Reports of Biochemistry
and Molecular Biology
Tue, Apr 16, 2024
[Archive]
Volume 10, Issue 4 (Vol.10 No.4 Jan 2022)
rbmb.net 2022, 10(4): 675-685 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Baghal-Sadriforoush S, Bagheri M, Abdi Rad I, Sotoodeh Nejadnematalahi F. PI3K Inhibition Sensitize the Cisplatin-resistant Human Ovarian Cancer Cell OVCAR3 by Induction of Oxidative Stress. rbmb.net 2022; 10 (4) :675-685
URL: http://rbmb.net/article-1-800-en.html
URL: http://rbmb.net/article-1-800-en.html
Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
Abstract: (2386 Views)
Background: This study evaluates the effect of simultaneous AKT inhibition and cisplatin therapy in changes of Reactive Oxygen Species (ROS) production, apoptosis induction, and cell survival in cisplatinresistant OVCAR3 cell.
Methods: OVCAR3 cancer cells were treated with cisplatin, Ly 294002 (LY), and cisplatin+Ly to investigate the cytotoxicity effect of the mentioned groups via MTT assay. Then, DCFH-DA (2′, 7′- dichlorodihydro fluorescein diacetate) assay kit is used to assess the potential of treated groups in intracellular ROS generation. Protein expression levels of caspase-3, cleaved caspase 3, PI3K, Akt, p-Akt, XIAP, and Survivin are estimated through immunoblotting assay in all three experimental groups.
Results: The results showed that all three treated groups, including cisplatin and Ly alone and coadministration of cisplatin+Ly, could reduce the cell vitality of OVCAR3 cancer cells, induced intracellular production of ROS and increased the expression level of activated caspase 3 and Akt protein, whereas downregulated the phosphorylation of Akt protein. However, the effect of combination therapy was more tangible compared to single therapy and control groups. In contrast, the expression amount of XIAP, Survivin, and PI3K did not show detectable changes in comparison with the control group.
Conclusions: The results showed that the AKT inhibition by Ly could sensitize the OVCAR3 cancer cells to the cisplatin and lower the effective dose of cisplatin through hyperactivation of oxidative stress.
Methods: OVCAR3 cancer cells were treated with cisplatin, Ly 294002 (LY), and cisplatin+Ly to investigate the cytotoxicity effect of the mentioned groups via MTT assay. Then, DCFH-DA (2′, 7′- dichlorodihydro fluorescein diacetate) assay kit is used to assess the potential of treated groups in intracellular ROS generation. Protein expression levels of caspase-3, cleaved caspase 3, PI3K, Akt, p-Akt, XIAP, and Survivin are estimated through immunoblotting assay in all three experimental groups.
Results: The results showed that all three treated groups, including cisplatin and Ly alone and coadministration of cisplatin+Ly, could reduce the cell vitality of OVCAR3 cancer cells, induced intracellular production of ROS and increased the expression level of activated caspase 3 and Akt protein, whereas downregulated the phosphorylation of Akt protein. However, the effect of combination therapy was more tangible compared to single therapy and control groups. In contrast, the expression amount of XIAP, Survivin, and PI3K did not show detectable changes in comparison with the control group.
Conclusions: The results showed that the AKT inhibition by Ly could sensitize the OVCAR3 cancer cells to the cisplatin and lower the effective dose of cisplatin through hyperactivation of oxidative stress.
Type of Article: Original Article |
Subject:
Biochemistry
Received: 2021/10/9 | Accepted: 2021/10/17 | Published: 2022/02/7
Received: 2021/10/9 | Accepted: 2021/10/17 | Published: 2022/02/7
References
1. Singh M, Chaudhry P, Fabi F, Asselin E. Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance. BMC cancer. 2013;13:233. [DOI:10.1186/1471-2407-13-233] [PMID] [PMCID]
2. Bugide S, Gonugunta VK, Penugurti V, Malisetty VL, Vadlamudi RK, Manavathi B. HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol (Dordr). 2017;40(2):133-144. [DOI:10.1007/s13402-016-0308-2] [PMID]
3. Liu M, Bamodu OA, Huang WC, Zucha MA, Lin YK, Wu ATH, et al. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway. Toxicol Appl Pharmacol. 2017;325:48-60. [DOI:10.1016/j.taap.2017.04.003] [PMID]
4. Zhou B, Sun C, Li N, Shan W, Lu H, Guo L, et al. Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. Int J Oncol. 2016;48(5):2087-2097. [DOI:10.3892/ijo.2016.3442] [PMID]
5. Li H, Xu H, Shen H, Li H. microRNA-106a modulates cisplatin sensitivity by targeting PDCD4 in human ovarian cancer cells. Oncol Lett. 2014;7(1):183-188. [DOI:10.3892/ol.2013.1644] [PMID] [PMCID]
6. Laatio L, Myllynen P, Serpi R, Rysä J, Ilves M, Lappi-Blanco E, et al. BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells. Tumour Biol. 2011;32(5):985-95. [DOI:10.1007/s13277-011-0200-7] [PMID]
7. Li B, Chen H, Wu N, Zhang WJ, Shang LX. Deregulation of miR-128 in ovarian cancer promotes cisplatin resistance. International Journal of Gynecologic Cancer. 2014;24(8):1381-1388. [DOI:10.1097/IGC.0000000000000252] [PMID]
8. Kim MG, Pak JH, Choi WH, Park JY, Nam JH, Kim JH. The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines. J Gynecol Oncol. 2012;23(3):182-189. [DOI:10.3802/jgo.2012.23.3.182] [PMID] [PMCID]
9. Ghaffari M, Dehghan G, Abedi-Gaballu F, Kashanian S, Baradaran B, Ezzati Nazhad Dolatabadi J, et al. Surface functionalized dendrimers as controlled-release delivery nanosystems for tumor targeting. Eur J Pharm Sci. 2018;122:311-330. [DOI:10.1016/j.ejps.2018.07.020] [PMID]
10. Fu X, Tian J, Zhang L, Chen Y, Hao Q. Involvement of microRNA‐93, a new regulator of PTEN/Akt signaling pathway, in regulation of chemotherapeutic drug cisplatin chemosensitivity in ovarian cancer cells. FEBS Lett. 2012;586(9):1279-86. [DOI:10.1016/j.febslet.2012.03.006] [PMID]
11. Cai Y, Tan X, Liu J, Shen Y, Wu D, Ren M, et al. Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chinese journal of cancer research. 2014; 26(5):564-72.
12. Gu J, Tang Y, Liu Y, Guo H, Wang Y, Cai L, et al. Murine double minute 2 siRNA and wild-type p53 gene therapy enhances sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin chemotherapy in vitro and in vivo. Cancer Lett. 2014;343(2):200-9. [DOI:10.1016/j.canlet.2013.10.011] [PMID]
13. Liu J, Liu X, Ma W, Kou W, Li C, Zhao J. Anticancer activity of cucurbitacin-A in ovarian cancer cell line SKOV3 involves cell cycle arrest, apoptosis and inhibition of mTOR/PI3K/Akt signaling pathway. J BUON. 2018;23(1):124-128.
14. Choi HJ, Heo JH, Park JY, Jeong JY, Cho HJ, Park KS, et al. A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer. Gynecologic oncol. 2019;153(1):135-148. [DOI:10.1016/j.ygyno.2019.01.012] [PMID]
15. Lin YH, Chen BY, Lai WT, Wu SF, Guh JH, Cheng AL, et al. The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2015;388(1):19-31. [DOI:10.1007/s00210-014-1032-y] [PMID]
16. Qiu XM, Bai X, Jiang HF, He P, Wang JH. 20-(s)-ginsenoside Rg3 induces apoptotic cell death in human leukemic U937 and HL-60 cells through PI3K/Akt pathways. Anticancer Drugs. 2014;25(9):1072-80. [DOI:10.1097/CAD.0000000000000147] [PMID]
17. Kunnimalaiyaan M, Ndiaye M, Chen H. Apoptosis-mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002. Surgery. 2006;140(6):1009-14. [DOI:10.1016/j.surg.2006.06.040] [PMID]
18. Farajdokht F, Mohaddes G, Karimi-Sales E, Kafshdooz T, Mahmoudi J, Aberoumandi SM. Inhibition of PTEN protects PC12 cells against oxygen-glucose deprivation induced cell death through mitoprotection. Brain Res. 2018;1692:100-109. [DOI:10.1016/j.brainres.2018.05.026] [PMID]
19. Zhang B, Wang X, Cai F, Chen W, Loesch U, Zhong XY. Antitumor properties of salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and in vivo: involvement of p38 MAPK activation. Oncol Rep. 2013;29(4):1371-8. [DOI:10.3892/or.2013.2241] [PMID]
20. Zhang Z, Xie Z, Sun G, Yang P, Li J, Yang H, et al. Reversing drug resistance of cisplatin by hsp90 inhibitors in human ovarian cancer cells. Int J Clin Exp Med. 2015;8(5):6687-701.
21. Sapi E, Alvero AB, Chen W, O'Malley D, Hao X-Y, Dwipoyono B, et al. Resistance of ovarian carcinoma cells to docetaxel is XIAP dependent and reversible by phenoxodiol. Oncol Res. 2004;14(11-12): 567-78. [DOI:10.3727/0965040042707943] [PMID]
22. Paramasivam A, Sambantham S, Shabnam J, Raghunandhakumar S, Anandan B, Rajiv R, et al. Anti-cancer effects of thymoquinone in mouse neuroblastoma (Neuro-2a) cells through caspase-3 activation with down-regulation of XIA. Toxicology Lett. 2012;213(2):151-9. [DOI:10.1016/j.toxlet.2012.06.011] [PMID]
23. Hanifeh Ahagh M, Dehghan G, Mehdipour M, Teimuri-Mofrad R, Payami E, Sheibani N, et al. Synthesis, characterization, anti-proliferative properties and DNA binding of benzochromene derivatives: Increased Bax/Bcl-2 ratio and caspase-dependent apoptosis in colorectal cancer cell line. Bioorganic chemistry. 2019; 93:103329. [DOI:10.1016/j.bioorg.2019.103329] [PMID]
24. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364-78. [DOI:10.1016/j.ejphar.2014.07.025] [PMID] [PMCID]
25. Fruman DA, Rommel C. PI3Kδ inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov. 2011;1(7):562-72. [DOI:10.1158/2159-8290.CD-11-0249] [PMID]
26. Pal I, Mandal M. PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes. Acta Pharmacol Sin. 2012;33(12):1441-1458. [DOI:10.1038/aps.2012.72] [PMID] [PMCID]
27. Ikezoe T, Nishioka C, Bandobashi K, Yang Y, Kuwayama Y, Adachi Y, et al. Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk Res. 2007;31(5):673-82. [DOI:10.1016/j.leukres.2006.08.001] [PMID]
28. Yamada T, Horinaka M, Shinnoh M, Yoshioka T, Miki T, Sakai T. A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. Int J Oncol. 2013;43(4):1080-6. [DOI:10.3892/ijo.2013.2042] [PMID]
29. Rho SB, Kim BR, Kang S. A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3′-kinase (PI3K)/AKT pathway in ovarian cancer cells. Gynecol Oncol. 2011;120(1):121-7. [DOI:10.1016/j.ygyno.2010.10.003] [PMID]
30. Osaki M, Kase S, Adachi K, Takeda A, Hashimoto K, Ito H. Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45. J Cancer Res Clin Oncol. 2004;130(1):8-14. [DOI:10.1007/s00432-003-0505-z] [PMID]
31. Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, et al. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol. 2009;8(1):25-33.
32. Li Y, Zhang P, Qiu F, Chen L, Miao C, Li J, et al. Inactivation of PI3K/Akt signaling mediates proliferation inhibition and G2/M phase arrest induced by andrographolide in human glioblastoma cells. Life sciences. 2012;90(25-26):962-7. [DOI:10.1016/j.lfs.2012.04.044] [PMID]
33. Mathiasen IS, Jäättelä M. Triggering caspase-independent cell death to combat cancer. Trends Mol Med. 2002;8(5):212-20. [DOI:10.1016/S1471-4914(02)02328-6]
34. Lou M, Zhang LN, Ji PG, Feng FQ, Liu JH, Yang C, et al. Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: in vitro and in vivo. Biomed Pharmacother. 2016;84:1-9. [DOI:10.1016/j.biopha.2016.08.055] [PMID]
35. Xiong Z, Fu Z, Shi J, Jiang X, Wan H. HtrA1 down-regulation induces cisplatin resistance in colon cancer by increasing XIAP and activating PI3K/Akt pathway. Ann Clin Lab Sci. 2017;47(3):264-270.
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
