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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Stimulation of Peroxisome Proliferator-Activated Receptor-Gamma (PPARγ) using Pioglitazone Decreases the Survival of Acute Promyelocytic Leukemia Cells through Up-Regulation of PTEN Expression

Author(s): Shadi Esmaeili, Ava Safaroghli-Azar, Atieh Pourbagheri-Sigaroodi, Sina Salari, Ahmad Gharehbaghian, Mohsen Hamidpour and Davood Bashash*

Volume 21 , Issue 1 , 2021

Published on: 17 August, 2020

Page: [108 - 119] Pages: 12

DOI: 10.2174/1871520620666200817101533

Price: $65

Abstract

Background: The intertwining between cancer pathogenesis and aberrant expression of either oncogenes or tumor suppressor proteins ushered the cancer therapeutic approaches into a limitless road of modern therapies. For the nonce and among the plethora of promising anticancer agents, intense interest has focused on pioglitazone, a first in-class of Thiazolidinedione (TZD) drugs that is currently used to treat patients with diabetes.

Objective: Intrigued by the overexpression of PPARγ in Acute Promylocytic Leukemia (APL), this study was designed to investigate the effects of pioglitazone in APL-derived NB4 cells.

Methods: To assess the anti-leukemic effect of pioglitazone on myeloid leukemia cell lines, we used MTT and trypan blue assays. Given the higher expression level of PPARγ in NB4 cells, we then expanded our experiments on this cell line. To ascertain the molecular mechanism action of pioglitazone in APL-derived NB4 cells, we evaluated the expression levels of a large cohort of target genes responsible for the regulation of apoptosis, autophagy and cell proliferation. Afterward, to examine whether there is a correlation between PPARγ and the PI3K signaling pathway, the amount of Akt phosphorylation was evaluated using western blot analysis.

Results: Our results showed that pioglitazone exerted its cytotoxic effect in wild-type PTEN-expressing NB4 cells, but not in leukemic K562 cells harboring mutant PTEN; suggesting that probably this member of TZD drugs induced its anti-leukemic effects through a PTEN-mediated manner. Moreover, we found that not only pioglitazone reduced the survival rate of NB4 through the induction of p21-mediated G1 arrest, also elevated the intracellular level of Reactive Oxygen Species (ROS) which was coupled with upregulated FOXO3a. Notably, this study proposed for the first time that the stimulation of autophagy as a result of the compensatory activation of PI3K pathway may act as a plausible mechanism through which the anti-leukemic effect of pioglitazone may be attenuated; suggestive of the application of either PI3K or autophagy inhibitors along with pioglitazone in APL.

Conclusion: By suggesting a mechanistic pathway, the results of the present study shed more light on the favorable anti-leukemic effect of pioglitazone and suggest it as a promising drug that should be clinically investigated in APL patients.

Keywords: Acute Promyelocytic Leukemia (APL), Peroxisome Proliferator-Activated Receptor-gamma (PPARγ), pioglitazone, PTEN, PI3K signaling pathway, autophagy.

Graphical Abstract
[1]
Cohen, I.; Tagliaferri, M.; Tripathy, D. Traditional chinese medicine in the treatment of breast cancer. Semin. Oncol., 2003, 29(6), 563-574.
[2]
Muñoz, M.; Coveñas, R. Neurokinin-1 receptor: A new promising target in the treatment of cancer. Discov. Med., 2010, 10(53), 305-313.
[PMID: 21034671]
[3]
Fan, P.; Abderrahman, B.; Chai, T.S.; Yerrum, S.; Jordan, V.C. Targeting peroxisome proliferator-activated receptor γ to increase estrogen-induced apoptosis in estrogen-deprived breast cancer cells. Mol. Cancer Ther., 2018, 17(12), 2732-2745.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-0088] [PMID: 30224430]
[4]
Murphy, G.J.; Holder, J.C. PPAR-γ agonists: Therapeutic role in diabetes, inflammation and cancer. Trends Pharmacol. Sci., 2000, 21(12), 469-474.
[http://dx.doi.org/10.1016/S0165-6147(00)01559-5] [PMID: 11121836]
[5]
Na, H-K.; Surh, Y-J. Peroxisome Proliferator-Activated Receptor γ (PPARgamma) ligands as bifunctional regulators of cell proliferation. Biochem. Pharmacol., 2003, 66(8), 1381-1391.
[http://dx.doi.org/10.1016/S0006-2952(03)00488-X] [PMID: 14555212]
[6]
Lützen, U.; Zhao, Y.; Lucht, K.; Zuhayra, M.; Marx, M.; Cascorbi, I.; Culman, J. Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism. Naunyn Schmiedebergs Arch. Pharmacol., 2017, 390(1), 37-48.
[http://dx.doi.org/10.1007/s00210-016-1291-x] [PMID: 27664035]
[7]
Lee, C.J.; Han, J.S.; Seo, C.Y.; Park, T.H.; Kwon, H.C.; Jeong, J.S.; Kim, I.H.; Yun, J.; Bae, Y.S.; Kwak, J.Y.; Park, J.I. Pioglitazone, a synthetic ligand for PPARgamma, induces apoptosis in RB-deficient human colorectal cancer cells. Apoptosis, 2006, 11(3), 401-411.
[http://dx.doi.org/10.1007/s10495-006-4003-z] [PMID: 16520894]
[8]
Belcher, G.; Matthews, D. Safety and tolerability of pioglitazone.Experimen. Clin. Endocrinol. Diabet., 2000, 108(Sup. 2), 267-273.
[http://dx.doi.org/10.1055/s-2000-8529]
[9]
Sertznig, P.; Seifert, M.; Tilgen, W.; Reichrath, J. Peroxisome Proliferator-Activated Receptor (PPAR) and Vitamin D Receptor (VDR) signaling pathways in melanoma cells: Promising new therapeutic targets? J. Steroid Biochem. Mol. Biol., 2010, 121(1-2), 383-386.
[http://dx.doi.org/10.1016/j.jsbmb.2010.03.003] [PMID: 20214982]
[10]
Ciaramella, V.; Sasso, F.C.; Di Liello, R.; Corte, C.M.D.; Barra, G.; Viscardi, G.; Esposito, G.; Sparano, F.; Troiani, T.; Martinelli, E.; Orditura, M.; De Vita, F.; Ciardiello, F.; Morgillo, F. Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC. J. Exp. Clin. Cancer Res., 2019, 38(1), 178.
[http://dx.doi.org/10.1186/s13046-019-1176-1] [PMID: 31027492]
[11]
Lv, S.; Wang, W.; Wang, H.; Zhu, Y.; Lei, C. PPARγ activation serves as therapeutic strategy against bladder cancer via inhibiting PI3K-Akt signaling pathway. BMC Cancer, 2019, 19(1), 204.
[http://dx.doi.org/10.1186/s12885-019-5426-6] [PMID: 30845932]
[12]
Dana, N.; Vaseghi, G.; Haghjooy Javanmard, S. PPAR gamma agonist, pioglitazone, suppresses melanoma cancer in mice by inhibiting TLR4 signaling. J. Pharm. Pharmaceut Sci., 2019, 22(1), 418-423.
[13]
Liu, J.J.; Guo, Y.W.; Fang, Z.G.; Si, X.N.; Wu, X.Y.; Liu, P.Q.; Lin, D.J.; Xiao, R.Z.; Xu, Y.; Wang, C.Z.; Li, X.D.; He, Y.; Huang, R.W. Activation of peroxisome proliferator-activated receptor-gamma induces apoptosis on acute promyelocytic leukemia cells via downregulation of XIAP. Int. J. Mol. Med., 2009, 24(5), 623-632.
[http://dx.doi.org/10.3892/ijmm_00000273] [PMID: 19787196]
[14]
Tsao, T.; Kornblau, S.; Safe, S.; Watt, J.C.; Ruvolo, V.; Chen, W.; Qiu, Y.; Coombes, K.R.; Ju, Z.; Abdelrahim, M.; Schober, W.; Ling, X.; Kardassis, D.; Meyer, C.; Schimmer, A.; Kantarjian, H.; Andreeff, M.; Konopleva, M. Role of peroxisome proliferator-activated receptor-gamma and its coactivator DRIP205 in cellular responses to CDDO (RTA-401) in acute myelogenous leukemia. Cancer Res., 2010, 70(12), 4949-4960.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1962] [PMID: 20501850]
[15]
Tabe, Y.; Konopleva, M.; Kondo, Y.; Contractor, R.; Tsao, T.; Konoplev, S.; Shi, Y.; Ling, X.; Watt, J.C.; Tsutsumi-Ishii, Y.; Ohsaka, A.; Nagaoka, I.; Issa, J.P.; Kogan, S.C.; Andreeff, M. PPARgamma-active triterpenoid CDDO enhances ATRA-induced differentiation in APL. Cancer Biol. Ther., 2007, 6(12), 1967-1977.
[http://dx.doi.org/10.4161/cbt.6.12.4982] [PMID: 18075297]
[16]
Bashash, D.H.; Ghaffari, S.; Zaker, F.; Kazerani, M.; Hezave, K.; Hassani, S. BIBR 1532 increases arsenic trioxide-mediated apoptosis in acute promyelocytic leukemia cells: Therapeutic potential for APL. Anticancer. Agents Med. Chem., 2013, 13(7), 1115-25.
[17]
Bashash, D.; Safaroghli-Azar, A.; Dadashi, M.; Safa, M.; Momeny, M.; Ghaffari, S.H. Anti-tumor activity of PI3K-δ inhibitor in hematologic malignant cells: Shedding new light on resistance to Idelalisib. Int. J. Biochem. Cell Biol., 2017, 85, 149-158.
[http://dx.doi.org/10.1016/j.biocel.2017.02.007] [PMID: 28254430]
[18]
Konopleva, M.; Andreeff, M. Role of peroxisome proliferator-activated receptor-γ in hematologic malignancies. Curr. Opin. Hematol., 2002, 9(4), 294-302.
[http://dx.doi.org/10.1097/00062752-200207000-00006] [PMID: 12042703]
[19]
Liu, J.; Lu, H.; Huang, R.; Lin, D.; Wu, X.; Lin, Q.; Wu, X.; Zheng, J.; Pan, X.; Peng, J.; Song, Y.; Zhang, M.; Hou, M.; Chen, F. Peroxisome proliferator activated receptor-γ ligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemia cells. Cancer Chemother. Pharmacol., 2005, 56(4), 400-408.
[http://dx.doi.org/10.1007/s00280-005-1029-9] [PMID: 15838654]
[20]
Teresi, R.E.; Waite, K.A. PPARγ, PTEN, and the Fight against Cancer. PPAR Res., 2008, 2008932632
[21]
Indran, I.R.; Hande, M.P.; Pervaiz, S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res., 2011, 71(1), 266-276.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1588] [PMID: 21071633]
[22]
Luo, H.; Yang, Y.; Duan, J.; Wu, P.; Jiang, Q.; Xu, C. PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis., 2013, 4(2)e481
[http://dx.doi.org/10.1038/cddis.2013.3]] [PMID: 23392169]
[23]
Lian, B.; Yang, D.; Liu, Y.; Shi, G.; Li, J.; Yan, X.; Jin, K.; Liu, X.; Zhao, J.; Shang, W.; Zhang, R. miR-128 targets the SIRT1/ROS/DR5 pathway to sensitize colorectal Cancer to TRAIL-induced apoptosis. Cell. Physiol. Biochem., 2018, 49(6), 2151-2162.
[http://dx.doi.org/10.1159/000493818] [PMID: 30257253]
[24]
Pant, K.; Yadav, A.K.; Gupta, P.; Islam, R.; Saraya, A.; Venugopal, S.K. Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells. Redox Biol., 2017, 12, 340-349.
[http://dx.doi.org/10.1016/j.redox.2017.03.006] [PMID: 28288414]
[25]
Gorman, A.M.; Healy, S.J.; Jäger, R.; Samali, A. Stress management at the ER: Regulators of ER stress-induced apoptosis. Pharmacol. Ther., 2012, 134(3), 306-316.
[http://dx.doi.org/10.1016/j.pharmthera.2012.02.003] [PMID: 22387231]
[26]
Levine, B.; Yuan, J. Autophagy in cell death: An innocent convict? J. Clin. Invest., 2005, 115(10), 2679-2688.
[http://dx.doi.org/10.1172/JCI26390] [PMID: 16200202]
[27]
Kanzawa, T.; Kondo, Y.; Ito, H.; Kondo, S.; Germano, I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res., 2003, 63(9), 2103-2108.
[PMID: 12727826]
[28]
White, E.; DiPaola, R.S. The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res., 2009, 15(17), 5308-5316.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-5023] [PMID: 19706824]
[29]
Toth, B.; Hornung, D.; Scholz, C.; Djalali, S.; Friese, K.; Jeschke, U. Peroxisome proliferator-activated receptors: New players in the field of reproduction. Am. J. Reprod. Immunol., 2007, 58(3), 289-310.
[http://dx.doi.org/10.1111/j.1600-0897.2007.00514.x] [PMID: 17681045]
[30]
Waugh, J.; Keating, G.M.; Plosker, G.L.; Easthope, S.; Robinson, D.M. Pioglitazone: A review of its use in type 2 diabetes mellitus. Drugs, 2006, 66(1), 85-109.
[http://dx.doi.org/10.2165/00003495-200666010-00005] [PMID: 16398569]
[31]
Tsubaki, M.; Takeda, T.; Tomonari, Y.; Kawashima, K.; Itoh, T.; Imano, M.; Satou, T.; Nishida, S. Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ-independent pathway. J. Cell. Physiol., 2018, 233(4), 3638-3647.
[http://dx.doi.org/10.1002/jcp.26225] [PMID: 29030979]
[32]
Mueller, E.; Sarraf, P.; Tontonoz, P.; Evans, R.M.; Martin, K.J.; Zhang, M.; Fletcher, C.; Singer, S.; Spiegelman, B.M. Terminal differentiation of human breast cancer through PPAR gamma. Mol. Cell, 1998, 1(3), 465-470.
[http://dx.doi.org/10.1016/S1097-2765(00)80047-7] [PMID: 9660931]
[33]
Shen, D.; Deng, C.; Zhang, M. Peroxisome proliferator-activated receptor gamma agonists inhibit the proliferation and invasion of human colon cancer cells. Postgrad. Med. J., 2007, 83(980), 414-419.
[http://dx.doi.org/10.1136/pmj.2006.052761] [PMID: 17551074]
[34]
Nemenoff, R.A. Peroxisome proliferator-activated receptor-γ in lung cancer: Defining specific versus “off-target” effectors. J. Thorac. Oncol., 2007, 2(11), 989-992.
[http://dx.doi.org/10.1097/JTO.0b013e318158cf0a] [PMID: 17975488]
[35]
Yang, Y-C.; Ho, T-C.; Chen, S-L.; Lai, H-Y.; Wu, J-Y.; Tsao, Y-P. Inhibition of cell motility by troglitazone in human ovarian carcinoma cell line. BMC Cancer, 2007, 7(1), 216.
[http://dx.doi.org/10.1186/1471-2407-7-216] [PMID: 18021457]
[36]
Papa, A.; Pandolfi, P.P. The PTENPI3K axis in cancer. Biomolecules, 2019, 9(4)E153
[http://dx.doi.org/10.3390/biom9040153]] [PMID: 30999672]
[37]
Faes, S.; Dormond, O. PI3K and AKT: Unfaithful partners in cancer. Int. J. Mol. Sci., 2015, 16(9), 21138-21152.
[http://dx.doi.org/10.3390/ijms160921138] [PMID: 26404259]
[38]
Sikand, K.; Kaul, D.; Varma, N. Receptor Ck-dependent signaling regulates hTERT gene transcription. BMC Cell Biol., 2006, 7(1), 2.
[http://dx.doi.org/10.1186/1471-2121-7-2] [PMID: 16405739]
[39]
Mitchell, K.O.; El-Deiry, W.S. Overexpression of c-Myc inhibits p21WAF1/CIP1 expression and induces S-phase entry in 12-O-tetradecanoylphorbol-13-acetate (TPA)-sensitive human cancer cells. Cell Growth Differ., 1999, 10(4), 223-230.
[PMID: 10319992]
[40]
Bashash, D.; Sayyadi, M.; Safaroghli-Azar, A.; Sheikh-Zeineddini, N.; Riyahi, N.; Momeny, M. Small molecule inhibitor of c-Myc 10058-F4 inhibits proliferation and induces apoptosis in acute leukemia cells, irrespective of PTEN status. Int. J. Biochem. Cell Biol., 2019, 108, 7-16.
[http://dx.doi.org/10.1016/j.biocel.2019.01.005] [PMID: 30639430]
[41]
Safaroghli-Azar, A.; Bashash, D.; Sadreazami, P.; Momeny, M.; Ghaffari, S.H. PI3K-δ inhibition using CAL-101 exerts apoptotic effects and increases doxorubicin-induced cell death in pre-B-acute lymphoblastic leukemia cells. Anticancer Drugs, 2017, 28(4), 436-445.
[http://dx.doi.org/10.1097/CAD.0000000000000477] [PMID: 28125433]
[42]
Bashash, D.; Safaroghli-Azar, A.; Delshad, M.; Bayati, S.; Nooshinfar, E.; Ghaffari, S.H. Inhibitor of pan class-I PI3K induces differentially apoptotic pathways in acute leukemia cells: Shedding new light on NVP-BKM120 mechanism of action. Int. J. Biochem. Cell Biol., 2016, 79, 308-317.
[http://dx.doi.org/10.1016/j.biocel.2016.09.004] [PMID: 27599915]
[43]
Zhang, J.; Zhang, Y.; Xiao, F.; Liu, Y.; Wang, J.; Gao, H.; Rong, S.; Yao, Y.; Li, J.; Xu, G. The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway. Biochem. Pharmacol., 2016, 101, 100-111.
[http://dx.doi.org/10.1016/j.bcp.2015.11.027] [PMID: 26673543]
[44]
Kim, K.Y.; Ahn, J.H.; Cheon, H.G. Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation. Mol. Pharmacol., 2007, 72(3), 674-685.
[http://dx.doi.org/10.1124/mol.107.035584] [PMID: 17535976]
[45]
Gozuacik, D.; Kimchi, A. Autophagy and cell death. Curr. Top. Dev. Biol., 2007, 78, 217-245.
[http://dx.doi.org/10.1016/S0070-2153(06)78006-1] [PMID: 17338918]
[46]
Chen, W.; Sun, Y.; Liu, K.; Sun, X. Autophagy: A double-edged sword for neuronal survival after cerebral ischemia. Neural Regen. Res., 2014, 9(12), 1210-1216.
[http://dx.doi.org/10.4103/1673-5374.135329] [PMID: 25206784]
[47]
Yan, S.; Yang, X.; Chen, T.; Xi, Z.; Jiang, X. The PPARγ agonist Troglitazone induces autophagy, apoptosis and necroptosis in bladder cancer cells. Cancer Gene Ther., 2014, 21(5), 188-193.
[http://dx.doi.org/10.1038/cgt.2014.16] [PMID: 24853624]
[48]
Huber, S.; Valente, S.; Chaimbault, P.; Schohn, H. Evaluation of ∆2-pioglitazone, an analogue of pioglitazone, on colon cancer cell survival: Evidence of drug treatment association with autophagy and activation of the Nrf2/Keap1 pathway. Int. J. Oncol., 2014, 45(1), 426-438.
[http://dx.doi.org/10.3892/ijo.2014.2408] [PMID: 24788124]
[49]
Riyahi, N.; Safaroghli-Azar, A.; Sheikh-Zeineddini, N.; Sayyadi, M.; Bashash, D. Synergistic effects of PI3K and c-Myc co-targeting in acute leukemia: Shedding new light on resistance to selective PI3K-δ inhibitor CAL-101. Cancer Invest., 2019, 37(7), 311-324.
[http://dx.doi.org/10.1080/07357907.2019.1651328] [PMID: 31412710]
[50]
Sheikh-Zeineddini, N.; Bashash, D.; Safaroghli-Azar, A.; Riyahi, N.; Shabestari, R.M.; Janzamin, E.; Safa, M. Suppression of c-Myc using 10058-F4 exerts caspase-3-dependent apoptosis and intensifies the antileukemic effect of vincristine in pre-B acute lymphoblastic leukemia cells. J. Cell. Biochem., 2019, 120(8), 14004-14016.
[http://dx.doi.org/10.1002/jcb.28675] [PMID: 30957273]

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