Overcome of Cisplatin Resistance in Ovarian Cancer by Combination of
Low-intensity Ultrasound and Cisplatin

Bilgi      Kip; Omer      Aydin

doi:10.2174/1567201819666220627100857

Abstract

Background: Platinum-based chemotherapeutics are the main treatment options for ovarium cancer. However, the development of drug resistance is one of the major issues in chemotherapy. Even targeting a specific pathway may not produce an efficient sensitization to the chemo agent due to various pathways related to developing resistance against cisplatin. Hence, more effective strategies against drug resistance are essential for cancer treatment. In the presence of the ultrasonic waves, increased membrane porosity enables more drug uptake into the cancer cell. Therefore, the promising method in cancer therapy is seen as the use of the combined effect of chemotherapy and low-Intensity Ultrasound (LIUS) to overcome chemoresistance.

Objective: The present study aimed to examine the effects of Ultrasound (US)+Cisplatin (Cis)- based combination therapy to advance an effective treatment against drug resistance in cisplatinresistant ovarian cancer cells A2780 (A2780cis) under in vitro conditions.

Methods: Treatment groups as Cis and LIUS with two different ultrasound parameters (10% duty cycle (DC), 1 MHz, 1.0 W/cm², 1 min and 50% DC, 1 MHz, 1.0 W/cm², 3 min) were investigated to cope with the chemoresistance in A2780cis. After Cis therapy with IC₅₀ concentrations determined in A2780 and A2780cis, drug-sensitive/resistant ovarian cancer cells were treated by ultrasound. The effects of the US+Cis combination therapy were evaluated by cell viability assays, colony formation, and cell cycle analyses.

Results: In both US parameters, the waveform was shown to be more effective in preventing drug resistance. While more than 80% of the cell population was suppressed with the US+Cis combination treatment, more than 90% of the colony formation was suppressed according to the colony formation test results. In addition, US+Cis combination therapy caused different cell cycle arrests in both A2780 and A2780cis cells.

Conclusion: Ultrasound-based combination therapies show promising results in combating chemoresistance, and the disadvantages of conventional cancer treatments, such as cancer recurrence, drug resistance, and high cost, might reduce by the effectiveness of combination therapy of ultrasound therapy and chemotherapy.

Keywords: Ovarian cancer, ultrasound therapy, cisplatin, drug resistance, combination therapy, A2780, A2780cis.

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[1]
An, Y.; Wang, X.; Wu, X.; Chen, L.; Yang, Y.; Lin, X.; Wang, N.; Duan, J.; Long, S.; Zhao, X. Oncolytic reovirus induces ovarian cancer cell apoptosis in a TLR3-dependent manner. Virus Res.,  2021, 301, 198440.
 [http://dx.doi.org/10.1016/j.virusres.2021.198440] [PMID:  33940002]

[2]
Aletti, G.D.; Gallenberg, M.M.; Cliby, W.A.; Jatoi, A.; Hartmann, L.C. Current management strategies for ovarian cancer. Mayo Clin. Proc.,  2007, 82(6), 751-770.

[3]
Chen, Y.; Wang, W.; Jiang, B.; Yao, L.; Xia, F.; Li, X. Integrating tumor stroma biomarkers with clinical indicators for colon cancer survival stratification. Front. Med. (Lausanne),  2020, 7, 584747.
 [http://dx.doi.org/10.3389/fmed.2020.584747] [PMID:  33365318]

[4]
Pokhriyal, R.; Hariprasad, R.; Kumar, L.; Hariprasad, G. Chemotherapy resistance in advanced ovarian cancer patients Biomark. Cancer,  2019, 11 1179299X19860815
 [http://dx.doi.org/10.1177/1179299X19860815]

[5]
a) Fuertes, M.; Castilla, J.; Alonso, C.; Pérez, J. Cisplatin biochemical mechanism of action: From cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways. Curr. Med. Chem.,  2003, 10(3), 257-266.
 [http://dx.doi.org/10.2174/0929867033368484] [PMID:  12570712]; 
b) Agarwal, R.; Kaye, S.B. Ovarian cancer: Strategies for overcoming resistance to chemotherapy. Nat. Rev. Cancer,  2003, 3(7), 502-516.
 [http://dx.doi.org/10.1038/nrc1123] [PMID:  12835670]; 
c) Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin resistance. Oncogene,  2012, 31(15), 1869-1883.
 [http://dx.doi.org/10.1038/onc.2011.384] [PMID:  21892204]

[6]
Amable, L. Cisplatin resistance and opportunities for precision medicine. Pharmacol. Res.,  2016, 106, 27-36.
 [http://dx.doi.org/10.1016/j.phrs.2016.01.001] [PMID:  26804248]

[7]
a) Di Lorenzo, G.; Ricci, G.; Severini, G.M.; Romano, F.; Biffi, S. Imaging and therapy of ovarian cancer: Clinical application of nanoparticles and future perspectives. Theranostics,  2018, 8(16), 4279-4294.
 [http://dx.doi.org/10.7150/thno.26345] [PMID:  30214620]; 
b) Kaczmarek, K.; Hornowski, T.; Kubovčíková, M.; Timko, M.; Koralewski, M.; Józefczak, A. Heating induced by therapeutic ultrasound in the presence of magnetic nanoparticles. ACS Appl. Mater. Interfaces,  2018, 10(14), 11554-11564.
 [http://dx.doi.org/10.1021/acsami.8b02496] [PMID:  29560717]

[8]
Miller, M.W.; Miller, D.L.; Brayman, A.A. A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med. Biol.,  1996, 22(9), 1131-1154.
 [http://dx.doi.org/10.1016/S0301-5629(96)00089-0] [PMID:  9123638]

[9]
a) Hrazdira, I.; Škorpíková, J.; Dolníková, M. Ultrasonically induced alterations of cultured tumour cells. Eur. J. Ultrasound,  1998, 8(1), 43-49.
 [http://dx.doi.org/10.1016/S0929-8266(98)00049-4] [PMID:  9795012]; 
b) Tachibana, K.; Uchida, T.; Ogawa, K.; Yamashita, N.; Tamura, K. Induction of cell-membrane porosity by ultrasound. Lancet,  1999, 353(9162), 1409.
 [http://dx.doi.org/10.1016/S0140-6736(99)01244-1] [PMID:  10227224]; 
c) Arthur, C.; Flaig, T.; Su, L.J.; Denney, R.; Barnes, F.; Glodé, L.M. The effect of ultrasonic irradiation on doxorubicin-induced cytotoxicity in three human bladder cancer cell lines. Ultrasonics,  2007, 46(1), 68-73.
 [http://dx.doi.org/10.1016/j.ultras.2006.10.003] [PMID:  17173946]

[10]
a) Stewart, D.J. Mechanisms of resistance to cisplatin and carboplatin. Crit. Rev. Oncol. Hematol.,  2007, 63(1), 12-31.
 [http://dx.doi.org/10.1016/j.critrevonc.2007.02.001] [PMID:  17336087]; 
b) Yu, T.; Yang, Y.; Zhang, J.; He, H.; Ren, X. Circumvention of cisplatin resistance in ovarian cancer by combination of cyclosporin A and low-intensity ultrasound. Eur. J. Pharm. Biopharm.,  2015, 91, 103-110.
 [http://dx.doi.org/10.1016/j.ejpb.2015.02.003] [PMID:  25668779]

[11]
a) Rawla, P. Epidemiology of prostate cancer. World J. Oncol.,  2019, 10(2), 63-89.
 [http://dx.doi.org/10.14740/wjon1191] [PMID:  31068988]; 
b) Evans, A.J.; Ryan, P.; Van derKwast, T. Treatment effects in the prostate including those associated with traditional and emerging therapies. Adv. Anat. Pathol.,  2011, 18(4), 281-293.
 [http://dx.doi.org/10.1097/PAP.0b013e318220f5b1] [PMID:  21654359]; 
c) Abdullah, L.N.; Chow, E.K.H. Mechanisms of chemoresistance in cancer stem cells. Clin. Transl. Med.,  2013, 2(1), 3.
 [http://dx.doi.org/10.1186/2001-1326-2-3] [PMID:  23369605]; 
d) von Amsberg, G.; Merseburger, A.S. Treatment of metastatic, castration-resistant prostate cancer. Urologe A,  2020, 59(6), 673-679.
 [http://dx.doi.org/10.1007/s00120-020-01187-9] [PMID:  32274540]; 
e) Lynn, J.G.; Zwemer, R.L.; Chick, A.J.; Miller, A.E. A new method for the generation and use of focused ultrasound in experimental biology. J. Gen. Physiol.,  1942, 26(2), 179-193.
 [http://dx.doi.org/10.1085/jgp.26.2.179] [PMID:  19873337]; 
f) Seah, B.C.Q.; Teo, B.M. Recent advances in ultrasound-based transdermal drug delivery. Int. J. Nanomedicine,  2018, 13, 7749-7763.
 [http://dx.doi.org/10.2147/IJN.S174759] [PMID:  30538456]; 
g) Xin, Z.; Lin, G.; Lei, H.; Lue, T.F.; Guo, Y. Clinical applications of low-intensity pulsed ultrasound and its potential role in urology. Transl. Androl. Urol.,  2016, 5(2), 255-266.
 [http://dx.doi.org/10.21037/tau.2016.02.04] [PMID:  27141455]

[12]
Bernard, V.; Škorpíková, J.; Mornstein, V.; Slaninová, I. Biological effects of combined ultrasound and cisplatin treatment on ovarian carcinoma cells. Ultrasonics,  2010, 50(3), 357-362.
 [http://dx.doi.org/10.1016/j.ultras.2009.08.010] [PMID:  19740505]

[13]
Liu, Y.; Zhang, W.W.; He, M.; Gong, C.; Xie, B.; Wen, X.; Li, D.; Zhang, L. Adverse effect analysis of high-intensity focused ultrasound in the treatment of benign uterine diseases. Int. J. Hyperthermia,  2018, 35(1), 56-61.
 [http://dx.doi.org/10.1080/02656736.2018.1473894] [PMID:  29792359]

[14]
Aydin, O.; Youssef, I.; Yuksel Durmaz, Y.; Tiruchinapally, G.; ElSayed, M.E.H. Formulation of acid-sensitive micelles for delivery of cabazitaxel into prostate cancer cells. Mol. Pharm.,  2016, 13(4), 1413-1429.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.6b00147] [PMID:  26977718]

[15]
Präbst, K.; Engelhardt, H.; Ringgeler, S.; Hübner, H. Basic colorimetric proliferation assays: MTT, WST, and resazurin. In: Cell Viability Assays; Gilbert, D.; Friedrich, O., Eds.; Humana Press: New York, NY, 2017; pp. 1-17.
 [http://dx.doi.org/10.1007/978-1-4939-6960-9_1]

[16]
Aydin, O.; Vlaisavljevich, E.; Yuksel Durmaz, Y.; Xu, Z.; ElSayed, M.E.H. Noninvasive ablation of prostate cancer spheroids using acoustically-activated nanodroplets. Mol. Pharm.,  2016, 13(12), 4054-4065.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.6b00617] [PMID:  27696857]

[17]
Yan, H.; Che, X.; Lv, Q.; Zhang, L.; Dongol, S.; Wang, Y.; Sun, H.; Jiang, J. Grifolin induces apoptosis and promotes cell cycle arrest in the A2780 human ovarian cancer cell line via inactivation of the ERK1/2 and Akt pathways. Oncol. Lett.,  2017, 13(6), 4806-4812.
 [http://dx.doi.org/10.3892/ol.2017.6092] [PMID:  28588729]

[18]
Jendželovská, Z.; Jendželovský, R.; Hiľovská, L.; Kovaľ, J.; Mikeš, J.; Fedoročko, P. Single pre-treatment with hypericin, a St. John’s wort secondary metabolite, attenuates cisplatin- and mitoxantrone-induced cell death in A2780, A2780cis and HL-60 cells. Toxicol. In Vitro,  2014, 28(7), 1259-1273.

[19]
a) Hayes, B.T.; Merrick, M.A.; Sandrey, M.A.; Cordova, M.L. Three-MHz ultrasound heats deeper into the tissues than originally theorized. J. Athl. Train.,  2004, 39(3), 230-234.
 [PMID:  15496991]; 
b) Lopez, W.; Nguyen, N.; Cao, J.; Eddow, C.; Shung, K.K.; Lee, N.S.; Chow, M.S.S. Ultrasound therapy, chemotherapy and their combination for prostate cancer. Technol. Cancer Res. Treat.,  2021, 20.
 [http://dx.doi.org/10.1177/15330338211011965] [PMID:  34013821]

[20]
Li, H.; Fan, H.; Wang, Z.; Zheng, J.; Cao, W. Potentiation of scutellarin on human tongue carcinoma xenograft by low-intensity ultrasound. PLoS One,  2013, 8(3), e59473-e59473.
 [http://dx.doi.org/10.1371/journal.pone.0059473] [PMID:  23536878]

[21]
Hu, Z.; Lv, G.; Li, Y.; Li, E.; Li, H.; Zhou, Q.; Yang, B.; Cao, W. Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound. J. Exp. Clin. Cancer Res.,  2016, 35(1), 71.
 [http://dx.doi.org/10.1186/s13046-016-0349-4] [PMID:  27102814]

[22]
a) Yang, Y.; Bai, W.; Chen, Y.; Lin, Y.; Hu, B. Optimization of low-frequency low-intensity ultrasound-mediated microvessel disruption on prostate cancer xenografts in nude mice using an orthogonal experimental design. Oncol. Lett.,  2015, 10(5), 2999-3007.
 [http://dx.doi.org/10.3892/ol.2015.3716] [PMID: 26722279]; 
b) Yang, Y.; Bai, W.; Chen, Y.; Zhang, W.; Wang, M.; Hu, B. Low-frequency and low-intensity ultrasound-mediated microvessel disruption enhance the effects of radiofrequency ablation on prostate cancer xenografts in nude mice. Mol. Med. Rep.,  2015, 12(5), 7517-7525.
 [http://dx.doi.org/10.3892/mmr.2015.4375] [PMID:  26458324]

[23]
Wang, D.S.; Panje, C.; Pysz, M.A.; Paulmurugan, R.; Rosenberg, J.; Gambhir, S.S.; Schneider, M.; Willmann, J.K. Cationic versus neutral microbubbles for ultrasound-mediated gene delivery in cancer. Radiology,  2012, 264(3), 721-732.
 [http://dx.doi.org/10.1148/radiol.12112368] [PMID:  22723497]

[24]
Pan, H.; Zhou, Y.; Izadnegahdar, O.; Cui, J.; Deng, C.X. Study of sonoporation dynamics affected by ultrasound duty cycle. Ultrasound Med. Biol.,  2005, 31(6), 849-856.
 [http://dx.doi.org/10.1016/j.ultrasmedbio.2005.03.014] [PMID:  15936500]

[25]
a) Thomas, R.G.; Jonnalagadda, U.S.; Kwan, J.J. Biomedical applications for gas-stabilizing solid cavitation agents. Langmuir,  2019, 35(31), 10106-10115.
 [http://dx.doi.org/10.1021/acs.langmuir.9b00795] [PMID:  31045378]; 
b) Barati, A.H.; Mokhtari-Dizaji, M.; Mozdarani, H.; Bathaie, Z.; Hassan, Z.M. Effect of exposure parameters on cavitation induced by low-level dual-frequency ultrasound. Ultrason. Sonochem.,  2007, 14(6), 783-789.
 [http://dx.doi.org/10.1016/j.ultsonch.2006.12.016] [PMID:  17347019]

[26]
Yu, T.; Li, S.; Zhao, J.; Mason, T. J. Ultrasound: A chemotherapy sensitizer. Technol. Cancer Res. Treat.,  2006, 5(1), 51-60.
 [http://dx.doi.org/10.1177/153303460600500107] [PMID:  16417402]

[27]
Shen, D.W.; Pouliot, L.M.; Hall, M.D.; Gottesman, M.M. Cisplatin resistance: A cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol. Rev.,  2012, 64(3), 706-721.
 [http://dx.doi.org/10.1124/pr.111.005637] [PMID:  22659329]

[28]
Wang, T.Y.; Choe, J.W.; Pu, K.; Devulapally, R.; Bachawal, S.; Machtaler, S.; Chowdhury, S.M.; Luong, R.; Tian, L.; Khuri-Yakub, B.; Rao, J.; Paulmurugan, R.; Willmann, J.K. Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer. J. Control. Release,  2015, 203, 99-108.
 [http://dx.doi.org/10.1016/j.jconrel.2015.02.018] [PMID:  25687306]

[29]
Pitt, W.G.; Husseini, G.A.; Staples, B.J. Ultrasonic drug delivery-a general review. Expert Opin. Drug Deliv.,  2004, 1(1), 37-56.
 [http://dx.doi.org/10.1517/17425247.1.1.37] [PMID:  16296719]

[30]
Tharkar, P.; Varanasi, R.; Wong, W.S.F.; Jin, C.T.; Chrzanowski, W. Nano-enhanced drug delivery and therapeutic ultrasound for cancer treatment and beyond. Front. Bioeng. Biotechnol.,  2019, 7, 324.
 [http://dx.doi.org/10.3389/fbioe.2019.00324] [PMID:  31824930]

[31]
Schweizer, F.E.; Ryan, T.A. The synaptic vesicle: Cycle of exocytosis and endocytosis. Curr. Opin. Neurobiol.,  2006, 16(3), 298-304.
 [http://dx.doi.org/10.1016/j.conb.2006.05.006] [PMID:  16707259]

[32]
Juffermans, L.J.M.; Kamp, O.; Dijkmans, P.A.; Visser, C.A.; Musters, R.J.P. Low-intensity ultrasound-exposed microbubbles provoke local hyperpolarization of the cell membrane via activation of BK(Ca) channels. Ultrasound Med. Biol.,  2008, 34(3), 502-508.
 [http://dx.doi.org/10.1016/j.ultrasmedbio.2007.09.010] [PMID:  17993242]

[33]
Hare, J.I.; Lammers, T.; Ashford, M.B.; Puri, S.; Storm, G.; Barry, S.T. Challenges and strategies in anti-cancer nanomedicine development: An industry perspective. Adv. Drug Deliv. Rev.,  2017, 108, 25-38.
 [http://dx.doi.org/10.1016/j.addr.2016.04.025] [PMID:  27137110]

[34]
Velma, V.; Dasari, S.R.; Tchounwou, P.B. Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark. Insights,  2016, 11 BMI.S39445.
 [http://dx.doi.org/10.4137/BMI.S39445] [PMID: 27594783]

[35]
Sharma, S.; Santiskulvong, C.; Rao, J.; Gimzewski, J.K.; Dorigo, O. The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells. Integr. Biol.,  2014, 6(6), 611-617.
 [http://dx.doi.org/10.1039/C3IB40246K] [PMID:  24718685]

[36]
Franken, N.A.P.; Rodermond, H.M.; Stap, J.; Haveman, J.; van Bree, C. Clonogenic assay of cells in vitro. Nat. Protoc.,  2006, 1(5), 2315-2319.
 [http://dx.doi.org/10.1038/nprot.2006.339] [PMID:  17406473]

[37]
Meng, E.; Long, B.; Sullivan, P.; McClellan, S.; Finan, M.A.; Reed, E.; Shevde, L.; Rocconi, R.P. CD44+/CD24−ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clin. Exp. Metastasis,  2012, 29(8), 939-948.
 [http://dx.doi.org/10.1007/s10585-012-9482-4] [PMID:  22610780]

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DOI https://dx.doi.org/10.2174/1567201819666220627100857	Print ISSN 1567-2018
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Overcome of Cisplatin Resistance in Ovarian Cancer by Combination of Low-intensity Ultrasound and Cisplatin

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