Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

Insights into the Biological Evaluation of Pterocarpanquinones and Carbapterocarpans with Anti-tumor Activity against MDR Leukemias

Author(s): Vivian M. Rumjanek*, Raquel C. Maia, Eduardo J. Salustiano* and Paulo R.R. Costa

Volume 19 , Issue 1 , 2019

Page: [29 - 37] Pages: 9

DOI: 10.2174/1871520618666180420165128

Price: $65


In an attempt to find anticancer agents that could overcome multidrug resistance (MDR), two new classes of modified isoflavonoids were designed and synthesized, and their effectiveness evaluated against a vast array of tumor cell lines. Pterocarpanquinone (LQB-118) and 11a-aza-5-carbapterocarpan (LQB-223) were the most promising. LQB-118 induced cell death, in vitro, in the µM range, to a number of human cancer cell lines as well as to fresh tumor cells obtained from patients with acute or chronic myeloid leukemia, independent on whether they exhibit the MDR phenotype or not. Furthermore, leukemic cells were more sensitive to LQB- 118 compared to cells from solid tumors. Given to mice, in vivo, LQB-118 affected the growth of melanoma, Ehrlich carcinoma and prostate cancer cells. Conversely, no general toxicity was observed in vivo, by biochemical, hematological, anatomical or histological parameters and toxicity in vitro against normal cells was low. The process involved in tumor cell death seemed to vary according to cell type. Apoptosis was studied by externalization of phosphatidylserine, DNA fragmentation, caspase-3 activation, reduced expression of XIAP and survivin, ER stress, cytosolic calcium increase and mitochondrial membrane depolarization. Autophagy was also evaluated inhibiting caspase-9, with no effect observed in beclin 1, whereas pre-treatment with rapamycin increased cytotoxicity induced by LQB-118. In addition, LQB-118 increased ROS, inhibited NFκB nuclear translocation and secretion of TNF-α, modulated microRNAs miR-9 and miR-21 and modified the cell cycle. Despite being less studied, the cytotoxic effect of the 11a-aza-5-carbapterocarpan LQB-223 was present against several tumor cell lines, including those with the MDR phenotype.

Keywords: Pterocarpanquinones, carbapterocarpans, anticancer agents, tumor cells, leukemias, MDR.

Graphical Abstract
Global Burden of Disease Cancer. C. The global burden of cancer 2013. JAMA Oncol., 2015, 1(4), 505-527.
Pedersen, J.K.; Engholm, G.; Skytthe, A.; Christensen, K. Cancer and aging: Epidemiology and methodological challenges. Acta Oncol., 2016, 55(Suppl. 1), 7-12.
Gottesman, M.M.; Lavi, O.; Hall, M.D.; Gillet, J.P. Toward a better understanding of the complexity of cancer drug resistance. Annu. Rev. Pharmacol. Toxicol., 2016, 56, 85-102.
Baguley, B.C. Classical and targeted anticancer drugs: An appraisal of mechanisms of multidrug resistance. Methods Mol. Biol., 2016, 1395, 19-37.
Chaudhuri, S.K.; Huang, L.; Fullas, F.; Brown, D.M.; Wani, M.C.; Wall, M.E. Isolation and structure identification of an active DNA strand-scission agent, (+)-3,4-di-hydroxy-8,9-methylenedioxypterocarpan. J. Nat. Prod., 1995, 58(12), 1966-1969.
Netto, C.D.; Santos, E.S.; Castro, C.P.; da Silva, A.J.; Rumjanek, V.M.; Costa, P.R. (+/-)-3,4-Dihydroxy-8,9-methylenedioxypterocarpan and derivatives: cytotoxic effect on human leukemia cell lines. Eur. J. Med. Chem., 2009, 44(2), 920-925.
da Silva, A.J.; Buarque, C.D.; Brito, F.V.; Aurelian, L.; Macedo, L.F.; Malkas, L.H.; Hickey, R.J.; Lopes, D.V.; Noel, F.; Murakami, Y.L.; Silva, N.M.; Melo, P.A.; Caruso, R.R.; Castro, N.G.; Costa, P.R. Synthesis and preliminary pharmacological evaluation of new (+/-) 1,4-naphthoquinones structurally related to lapachol. Bioorg. Med. Chem., 2002, 10(8), 2731-2738.
Salustiano, E.J.; Netto, C.D.; Fernandes, R.F.; da Silva, A.J.; Bacelar, T.S.; Castro, C.P.; Buarque, C.D.; Maia, R.C.; Rumjanek, V.M.; Costa, P.R. Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells. Invest. New Drugs, 2010, 28(2), 139-144.
Casini, A.; Scozzafava, A.; Mastrolorenzo, A.; Supuran, L.T. Sulfonamides and sulfonylated derivatives as anticancer agents. Curr. Cancer Drug Targets, 2002, 2(1), 55-75.
Netto, C.D.; da Silva, A.J.; Salustiano, E.J.; Bacelar, T.S.; Rica, I.G.; Cavalcante, M.C.; Rumjanek, V.M.; Costa, P.R. New pterocarpanquinones: Synthesis, antineoplasic activity on cultured human malignant cell lines and TNF-alpha modulation in human PBMC cells. Bioorg. Med. Chem., 2010, 18(4), 1610-1616.
Buarque, C.D.; Militao, G.C.; Lima, D.J.; Costa-Lotufo, L.V.; Pessoa, C.; de Moraes, M.O.; Cunha-Junior, E.F.; Torres-Santos, E.C.; Netto, C.D.; Costa, P.R. Pterocarpanquinones, aza-pterocarpanquinone and derivatives: Synthesis, antineoplasic activity on human malignant cell lines and antileishmanial activity on Leishmania amazonensis. Bioorg. Med. Chem., 2011, 19(22), 6885-6891.
Lemos, L.G.; de Moraes, N.G.; Delbue, D.; Fda, V.C.; Bernardo, P.S.; Lam, E.W.; Buarque, C.D.; Costa, P.R.; Maia, R.C. 11a-N-Tosyl-5-deoxi-pterocarpan, LQB-223, a novel compound with potent antineoplastic activity toward breast cancer cells with different phenotypes. J. Cancer Res. Clin. Oncol., 2016, 142(10), 2119-2130.
Salustiano, E.J.; Dumas, M.L.; Silva-Santos, G.G.; Netto, C.D.; Costa, P.R.; Rumjanek, V.M. In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118. Invest. New Drugs, 2016, 34(5), 541-551.
Reis, S.F.R.; de Faria, F.C.; Castro, C.P.; de Souza, P.S.; da Cunha Vasconcelos, F.; Bello, R.D.; da Silva, A.J.; Costa, P.R.; Maia, R.C. The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells. Anticancer. Agents Med. Chem., 2013, 13(2), 341-351.
Bacelar, S.T.; da Silva, A.J.; Costa, P.R.; Rumjanek, V.M. The pterocarpanquinone LQB 118 induces apoptosis in tumor cells through the intrinsic pathway and the endoplasmic reticulum stress pathway. Anticancer Drugs, 2013, 24(1), 73-83.
de Moraes, N.G.; Castro, C.P.; Salustiano, E.J.; Dumas, M.L.; Costas, F.; Lam, E.W.; Costa, P.R.; Maia, R.C. 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., 2014, 45(5), 1949-1958.
Martino, T.; Magalhaes, F.C.; Justo, G.A.; Coelho, M.G.; Netto, C.D.; Costa, P.R.; Sabino, K.C. 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., 2014, 22(12), 3115-3122.
Nakamura, S.; Hirano, I.; Okinaka, K.; Takemura, T.; Yokota, D.; Ono, T.; Shigeno, K.; Shibata, K.; Fujisawa, S.; Ohnishi, K. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis, 2010, 31(11), 2012-2021.
Wang, I.C.; Chen, Y.J.; Hughes, D.; Petrovic, V.; Major, M.L.; Park, H.J.; Tan, Y.; Ackerson, T.; Costa, R.H. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell. Biol., 2005, 25(24), 10875-10894.
Guerra, B.; Martin-Rodriguez, P.; Diaz-Chico, J.C.; McNaughton-Smith, G.; Jimenez-Alonso, S.; Hueso-Falcon, I.; Montero, J.C.; Blanco, R.; Leon, J.; Rodriguez-Gonzalez, G.; Estevez-Braun, A.; Pandiella, A.; Diaz-Chico, B.N.; Fernandez-Perez, L. CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia. Oncotarget, 2017, 8(18), 29679-29698.
de Faria, F.C.; Leal, M.E.; Bernardo, P.S.; Costa, P.R.; Maia, R.C. NFkappaB pathway and microRNA-9 and -21 are involved in sensitivity to the pterocarpanquinone LQB-118 in different CML cell lines. Anticancer. Agents Med. Chem., 2015, 15(3), 345-352.
Maia, R.C.; Vasconcelos, F.C.; Bacelar, S.T.; Salustiano, E.J.; da Silva, L.F.; Pereira, D.L.; Moellman-Coelho, A.; Netto, C.D.; da Silva, A.J.; Rumjanek, V.M.; Costa, P.R. 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. Invest. New Drugs, 2011, 29(6), 1143-1155.
da Cunha-Junior, E.F.; Pacienza-Lima, W.; Ribeiro, G.A.; Netto, C.D.; do Canto-Cavalheiro, M.M.; da Silva, A.J.; Costa, P.R.; Rossi-Bergmann, B.; Torres-Santos, E.C. Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis. J. Antimicrob. Chemother., 2011, 66(7), 1555-1559.
Costa, L.; Pinheiro, R.O.; Dutra, P.M.; Santos, R.F.; Cunha-Junior, E.F.; Torres-Santos, E.C.; da Silva, A.J.; Costa, P.R.; Da-Silva, S.A. Pterocarpanquinone LQB-118 induces apoptosis in Leishmania (Viannia) braziliensis and controls lesions in infected hamsters. PLoS One, 2014, 9(10), e109672.
Jde, P.A.; Netto, C.D.; da Silva, A.J.; Costa, P.R.; DaMatta, R.A.; dos Santos, T.A.; De Souza, W.; Seabra, S.H. A new type of pterocarpanquinone that affects Toxoplasma gondii tachyzoites in vitro. Vet. Parasitol., 2012, 186(3-4), 261-269.
Cortopassi, W.A.; Penna-Coutinho, J.; Aguiar, A.C.; Pimentel, A.S.; Buarque, C.D.; Costa, P.R.; Alves, B.R.; Franca, T.C.; Krettli, A.U. Theoretical and experimental studies of new modified isoflavonoids as potential inhibitors of topoisomerase I from Plasmodium falciparum. PLoS One, 2014, 9(3), e91191.
Salustiano, E.J. Anti-tumor effect of new synthetic compounds on multidrug resistant cell lines., MSc Dissertation, Federal University of Rio de Janeiro: Rio de Janeiro, October. 2008.
Feng, W.; Yoshida, A.; Ueda, T. YM155 induces caspase-8 dependent apoptosis through downregulation of survivin and Mcl-1 in human leukemia cells. Biochem. Biophys. Res. Commun., 2013, 435(1), 52-57.
Lien, Y.C.; Kung, H.N.; Lu, K.S.; Jeng, C.J.; Chau, Y.P. Involvement of endoplasmic reticulum stress and activation of MAP kinases in beta-lapachone-induced human prostate cancer cell apoptosis. Histol. Histopathol., 2008, 23(11), 1299-1308.
Lorin, S.; Hamai, A.; Mehrpour, M.; Codogno, P. Autophagy regulation and its role in cancer. Semin. Cancer Biol., 2013, 23(5), 361-379.
Silva, T.L.; Ferreira, F.R.; de Vasconcelos, C.C.; da Silva, R.C.; Lima, D.J.P.; Costa, P.R.R.; Netto, C.D.; Goulart, M.O.F. ROS release, alkylating ability and DNA interaction of a pterocarpanquinone: A test case for electrochemistry. ChemElectroChem, 2016, 3, 2252-2263.
Chen, J. Reactive oxygen species and drug resistance in cancer chemotherapy. Austin J. Clin. Pathol., 2014, 1(4), 1017.
Bacelar, S.T. LQB 118: Diferentes Formas de Matar (LQB 118: different ways to kill), PhD Thesis, Federal University of Rio de Janeiro: Rio de Janeiro, August 2014.
Rumjanek, V.M.; Trindade, G.S.; Wagner-Souza, K.; de-Oliveira, M.C.; Marques-Santos, L.F.; Maia, R.C.; Capella, M.A. Multidrug resistance in tumour cells: characterization of the multidrug resistant cell line K562-Lucena 1. An. Acad. Bras. Cienc., 2001, 73(1), 57-69.
Oh, E.T.; Park, H.J. Implications of NQO1 in cancer therapy. BMB Rep., 2015, 48(11), 609-617.
Krishnan, S.; Miller, R.M.; Tian, B.; Mullins, R.D.; Jacobson, M.P.; Taunton, J. Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis. J. Am. Chem. Soc., 2014, 136(36), 12624-12630.
Lee, C.H.; Jeon, Y.T.; Kim, S.H.; Song, Y.S. NF-kappaB as a potential molecular target for cancer therapy. Biofactors, 2007, 29(1), 19-35.
Rica, I.G.; Netto, C.D.; Renno, M.N.; Abreu, P.A.; Costa, P.R.; da Silva, A.J.; Cavalcante, M.C. Anti-inflammatory properties of pterocarpanquinone LQB-118 in mice. Bioorg. Med. Chem., 2016, 24(18), 4415-4423.
Phillips, R.M. Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs. Cancer Chemother. Pharmacol., 2016, 77(3), 441-457.
Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer, 2003, 3(10), 721-732.
van Uden, P.; Kenneth, N.S.; Rocha, S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem. J., 2008, 412(3), 477-484.
Ribeiro, G.A.; Cunha-Junior, E.F.; Pinheiro, R.O.; da-Silva, S.A.; Canto-Cavalheiro, M.M.; da Silva, A.J.; Costa, P.R.; Netto, C.D.; Melo, R.C.; Almeida-Amaral, E.E.; Torres-Santos, E.C. LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis. J. Antimicrob. Chemother., 2013, 68(4), 789-799.
Lu, T.; Sathe, S.S.; Swiatkowski, S.M.; Hampole, C.V.; Stark, G.R. Secretion of cytokines and growth factors as a general cause of constitutive NFkappaB activation in cancer. Oncogene, 2004, 23(12), 2138-2145.
Jansson, M.D.; Lund, A.H. MicroRNA and cancer. Mol. Oncol., 2012, 6(6), 590-610.
Boldin, M.P.; Baltimore, D. MicroRNAs, new effectors and regulators of NF-kappaB. Immunol. Rev., 2012, 246(1), 205-220.
Moreira, M.A.; Bagni, C.; de Pinho, M.B.; Mac-Cormick, T.M.; Mota, S.M.; Pinto-Silva, F.E.; Daflon-Yunes, N.; Rumjanek, V.M. Changes in gene expression profile in two multidrug resistant cell lines derived from a same drug sensitive cell line. Leuk. Res., 2014, 38(8), 983-987.
Rumjanek, V.M.; Vidal, R.S.; Maia, R.C. Multidrug resistance in chronic myeloid leukaemia: How much can we learn from MDR-CML cell lines? Biosci. Rep., 2013, 33(6), e00081.
Daflon-Yunes, N.; Pinto-Silva, F.E.; Vidal, R.S.; Novis, B.F.; Berguetti, T.; Lopes, R.R.; Polycarpo, C.; Rumjanek, V.M. Characterization of a multidrug-resistant chronic myeloid leukemia cell line presenting multiple resistance mechanisms. Mol. Cell. Biochem., 2013, 383(1-2), 123-135.
Shi, Z.; Liang, Y.J.; Chen, Z.S.; Wang, X.H.; Ding, Y.; Chen, L.M.; Fu, L.W. Overexpression of survivin and XIAP in MDR cancer cells unrelated to P-glycoprotein. Oncol. Rep., 2007, 17(4), 969-976.
Souza, P.S.; Vasconcelos, F.C.; Reis, S.F.R.; De Moraes, N.G.; Maia, R.C. P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells. Int. J. Oncol., 2011, 39(4), 925-933.
Trindade, G.S.; Capella, M.A.; Capella, L.S.; Affonso-Mitidieri, O.R.; Rumjanek, V.M. Differences in sensitivity to UVC, UVB and UVA radiation of a multidrug-resistant cell line overexpressing P-glycoprotein. Photochem. Photobiol., 1999, 69(6), 694-699.
Votto, S.A.P.; Renon, V.P.; Yunes, J.S.; Rumjanek, V.M.; Marques Capella, M.A.; Neto, V.M.; de Freitas, S.M.; Geracitano, A.L.; Monserrat, J.M.; Trindade, G.S. Sensitivity to microcystins: A comparative study in human cell lines with and without multidrug resistance phenotype. Cell Biol. Int., 2007, 31(11), 1359-1366.
Vidal, S.R. Therapeutic targets in the multiple drug resistance phenotype., PhD Thesis, Federal University of Rio de Janeiro: Rio de Janeiro. 2017.
Lenehan, P.F.; Gutierrez, P.L.; Wagner, J.L.; Milak, N.; Fisher, G.R.; Ross, D.D. Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to the resistance to daunorubicin manifested by these cells. Cancer Chemother. Pharmacol., 1995, 35(5), 377-386.
Maia, R.C.; Vasconcelos, F.C.; Souza, P.S.; Rumjanek, V.M. Towards comprehension of the ABCB1/P-Glycoprotein role in chronic myeloid leukemia. Molecules, 2018, 23(1), 119.
Cunha-Junior, E.F.; Martins, T.M.; Canto-Cavalheiro, M.M.; Marques, P.R.; Portari, E.A.; Coelho, M.G.; Netto, C.D.; Costa, P.R.; Sabino, K.C.; Torres-Santos, E.C. Preclinical studies evaluating subacute toxicity and therapeutic efficacy of lqb-118 in experimental visceral leishmaniasis. Antimicrob. Agents Chemother., 2016, 60(6), 3794-3801.
Martino, T.; Kudrolli, T.A.; Kumar, B.; Salviano, I.; Mencalha, A.; Coelho, M.G.P.; Justo, G.; Costa, P.R.R.; Sabino, K.C.C.; Lupold, S.E. The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress. Prostate, 2018, 78(2), 140-151.
Buarque, C.D.; Salustiano, E.J.; Fraga, K.C.; Alves, B.R.; Costa, P.R. 11a-N-Tosyl-5-deoxi-pterocarpan (LQB-223), a promising prototype for targeting MDR leukemia cell lines. Eur. J. Med. Chem., 2014, 78, 190-197.
Silva, M.M.; Nascimento, E.O.; Silva, E.F., Jr; Araújo, J.X., Jr; Santana, C.C.; Grillo, L.A.; de Oliveira, R.S.; Costa, P.R.R.; Buarque, C.D.; Santos, J.C.; Figueiredo, I.M. Interaction between bioactive compound 11a-N-tosyl-5-deoxi-pterocarpan (LQB-223) and calf thymus DNA: Spectroscopic approach, electrophoresis and theoretical studies. Int. J. Biol. Macromol., 2017, 96, 223-233.
Da Silva, A.J.M.; Rumjanek, V.M.B.D.; Bergmann, B.R.; Salustiano, E.J.; Costa, P.R.R.; Netto, C.D.; Lima, W.P.; Dos Santos, E.C.T.; Cavalcante, M.C.M.; Seabra, S.H. Compounds of the pterocarpanquinone family, method for preparing the same, pharmaceutical composition containing the new compounds of the pterocarpanquinone family, uses and therapeutic method. U.S. Patent 8,835,489 B2, September 16, 2014.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy