Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma

Author(s): Shabierjiang Jiapaer, Takuya Furuta, Yu Dong, Tomohiro Kitabayashi, Hemragul Sabit, Jiakang Zhang, Guangtao Zhang, Shingo Tanaka, Masahiko Kobayashi, Atsushi Hirao, Mitsutoshi Nakada*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 36 , 2020


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Abstract:

Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes.

Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications.

Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis.

Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter.

Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

Keywords: Glioma, drug screening, 2-fluoropalmitic acid, temozolomide, matrix metalloproteinase, glioma stem cells.

[1]
Jiapaer S, Furuta T, Tanaka S, Kitabayashi T, Nakada M. Potential strategies overcoming the temozolomide resistance for glioblastoma. Neurol Med Chir (Tokyo) 2018; 58(10): 405-21.
[http://dx.doi.org/10.2176/nmc.ra.2018-0141 ] [PMID: 30249919]
[2]
Kim M, Kotas J, Rockhill J, Phillips M. A feasibility study of personalized prescription schemes for glioblastoma patients using a proliferation and invasion glioma model. Cancers (Basel) 2017; 9(5): E51
[http://dx.doi.org/10.3390/cancers9050051 ] [PMID: 28505072]
[3]
Trinh AL, Chen H, Chen Y, et al. Tracking functional tumor cell subpopulations of malignant glioma by phasor fluorescence lifetime imaging microscopy of NADH. Cancers (Basel) 2017; 9(12): E168
[http://dx.doi.org/10.3390/cancers9120168 ] [PMID: 29211022]
[4]
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-96.
[http://dx.doi.org/10.1056/NEJMoa043330 ] [PMID: 15758009]
[5]
Huse JT, Holland EC. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer 2010; 10(5): 319-31.
[http://dx.doi.org/10.1038/nrc2818 ] [PMID: 20414201]
[6]
Cruceru ML, Neagu M, Demoulin JB, Constantinescu SN. Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms. J Cell Mol Med 2013; 17(10): 1218-35.
[http://dx.doi.org/10.1111/jcmm.12122 ] [PMID: 23998913]
[7]
Mimeault M, Hauke R, Mehta PP, Batra SK. Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med 2007; 11(5): 981-1011.
[http://dx.doi.org/10.1111/j.1582-4934.2007.00088.x ] [PMID: 17979879]
[8]
Nosengo N. Can you teach old drugs new tricks? Nature 2016; 534(7607): 314-6.
[http://dx.doi.org/10.1038/534314a ] [PMID: 27306171]
[9]
Dong Y, Furuta T, Sabit H, et al. Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug. Oncotarget 2017; 8(67): 111728-41.
[http://dx.doi.org/10.18632/oncotarget.22904 ] [PMID: 29340087]
[10]
Kitabayashi T, Dong Y, Furuta T, et al. Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma. Sci Rep 2019; 9(1): 10049.
[http://dx.doi.org/10.1038/s41598-019-46454-8 ] [PMID: 31296906]
[11]
Vu HT, Kobayashi M, Hegazy AM, et al. Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas. Cancer Sci 2018; 109(8): 2497-508.
[http://dx.doi.org/10.1111/cas.13695 ] [PMID: 29902340]
[12]
Soltysiak RM, Matsuura F, Bloomer D, Sweeley CCD. D,L-alpha-Fluoropalmitic acid inhibits sphingosine base formation and accumulates in membrane lipids of cultured mammalian cells. Biochim Biophys Acta 1984; 792(2): 214-26.
[http://dx.doi.org/10.1016/0005-2760(84)90225-X ] [PMID: 6696931]
[13]
Muraguchi T, Tanaka S, Yamada D, et al. NKX2.2 suppresses self-renewal of glioma-initiating cells. Cancer Res 2011; 71(3): 1135-45.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2304 ] [PMID: 21169405]
[14]
Yamada D, Hoshii T, Tanaka S, et al. Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals. J Biochem 2014; 155(4): 227-33.
[http://dx.doi.org/10.1093/jb/mvt112 ] [PMID: 24368778]
[15]
Nakada M, Niska JA, Miyamori H, et al. The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells. Cancer Res 2004; 64(9): 3179-85.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3667 ] [PMID: 15126357]
[16]
Pyko IV, Nakada M, Sabit H, et al. Glycogen synthase kinase 3β inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling. Carcinogenesis 2013; 34(10): 2206-17.
[http://dx.doi.org/10.1093/carcin/bgt182 ] [PMID: 23715499]
[17]
Suzuki T, Nakada M, Yoshida Y, et al. The correlation between promoter methylation status and the expression level of O6-methylguanine-DNA methyltransferase in recurrent glioma. Jpn J Clin Oncol 2011; 41(2): 190-6.
[http://dx.doi.org/10.1093/jjco/hyq224 ] [PMID: 21148162]
[18]
Lee MM, Chen YY, Liu PY, Hsu S, Sheu MJ. Pipoxolan inhibits CL1-5 lung cancer cells migration and invasion through inhibition of MMP-9 and MMP-2. Chem Biol Interact 2015; 236: 19-30.
[http://dx.doi.org/10.1016/j.cbi.2015.04.012 ] [PMID: 25899827]
[19]
Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med (Maywood) 2008; 233(5): 507-21.
[http://dx.doi.org/10.3181/0710-MR-287 ] [PMID: 18375835]
[20]
Coleman RA, Lewin TM, Van Horn CG, Gonzalez-Baró MR. Do long-chain acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways? J Nutr 2002; 132(8): 2123-6.
[http://dx.doi.org/10.1093/jn/132.8.2123 ] [PMID: 12163649]
[21]
Mashima T, Sato S, Sugimoto Y, Tsuruo T, Seimiya H. Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. Oncogene 2009; 28(1): 9-19.
[http://dx.doi.org/10.1038/onc.2008.355 ] [PMID: 18806831]
[22]
Mashima T, Oh-hara T, Sato S, et al. p53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target. J Natl Cancer Inst 2005; 97(10): 765-77.
[http://dx.doi.org/10.1093/jnci/dji133 ] [PMID: 15900046]
[23]
Mashima T, Sato S, Okabe S, et al. Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide. Cancer Sci 2009; 100(8): 1556-62.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01203.x ] [PMID: 19459852]
[24]
Yamashita Y, Kumabe T, Cho YY, et al. Fatty acid induced glioma cell growth is mediated by the acyl-CoA synthetase 5 gene located on chromosome 10q25.1-q25.2, a region frequently deleted in malignant gliomas. Oncogene 2000; 19(51): 5919-25.
[http://dx.doi.org/10.1038/sj.onc.1203981 ] [PMID: 11127823]
[25]
Glumac PM, LeBeau AM. The role of CD133 in cancer: a concise review. Clin Transl Med 2018; 7(1): 18.
[http://dx.doi.org/10.1186/s40169-018-0198-1 ] [PMID: 29984391]
[26]
Bien-Möller S, Balz E, Herzog S, et al. Association of glioblastoma multiforme stem cell characteristics, differentiation, and microglia marker genes with patient survival. Stem Cells Int 2018; 2018: 9628289
[http://dx.doi.org/10.1155/2018/9628289 ] [PMID: 29535786]
[27]
Wuebben EL, Rizzino A. The dark side of SOX2: cancer - A comprehensive overview. Oncotarget 2017; 8(27): 44917-43.
[http://dx.doi.org/10.18632/oncotarget.16570 ] [PMID: 28388544]
[28]
Salaroglio IC, Mungo E, Gazzano E, Kopecka J, Riganti C. ERK is a pivotal player of chemo-immune-resistance in cancer. Int J Mol Sci 2019; 20(10): E2505
[http://dx.doi.org/10.3390/ijms20102505 ] [PMID: 31117237]
[29]
Tung SL, Huang WC, Hsu FC, et al. miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway. Oncogenesis 2017; 6(5): e326
[http://dx.doi.org/10.1038/oncsis.2017.25 ] [PMID: 28459431]
[30]
Kwon SJ, Kwon OS, Kim KT, et al. Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii. Mol Cancer 2017; 16(1): 140.
[http://dx.doi.org/10.1186/s12943-017-0703-y ] [PMID: 28830458]
[31]
Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today 2015; 20(7): 899-905.
[http://dx.doi.org/10.1016/j.drudis.2015.02.011 ] [PMID: 25744176]
[32]
Atkins RJ, Ng W, Stylli SS, Hovens CM, Kaye AH. Repair mechanisms help glioblastoma resist treatment. J clinical Neuroscience: official journal of the Neurosurgical Society of Australasia 2015; 22(1): 14-20.
[http://dx.doi.org/10.1016/j.jocn.2014.09.003]
[33]
Liu F, Yang X, Geng M, Huang M. Targeting ERK, an Achilles’ Heel of the MAPK pathway, in cancer therapy. Acta Pharm Sin B 2018; 8(4): 552-62.
[http://dx.doi.org/10.1016/j.apsb.2018.01.008 ] [PMID: 30109180]
[34]
Wu H, Li X, Feng M, et al. Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway. Oncol Rep 2018; 40(6): 3285-96.
[http://dx.doi.org/10.3892/or.2018.6744 ] [PMID: 30272353]
[35]
Chen H, Guo R, Zhang Q, et al. Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells. Proc Natl Acad Sci USA 2015; 112(44): E5936-43.
[http://dx.doi.org/10.1073/pnas.1516319112 ] [PMID: 26483458]
[36]
Maik-Rachline G, Hacohen-Lev-Ran A, Seger R. Nuclear erk: mechanism of translocation, substrates, and role in cancer. Int J Mol Sci 2019; 20(5): E1194
[http://dx.doi.org/10.3390/ijms20051194 ] [PMID: 30857244]
[37]
Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991; 64(2): 327-36.
[http://dx.doi.org/10.1016/0092-8674(91)90642-C ] [PMID: 1703045]
[38]
Aroui S, Aouey B, Chtourou Y, Meunier AC, Fetoui H, Kenani A. Naringin suppresses cell metastasis and the expression of matrix metalloproteinases (MMP-2 and MMP-9) via the inhibition of ERK-P38-JNK signaling pathway in human glioblastoma. Chem Biol Interact 2016; 244: 195-203.
[http://dx.doi.org/10.1016/j.cbi.2015.12.011 ] [PMID: 26721195]
[39]
Hu XH, Fan L, Ruan CG. Function of matrix metalloprotenase-2 by RNA interference. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008; 16(2): 381-6.
[PMID: 18426670]
[40]
Wang M, Wang T, Liu S, Yoshida D, Teramoto A. The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol 2003; 20(2): 65-72.
[http://dx.doi.org/10.1007/BF02483449 ] [PMID: 14756443]
[41]
Guo G, Yao W, Zhang Q, Bo Y. Oleanolic acid suppresses migration and invasion of malignant glioma cells by inactivating MAPK/ERK signaling pathway. PLoS One 2013; 8(8): e72079
[http://dx.doi.org/10.1371/journal.pone.0072079 ] [PMID: 23991044]
[42]
Guan H, Guo Z, Liang W, et al. Trop2 enhances invasion of thyroid cancer by inducing MMP2 through ERK and JNK pathways. BMC Cancer 2017; 17(1): 486.
[http://dx.doi.org/10.1186/s12885-017-3475-2 ] [PMID: 28709407]
[43]
Wu W, Gao H, Li X, et al. β-hCG promotes epithelial ovarian cancer metastasis through ERK/MMP2 signaling pathway. Cell Cycle 2019; 18(1): 46-59.
[http://dx.doi.org/10.1080/15384101.2018.1558869 ] [PMID: 30582718]
[44]
Kitange GJ, Carlson BL, Schroeder MA, et al. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro-oncol 2009; 11(3): 281-91.
[http://dx.doi.org/10.1215/15228517-2008-090 ] [PMID: 18952979]
[45]
Chen X, Zhang M, Gan H, et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat Commun 2018; 9(1): 2949.
[http://dx.doi.org/10.1038/s41467-018-05373-4 ] [PMID: 30054476]
[46]
Çıtışlı V, Dodurga Y, Eroğlu C, Seçme M, Avcı CB, Şatıroğlu-Tufan NL. Temozolomide may induce cell cycle arrest by interacting with URG4/URGCP in SH-SY5Y neuroblastoma cells. Tumour Biol 2015; 36(9): 6765-72.
[http://dx.doi.org/10.1007/s13277-015-3373-7 ] [PMID: 25835972]


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Article Details

VOLUME: 26
ISSUE: 36
Year: 2020
Published on: 22 October, 2020
Page: [4675 - 4684]
Pages: 10
DOI: 10.2174/1381612826666200429092742
Price: $65

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