LQB‑118 compound inhibits migration and induces cell death in glioblastoma cells

Bernardo,Paula   Sabbo; Guimarães,Gustavo Henrique   C.; De Faria,Fernanda   Costas C.; Longo,Gabriel   M. Da Cunha; Lopes,Giselle  P. De Faria; Netto,Chaquip   Daher; Costa,Paulo   R.R.; Maia,Raquel   C.

doi:10.3892/or.2019.7402

LQB‑118 compound inhibits migration and induces cell death in glioblastoma cells

Authors:
- Paula Sabbo Bernardo
- Gustavo Henrique C. Guimarães
- Fernanda Costas C. De Faria
- Gabriel M. Da Cunha Longo
- Giselle P. De Faria Lopes
- Chaquip Daher Netto
- Paulo R.R. Costa
- Raquel C. Maia
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Affiliations: Laboratory of Cellular and Molecular Hemato‑Oncology, Program of Molecular Hemato‑Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ 20230‑130, Brazil, Chemistry Laboratory, Federal University of Rio de Janeiro (UFRJ), Macaé Campus, Rio de Janeiro, RJ 27930‑560, Brazil, Bioorganic Chemistry Laboratory, Natural Products Research Institute (IPPN), Rio de Janeiro Federal University (UFRJ), Rio de Janeiro, RJ 21941‑599, Brazil
Published online on: November 6, 2019 https://doi.org/10.3892/or.2019.7402
Pages: 346-357

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Abstract

Glioblastoma (GBM) is the most frequent malignant brain tumor. It represents the most aggressive astrocytoma with an overall survival of 14 months. Despite improvements in surgery techniques, radio‑ and chemotherapy, most patients present treatment resistance, recurrence and disease progression. Therefore, development of effective alternative therapies is essential to overcome treatment failure. The purpose of the study was to evaluate the antitumoral activity of the synthetic compound LQB‑118, in vitro. Monolayer and three‑dimensional (3D) cell culture systems of human‑derived GBM cell lines were used to evaluate the effect of LQB‑118 on cell viability, cell death and migration. LQB‑118 reduced cell viability as determined by MTT and trypan blue exclusion assays and promoted apoptosis in monolayer cell lines with an intrinsic temozolomide (TMZ)‑resistance profile. In 3D culture models, LQB‑118 reduced cell viability as evaluated by APH assay and inhibited cell migration while the TMZ resistance profile was maintained. Moreover, LQB‑118 reduced p38 and AKT expression and phosphorylation, whereas it reduced only the phosphorylated ERK1/2 form. LQB‑118 reduced p38 and NRF2 expression, an axis that is associated with TMZ resistance, revealing a mechanism to overcome resistance. LQB‑118 also demonstrated an additional effect when combined with ionizing radiation and cisplatin. In conclusion, the present data demonstrated that LQB‑118 maintained its effectiveness in a 3D cell conformation, which shares more similarities with the tumor mass. LQB‑118 is a promising agent for GBM treatment as monotherapy and associated with radiotherapy or cisplatin. Its effect is associated with inhibition of GBM‑related survival signaling pathways.

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1	Omuro A and DeAngelis LM: Glioblastoma and other malignant gliomas: A clinical review. JAMA. 310:1842–1850. 2013. View Article : Google Scholar : PubMed/NCBI
2	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
3	Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, Henriksson R, Le Rhun E, Balana C, Chinot O, et al: European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 18:e315–e329. 2017. View Article : Google Scholar : PubMed/NCBI
4	Dresemann G: Temozolomide in malignant glioma. Onco Targets Ther. 3:139–146. 2010. View Article : Google Scholar : PubMed/NCBI
5	Netto CD, da Silva AJ, Salustiano EJ, Bacelar TS, Riça IG, Cavalcante MC, Rumjanek VM and Costa PR: 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. 2010. View Article : Google Scholar : PubMed/NCBI
6	de Souza Reis FR, de Faria FC, Castro CP, de Souza PS, da Cunha Vasconcelos F, Bello RD, da Silva AJ, Costa PR and Maia RC: The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells. Anticancer Agents Med Chem. 13:341–351. 2013. View Article : Google Scholar : PubMed/NCBI
7	Maia RC, Vasconcelos FC, de Sá, Bacelar T, Salustiano EJ, da Silva LF, Pereira DL, Moellman-Coelho A, Netto CD, da Silva AJ, Rumjanek VM and Costa PR: 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. 29:1143–1155. 2011. View Article : Google Scholar : PubMed/NCBI
8	Nestal de Moraes G, Castro CP, Salustiano EJ, Dumas ML, Costas F, Lam EW, Costa PR and Maia RC: 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. 2014. View Article : Google Scholar : PubMed/NCBI
9	Martino T, Magalhães FC, Justo GA, Coelho MG, Netto CD, Costa PR and Sabino KC: 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. 2014. View Article : Google Scholar : PubMed/NCBI
10	Martino T, Kudrolli TA, Kumar B, Salviano I, Mencalha A, Coelho MGP, Justo G, Costa PRR, Sabino KCC and Lupold SE: The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress. Prostate. 78:140–151. 2018. View Article : Google Scholar : PubMed/NCBI
11	Cunha-Júnior EF, Martins TM, Canto-Cavalheiro MM, Marques PR, Portari EA, Coelho MG, Netto CD, Costa PR, Sabino KC and Torres-Santos EC: Preclinical studies evaluating subacute toxicity and therapeutic efficacy of LQB-118 in experimental visceral leishmaniasis. Antimicrob Agents Chemother. 60:3794–3801. 2016. View Article : Google Scholar : PubMed/NCBI
12	de Sá, Bacelar T, da Silva AJ, Costa PR and Rumjanek VM: The pterocarpanquinone LQB 118 induces apoptosis in tumor cells through the intrinsic pathway and the endoplasmic reticulum stress pathway. Anticancer Drugs. 24:73–83. 2013. View Article : Google Scholar : PubMed/NCBI
13	de Faria FC, Leal ME, Bernardo PS, Costa PR and Maia RC: NFkB pathway and microRNA-9 and −21 are involved in sensitivity to the pterocarpanquinone LQB-118 in different CML cell lines. Anticancer Agents Med Chem. 15:345–352. 2015. View Article : Google Scholar : PubMed/NCBI
14	Molina JR, Hayashi Y, Stephens C and Georgescu MM: Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia. 12:453–463. 2010. View Article : Google Scholar : PubMed/NCBI
15	Ma L, Liu J, Zhang X, Qi J, Yu W and Gu Y: p38 MAPK-dependent Nrf2 induction enhances the resistance of glioma cells against TMZ. Med Oncol. 32:692015. View Article : Google Scholar : PubMed/NCBI
16	Jiang Z, Pore N, Cerniglia GJ, Mick R, Georgescu MM, Bernhard EJ, Hahn SM, Gupta AK and Maity A: Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res. 67:4467–4473. 2007. View Article : Google Scholar : PubMed/NCBI
17	Friedrich J, Seidel C, Ebner R and Kunz-Schughart LA: Spheroid-based drug screen: Considerations and practical approach. Nat Protoc. 4:309–324. 2009. View Article : Google Scholar : PubMed/NCBI
18	Friedrich J, Eder W, Castaneda J, Doss M, Huber E, Ebner R and Kunz-Schughart LA: A reliable tool to determine cell viability in complex 3-d culture: The acid phosphatase assay. J Biomol Screen. 12:925–937. 2007. View Article : Google Scholar : PubMed/NCBI
19	Schneider CA, Rasband WS and Eliceiri KW: NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 9:671–675. 2012. View Article : Google Scholar : PubMed/NCBI
20	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
21	Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 58:621–681. 2006. View Article : Google Scholar : PubMed/NCBI
22	Ostermann S, Csajka C, Buclin T, Leyvraz S, Lejeune F, Decosterd LA and Stupp R: Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 10:3728–3736. 2004. View Article : Google Scholar : PubMed/NCBI
23	Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC and Van Meir EG: Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol. 9:469–479. 1999. View Article : Google Scholar : PubMed/NCBI
24	Shield K, Ackland ML, Ahmed N and Rice GE: Multicellular spheroids in ovarian cancer metastases: Biology and pathology. Gynecol Oncol. 113:143–148. 2009. View Article : Google Scholar : PubMed/NCBI
25	Cancer Genome Atlas Research Network, . Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008. View Article : Google Scholar : PubMed/NCBI
26	Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, et al: Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res. 12:3935–3941. 2006. View Article : Google Scholar : PubMed/NCBI
27	Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol. 20 (Suppl 4):iv1–iv86. 2018. View Article : Google Scholar : PubMed/NCBI
28	Stupp R, Brada M, van den Bent MJ, Tonn JC and Pentheroudakis G; ESMO Guidelines Working Group, : High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 25 Suppl 3:iii93–iii101. 2014. View Article : Google Scholar : PubMed/NCBI
29	Lwin Z, MacFadden D, Al-Zahrani A, Atenafu E, Miller BA, Sahgal A, Menard C, Laperriere N and Mason WP: Glioblastoma management in the temozolomide era: Have we improved outcome? J Neurooncol. 115:303–310. 2013. View Article : Google Scholar : PubMed/NCBI
30	Salustiano EJ, Dumas ML, Silva-Santos GG, Netto CD, Costa PR and Rumjanek VM: In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118. Invest New Drugs. 34:541–551. 2016. View Article : Google Scholar : PubMed/NCBI
31	da Silva AJ, Buarque CD, Brito FV, Aurelian L, Macedo LF, Malkas LH, Hickey RJ, Lopes DV, Noël F, Murakami YL, et al: Synthesis and preliminary pharmacological evaluation of new (+/-) 1,4-naphthoquinones structurally related to lapachol. Bioorg Med Chem. 10:2731–2738. 2002. View Article : Google Scholar : PubMed/NCBI
32	van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T and de Vries HE: Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat. 19:1–12. 2015. View Article : Google Scholar : PubMed/NCBI
33	Baharvand H, Hashemi SM, Kazemi Ashtiani S and Farrokhi A: Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol. 50:645–652. 2006. View Article : Google Scholar : PubMed/NCBI
34	Barbone D, Van Dam L, Follo C, Jithesh PV, Zhang SD, Richards WG, Bueno R, Fennell DA and Broaddus VC: Analysis of gene expression in 3D spheroids highlights a survival role for ASS1 in mesothelioma. PLoS One. 11:e01500442016. View Article : Google Scholar : PubMed/NCBI
35	Nelson CM and Bissell MJ: Modeling dynamic reciprocity: Engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation. Semin Cancer Biol. 15:342–352. 2005. View Article : Google Scholar : PubMed/NCBI
36	Hongisto V, Jernström S, Fey V, Mpindi JP, Kleivi Sahlberg K, Kallioniemi O and Perälä M: High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1 breast cancer cells. PLoS One. 8:e772322013. View Article : Google Scholar : PubMed/NCBI
37	Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI
38	Fan QW and Weiss WA: Targeting the RTK-PI3K-mTOR axis in malignant glioma: Overcoming resistance. Curr Top Microbiol Immunol. 347:279–296. 2010.PubMed/NCBI
39	McNeill RS, Canoutas DA, Stuhlmiller TJ, Dhruv HD, Irvin DM, Bash RE, Angus SP, Herring LE, Simon JM, Skinner KR, et al: Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma. Neuro Oncol. 19:1469–1480. 2017. View Article : Google Scholar : PubMed/NCBI
40	Li K, Ouyang L, He M, Luo M, Cai W, Tu Y, Pi R and Liu A: IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway. Oncotarget. 8:28865–28879. 2017.PubMed/NCBI
41	Sato A, Sunayama J, Matsuda K, Seino S, Suzuki K, Watanabe E, Tachibana K, Tomiyama A, Kayama T and Kitanaka C: MEK-ERK signaling dictates DNA-repair gene MGMT expression and temozolomide resistance of stem-like glioblastoma cells via the MDM2-p53 axis. Stem Cells. 29:1942–1951. 2011. View Article : Google Scholar : PubMed/NCBI