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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Liguang Zhou, Jing Liu, Wen Meng, Huawei Zhang and Bo Chen*

DOI: 10.2174/1871520621666210608101649

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Evaluation of Silibinin-Loaded Microbubbles Combined with Ultrasound in Ovarian Cancer Cells: Cytotoxicity and Mechanisms

Page: [1320 - 1327] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: The anticancer activity of silibinin (SB) has been demonstrated in various cancer cell types. However, its low solubility and poor bioavailability limit its clinical potential in biomedical applications. Microbubbles in combination with ultrasound are promising vehicles for local drug delivery.

Objective: The present study determined the antitumour effects and molecular mechanism of silibinin-loaded microbubbles (SBMBs) in combination with ultrasound on ovarian cancer in vitro.

Methods: SBMBs were prepared using mechanical vibration. The viability of A2780 cells was determined using the MTT assay. Flow cytometry was performed to detect cell apoptosis and the cell cycle. The expression of Receptor Tyrosine Kinase (RTK)-associated downstream proteins was detected using multiplex assays and Western blots.

Results: The present study designed and synthesized SBMBs. SBMBs in combination with ultrasound decreased A2780 cell viability in a dose- and time-dependent manner. The half maximal inhibitory concentration (IC50) showed that the cytotoxicity of the SBMBs was approximately 1.5 times greater than that of the SB in A2780 cells. SBMBs in combination with ultrasound resulted in significantly higher apoptosis efficiency compared to the SB group, and the SBMB population of cells was arrested in the G1/G0 phase. Further experiments demonstrated that SBMBs decreased the expression of signal transducer and activator of transcription 3 (STAT3), Ak strain transforming (AKT), and extracellular signal-regulated kinase (Erk) and had a greater effect than SB in A2780 cells. Inhibitors of AKT, Erk and STAT3 promoted the cytotoxicity of SBMBs.

Conclusion: SBMBs in combination with ultrasound may enhance the cytotoxicity efficiency of SB via the promotion of apoptosis and cell cycle arrest in ovarian cancer cells and the inactivation of the STAT3, AKT and Erk signalling pathways.

Keywords: Silibinin, ultrasound, microbubbles, ovarian cancer, cytotoxicity, SBMB.

Graphical Abstract

[1]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin., 2013, 63(1), 11-30.
[http://dx.doi.org/10.3322/caac.21166] [PMID: 23335087]
[2]
Kemp, Z.; Ledermann, J. Update on first-line treatment of advanced ovarian carcinoma. Int. J. Womens Health, 2013, 5, 45-51.
[PMID: 23378788]
[3]
Aletti, G.D.; Podratz, K.C.; Cliby, W.A.; Gostout, B.S. Stage IV ovarian cancer: disease site-specific rationale for postoperative treatment. Gynecol. Oncol., 2009, 112(1), 22-27.
[http://dx.doi.org/10.1016/j.ygyno.2008.09.010] [PMID: 18947860]
[4]
Terplan, M.; Smith, E.J.; Temkin, S.M. Race in ovarian cancer treatment and survival: a systematic review with meta-analysis. Cancer Causes Control, 2009, 20(7), 1139-1150.
[http://dx.doi.org/10.1007/s10552-009-9322-2] [PMID: 19288217]
[5]
Banerjee, S.; Kaye, S.B. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin. Cancer Res., 2013, 19(5), 961-968.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2243] [PMID: 23307860]
[6]
Bhatt, A.; Glehen, O. The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer: a review. Indian J. Surg. Oncol., 2016, 7(2), 188-197.
[http://dx.doi.org/10.1007/s13193-016-0501-9] [PMID: 27065709]
[7]
Kapahi, B.K.; Srivastava, T.N.; Balyan, S.S.; Sarin, Y.K. Cultivation of silybum marianum gaertn., a promising medicinal plant. Anc. Sci. Life, 1995, 14(4), 240-244.
[PMID: 22556704]
[8]
Sozen, H.; Celik, O.I.; Cetin, E.S.; Yilmaz, N.; Aksozek, A.; Topal, Y.; Cigerci, I.H.; Beydilli, H. Evaluation of the protective effect of silibinin in rats with liver damage caused by itraconazole. Cell Biochem. Biophys., 2015, 71(2), 1215-1223.
[http://dx.doi.org/10.1007/s12013-014-0331-8] [PMID: 25395192]
[9]
Cheung, C.W.; Gibbons, N.; Johnson, D.W.; Nicol, D.L. Silibinin--a promising new treatment for cancer. Anticancer. Agents Med. Chem., 2010, 10(3), 186-195.
[http://dx.doi.org/10.2174/1871520611009030186] [PMID: 20015009]
[10]
Liang, Z.; Yang, Y.; Wang, H.; Yi, W.; Yan, X.; Yan, J.; Li, Y.; Feng, Y.; Yu, S.; Yang, J.; Jin, Z.; Duan, W.; Chen, W. Inhibition of SIRT1 signaling sensitizes the antitumor activity of silybin against human lung adenocarcinoma cells in vitro and in vivo. Mol. Cancer Ther., 2014, 13(7), 1860-1872.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0942] [PMID: 24798868]
[11]
Brandon-Warner, E.; Eheim, A.L.; Foureau, D.M.; Walling, T.L.; Schrum, L.W.; McKillop, I.H. Silibinin (Milk Thistle) potentiates ethanol-dependent hepatocellular carcinoma progression in male mice. Cancer Lett., 2012, 326(1), 88-95.
[http://dx.doi.org/10.1016/j.canlet.2012.07.028] [PMID: 22863537]
[12]
Nambiar, D.; Prajapati, V.; Agarwal, R.; Singh, R.P. In vitro and in vivo anticancer efficacy of silibinin against human pancreatic cancer BxPC-3 and PANC-1 cells. Cancer Lett., 2013, 334(1), 109-117.
[http://dx.doi.org/10.1016/j.canlet.2012.09.004] [PMID: 23022268]
[13]
Zhou, L.; Liu, P.; Chen, B.; Wang, Y.; Wang, X.; Chiriva Internati, M.; Wachtel, M.S.; Frezza, E.E. Silibinin restores paclitaxel sensitivity to paclitaxel-resistant human ovarian carcinoma cells. Anticancer Res., 2008, 28(2A), 1119-1127.
[PMID: 18507063]
[14]
Cufí, S.; Bonavia, R.; Vazquez-Martin, A.; Corominas-Faja, B.; Oliveras-Ferraros, C.; Cuyàs, E.; Martin-Castillo, B.; Barrajón-Catalán, E.; Visa, J.; Segura-Carretero, A.; Bosch-Barrera, J.; Joven, J.; Micol, V.; Menendez, J.A. Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. Food Chem. Toxicol., 2013, 60, 360-368.
[http://dx.doi.org/10.1016/j.fct.2013.07.063] [PMID: 23916468]
[15]
Sirsi, S.; Borden, M. Microbubble compositions, properties and biomedical applications. Bubble Sci. Eng. Technol., 2009, 1(1-2), 3-17.
[http://dx.doi.org/10.1179/175889709X446507] [PMID: 20574549]
[16]
Li, H.; Wang, J.; Huang, G.; Wang, P.; Zheng, R.; Zhang, C.; Jiang, Q. Multifunctionalized microbubbles for cancer diagnosis and therapy. Anticancer. Agents Med. Chem., 2013, 13(3), 403-413.
[PMID: 23092268]
[17]
Escoffre, J.M.; Novell, A.; Serrière, S.; Lecomte, T.; Bouakaz, A. Irinotecan delivery by microbubble-assisted ultrasound: in vitro validation and a pilot preclinical study. Mol. Pharm., 2013, 10(7), 2667-2675.
[http://dx.doi.org/10.1021/mp400081b] [PMID: 23675982]
[18]
Liu, L.; Chang, S.; Sun, J.; Zhu, S.; Yin, M.; Zhu, Y.; Wang, Z.; Xu, R.X. Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts. Cancer Lett., 2015, 361(1), 147-154.
[http://dx.doi.org/10.1016/j.canlet.2015.02.052] [PMID: 25754815]
[19]
Lakshmanan, S.; Gupta, G.K.; Avci, P.; Chandran, R.; Sadasivam, M.; Jorge, A.E.; Hamblin, M.R. Physical energy for drug delivery; poration, concentration and activation. Adv. Drug Deliv. Rev., 2014, 71, 98-114.
[http://dx.doi.org/10.1016/j.addr.2013.05.010] [PMID: 23751778]
[20]
Sorace, A.G.; Warram, J.M.; Umphrey, H.; Hoyt, K. Microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer. J. Drug Target., 2012, 20(1), 43-54.
[http://dx.doi.org/10.3109/1061186X.2011.622397] [PMID: 21981609]
[21]
Luo, M.H.; Yeh, C.K.; Situ, B.; Yu, J.S.; Li, B.C.; Chen, Z.Y. Microbubbles: a novel strategy for chemotherapy. Curr. Pharm. Des., 2017, 23(23), 3383-3390.
[http://dx.doi.org/10.2174/1381612823666170113092148] [PMID: 28088911]
[22]
Kumar, N.; Rai, A.; Reddy, N.D.; Raj, P.V.; Jain, P.; Mathew, G.; Kutty, G.; Udupa, N.; Rao, C.W. Silymarin liposomes improves oral bioavailability of silybin besides targeting hepatocytes, and immune cells. Pharmacol. Rep., 2014, 66, 788-798.
[23]
Sun, H.P.; Su, J.H.; Meng, H.P.; Su, J.H.; Su, J.H.; Meng, Q.S.; Yin, Q.; Zhang, Z.W.; Yu, H.J. Zhang. P.C.; Wang, S.L.; Li, Y.P. Silibin and indocyanine green-loaded nanoparticles inhibit the growth and metastasis of mammalian breast cancer cells in vitro. Acta Pharmacol. Sin., 2016, 37, 941-949.
[24]
Boissenot, T.; Bordat, A.; Fattal, E.; Tsapis, N. Ultrasound-triggered drug delivery for cancer treatment using drug delivery systems: From theoretical considerations to practical applications. J. Control. Release, 2016, 241, 144-163.
[http://dx.doi.org/10.1016/j.jconrel.2016.09.026] [PMID: 27667179]
[25]
Jain, A.; Tiwari, A.; Verma, A.; Jain, S.K. Ultrasound-based triggered drug delivery to tumors. Drug Deliv. Transl. Res., 2018, 8(1), 150-164.
[http://dx.doi.org/10.1007/s13346-017-0448-6] [PMID: 29204925]
[26]
Lentacker, I.; De Cock, I.; Deckers, R.; De Smedt, S.C.; Moonen, C.T. Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. Adv. Drug Deliv. Rev., 2014, 72, 49-64.
[http://dx.doi.org/10.1016/j.addr.2013.11.008] [PMID: 24270006]
[27]
Delalande, A.; Kotopoulis, S.; Postema, M.; Midoux, P.; Pichon, C. Sonoporation: mechanistic insights and ongoing challenges for gene transfer. Gene, 2013, 525(2), 191-199.
[http://dx.doi.org/10.1016/j.gene.2013.03.095] [PMID: 23566843]
[28]
Juffermans, L.J.; Kamp, O.; Dijkmans, P.A.; Visser, C.A.; Musters, R.J. 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]
[29]
Saliez, J.; Bouzin, C.; Rath, G.; Ghisdal, P.; Desjardins, F.; Rezzani, R.; Rodella, L.F.; Vriens, J.; Nilius, B.; Feron, O.; Balligand, J.L.; Dessy, C. Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells. Circulation, 2008, 117(8), 1065-1074.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.731679] [PMID: 18268148]
[30]
Hubbard, S.R.; Miller, W.T. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr. Opin. Cell Biol., 2007, 19(2), 117-123.
[http://dx.doi.org/10.1016/j.ceb.2007.02.010] [PMID: 17306972]
[31]
Zwick, E.; Bange, J.; Ullrich, A. Receptor tyrosine kinases as targets for anticancer drugs. Trends Mol. Med., 2002, 8(1), 17-23.
[http://dx.doi.org/10.1016/S1471-4914(01)02217-1] [PMID: 11796262]
[32]
Drevs, J.; Medinger, M.; Schmidt-Gersbach, C.; Weber, R.; Unger, C. Receptor tyrosine kinases: the main targets for new anticancer therapy. Curr. Drug Targets, 2003, 4(2), 113-121.
[http://dx.doi.org/10.2174/1389450033346885] [PMID: 12558064]
[33]
Teillet, F.; Boumendjel, A.; Boutonnat, J.; Ronot, X. Flavonoids as RTK inhibitors and potential anticancer agents. Med. Res. Rev., 2008, 28(5), 715-745.
[http://dx.doi.org/10.1002/med.20122] [PMID: 18080331]
[34]
Binienda, A.; Ziolkowska, S.; Pluciennik, E. The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer. Anticancer. Agents Med. Chem., 2020, 20(15), 1787-1796.
[http://dx.doi.org/10.2174/1871520620666191220142741] [PMID: 31858905]
[35]
Bosch-Barrera, J.; Menendez, J.A. Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat. Rev., 2015, 41(6), 540-546.
[http://dx.doi.org/10.1016/j.ctrv.2015.04.008] [PMID: 25944486]