother 66:1555–1559. doi: 10.1093/jac/dkr158 CrossRefPubMedGoogle Scholar
- 12.Salustiano EJ, Netto CD, Fernandes RF, da Silva AJ, Bacelar TS, Castro CP, Buarque CD, Maia RC, Rumjanek VM, Costa PR (2010) Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells. Investig New Drugs 28:139–144. doi: 10.1007/s10637-009-9231-y CrossRefGoogle Scholar
- 13.Netto CD, da Silva AJ, Salustiano EJ, Bacelar TS, Rica IG, Cavalcante MC, Rumjanek VM, Costa PR (2010) New pterocarpanquinones: synthesis, antineoplasic activity on cultured human malignant cell lines and TNF-alpha modulation in human PBMC cells. Bioorg Med Chem 18:1610–1616. doi: 10.1016/j.bmc.2009.12.073 CrossRefPubMedGoogle Scholar
- 14.Da Silva AJM, Rumjanek VMBD, Bergmann BR, Salustiano EJ, Costa PRR, Netto CD, Lima WP, Dos Santos ECT, Cavalcante MCM, Seabra SH (2014) Compounds of the pterocarpanquinone family, method for preparing the same, pharmaceutical composition containing the new compounds of the pterocarpanquinone family, uses and therapeutic method. United States Patent US8835489-B2, 16–09-2014 doi: 10.13140/RG.2.1.1944.7769
- 15.Martino T, Magalhaes FC, Justo GA, Coelho MG, Netto CD, Costa PR, Sabino KC (2014) The pterocarpanquinone LQB-118 inhibits tumor cell proliferation by downregulation of c-Myc and cyclins D1 and B1 mRNA and upregulation of p21 cell cycle inhibitor expression. Bioorg Med Chem 22:3115–3122. doi: 10.1016/j.bmc.2014.04.025 CrossRefPubMedGoogle Scholar
- 16.Ribeiro GA, Cunha-Junior EF, Pinheiro RO, da-Silva SA, Canto-Cavalheiro MM, da Silva AJ, Costa PR, Netto CD, Melo RC, Almeida-Amaral EE, Torres-Santos EC (2013) LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis. J Antimicrob Chemother 68:789–799. doi: 10.1093/jac/dks498 CrossRefPubMedGoogle Scholar
- 17.Nestal de Moraes G, Castro CP, Salustiano EJ, Dumas ML, Costas F, Lam EW, Costa PR, Maia RC (2014) The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors. Int J Oncol 45:1949–1958. doi: 10.3892/ijo.2014.2615 PubMedGoogle Scholar
- 20.Maia RC, Vasconcelos FC, de Sa BT, Salustiano EJ, da Silva LF, Pereira DL, Moellman-Coelho A, Netto CD, da Silva AJ, Rumjanek VM, Costa PR (2011) 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. Investig New Drugs 29:1143–1155. doi: 10.1007/s10637-010-9453-z CrossRefGoogle Scholar
- 21.Buarque CD, Militao GC, Lima DJ, Costa-Lotufo LV, Pessoa C, de Moraes MO, Cunha-Junior EF, Torres-Santos EC, Netto CD, Costa PR (2011) Pterocarpanquinones, aza-pterocarpanquinone and derivatives: synthesis, antineoplasic activity on human malignant cell lines and antileishmanial activity on Leishmania amazonensis. Bioorg Med Chem 19:6885–6891. doi: 10.1016/j.bmc.2011.09.025 CrossRefPubMedGoogle Scholar
- 22.de Souza Reis FR, de Faria FC, Castro CP, de Souza PS, da Cunha VF, Bello RD, da Silva AJ, Costa PR, Maia RC (2013) The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells. Anti Cancer Agents Med Chem 13:341–351. doi: 10.2174/1871520611313020019 CrossRefGoogle Scholar
- 25.Cheng SM, Chang YC, Liu CY, Lee JY, Chan HH, Kuo CW, Lin KY, Tsai SL, Chen SH, Li CF, Leung E, Kanwar JR, Huang CC, Chang JY, Cheung CH (2015) YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells. Br J Pharmacol 172:214–234. doi: 10.1111/bph.12935 CrossRefPubMedGoogle Scholar
- 30.Capone F, Guerriero E, Sorice A, Colonna G, Storti G, Pagliuca J, Castello G, Costantini S (2014) Synergistic antitumor effect of doxorubicin and tacrolimus (FK506) on hepatocellular carcinoma cell lines. ScientificWorldJournal 2014:450390. doi: 10.1155/2014/450390 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Allodji RS, Schwartz B, Veres C, Haddy N, Rubino C, Le Deley MC, Labbe M, Diop F, Jackson A, Dayet F, Benabdennebi A, Llanas D, Vu Bezin J, Chavaudra J, Lefkopoulos D, Deutsch E, Oberlin O, de Vathaire F, Diallo I (2015) Risk of subsequent leukemia after a solid tumor in childhood: impact of bone marrow radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 93:658–667. doi: 10.1016/j.ijrobp.2015.07.2270 CrossRefPubMedGoogle Scholar
- 39.de Oliveira SI, Andrade LN, Onuchic AC, Nonogaki S, Fernandes PD, Pinheiro MC, Rohde CB, Chammas R, Jancar S (2010) Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy. BMC Cancer 10:200. doi: 10.1186/1471-2407-10-200 CrossRefPubMedPubMedCentralGoogle Scholar