Effects of 2-Hydroxypropil-Β-Cyclodextrin-Lidocaine on Tumor Growth and Inflammatory Response

Author(s): Luiz Eduardo Nunes Ferreira*, Henrique Ballassini Abdalla, Jéssica Pereira da Costa, Juliana Souza de Freitas Domingues, Jonny Burga-Sánchez, Francisco Carlos Groppo, Maria Cristina Volpato

Journal Name: Current Drug Delivery

Volume 17 , Issue 7 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Antiproliferative and cytotoxic effects of lidocaine have been reported in tumor cells. However, the use of these drugs is restricted due to their short action with rapid dispersion from the injected site. The complexation of local anesthetics in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is able to improve pharmacological features.

Objective: This study evaluated the antitumor effects of lidocaine and the complex HP-β-CD-lidocaine (HP-β-CD-lido).

Methods: In vitro, human adenocarcinoma (HeLa) and keratinocytes (HaCaT) were exposed to lidocaine formulations and cell viability, proliferation and apoptosis induction were measured. In vivo, Walker 256 carcinoma cells were subcutaneously injected into the plantar region of the rat right hind paw. The animals were treated with a local application of 5% lidocaine or 5% HP-β-CD-lido. Doxorubicin (3 mg/Kg/day, intraperitoneal) was used as a positive control. Edema sizes were measured daily and the release of cytokines (TNF-α, IL-1α and CXCL-1) and prostaglandin E2 was evaluated. Histological analysis was also performed.

Results: HaCaT IG50 values were 846 μM and 2253 μM for lido and HP-β-CD-lido, respectively. In HeLa cells, the IG50 was 1765 μM for lido and 2044 μM for HP-β-CD-lido. Lidocaine formulations significantly reduced the paw edema on day 6 after Walker 256 cells inoculation. However, there were no differences in the release of inflammatory mediators in comparison to the control group.

Conclusion: Lidocaine formulations were able to reduce the edema in vivo, without affecting the tumor- induced inflammatory response. The antiproliferative effects of lidocaine formulations may have contributed to tumor reduction.

Keywords: Lidocaine, 2-hydroxypropyl-β-cyclodextrin, antiproliferative, Walker 256 carcinoma, paw edema, inflammatory response.

Kobayashi, K.; Ohno, S.; Uchida, S.; Amano, O.; Sakagami, H.; Nagasaka, H. Cytotoxicity and type of cell death induced by local anesthetics in human oral normal and tumor cells. Anticancer Res., 2012, 32(7), 2925-2933.
[PMID: 22753757]
Chamaraux-Tran, T.N.; Piegeler, T. The amide local anesthetic lidocaine in cancer surgery-potential antimetastatic effects and preservation of immune cell function? A narrative review. Front. Med. (Lausanne), 2017, 4, 235.
[http://dx.doi.org/10.3389/fmed.2017.00235] [PMID: 29326939]
Martinsson, T. Ropivacaine inhibits serum-induced proliferation of colon adenocarcinoma cells in vitro. J. Pharmacol. Exp. Ther., 1999, 288(2), 660-664.
[PMID: 9918572]
Jiang, Y.; Gou, H.; Zhu, J.; Tian, S.; Yu, L. Lidocaine inhibits the invasion and migration of TRPV6-expressing cancer cells by TRPV6 downregulation. Oncol. Lett., 2016, 12(2), 1164-1170.
[http://dx.doi.org/10.3892/ol.2016.4709] [PMID: 27446413]
Lucchinetti, E.; Awad, A.E.; Rahman, M.; Feng, J.; Lou, P.H.; Zhang, L.; Ionescu, L.; Lemieux, H.; Thébaud, B.; Zaugg, M. Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing. Anesthesiology, 2012, 116(4), 841-856.
[http://dx.doi.org/10.1097/ALN.0b013e31824babfe] [PMID: 22343474]
Ferreira, L.E.N.; Antunes, G.B.M.; Muniz, B.V.; Burga-Sánchez, J.; de Melo, N.F.S.; Groppo, F.C.; Fraceto, L.F.; Volpato, M.C. Effects of lidocaine and the inclusion complex with 2-hydroxypropyl-β-cyclodextrin on cell viability and proliferation of oral squamous cell carcinoma. J. Pharm. Pharmacol., 2018, 70(7), 874-882.
[http://dx.doi.org/10.1111/jphp.12917] [PMID: 29633269]
Grishko, V.; Xu, M.; Wilson, G.; Pearsall, A.W., IV Apoptosis and mitochondrial dysfunction in human chondrocytes following exposure to lidocaine, bupivacaine, and ropivacaine. J. Bone Joint Surg. Am., 2010, 92(3), 609-618.
[http://dx.doi.org/10.2106/JBJS.H.01847] [PMID: 20194319]
Lahav, M.; Levite, M.; Bassani, L.; Lang, A.; Fidder, H.; Tal, R.; Bar-Meir, S.; Mayer, L.; Chowers, Y. Lidocaine inhibits secretion of IL-8 and IL-1β and stimulates secretion of IL-1 receptor antagonist by epithelial cells. Clin. Exp. Immunol., 2002, 127(2), 226-233.
[http://dx.doi.org/10.1046/j.1365-2249.2002.01747.x] [PMID: 11876744]
Lang, A.; Ben Horin, S.; Picard, O.; Fudim, E.; Amariglio, N.; Chowers, Y. Lidocaine inhibits epithelial chemokine secretion via inhibition of nuclear factor kappa B activation. Immunobiology, 2010, 215(4), 304-313.
[http://dx.doi.org/10.1016/j.imbio.2009.05.006] [PMID: 19559500]
Sinclair, R.; Eriksson, A.S.; Gretzer, C.; Cassuto, J.; Thomsen, P. Inhibitory effects of amide local anaesthetics on stimulus-induced human leukocyte metabolic activation, LTB4 release and IL-1 secretion in vitro. Acta Anaesthesiol. Scand., 1993, 37(2), 159-165.
[http://dx.doi.org/10.1111/j.1399-6576.1993.tb03693.x] [PMID: 8383401]
Flondor, M.; Listle, H.; Kemming, G.I.; Zwissler, B.; Hofstetter, C. Effect of inhaled and intravenous lidocaine on inflammatory reaction in endotoxaemic rats. Eur. J. Anaesthesiol., 2010, 27(1), 53-60.
[http://dx.doi.org/10.1097/EJA.0b013e32832b8a70] [PMID: 19444124]
Weng, M.; Chen, W.; Hou, W.; Li, L.; Ding, M.; Miao, C. The effect of neuraxial anesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis. Oncotarget, 2016, 7(12), 15262-15273.
[http://dx.doi.org/10.18632/oncotarget.7683] [PMID: 26918830]
Grant, S.A. The Holy grail: long-acting local anaesthetics and liposomes. Best Pract. Res. Clin. Anaesthesiol., 2002, 16(2), 345-352.
[http://dx.doi.org/10.1053/bean.2002.0242] [PMID: 12491562]
de Paula, E.; Cereda, C.M.; Tofoli, G.R.; Franz-Montan, M.; Fraceto, L.F.; de Araújo, D.R. Drug delivery systems for local anesthetics. Recent Pat. Drug Deliv. Formul., 2010, 4(1), 23-34.
[http://dx.doi.org/10.2174/187221110789957228] [PMID: 19807683]
Han, B.; Yang, B.; Yang, X.; Zhao, Y.; Liao, X.; Gao, C.; Wang, F.; Jiang, R. Host-guest inclusion system of norathyriol with β-cyclodextrin and its derivatives: preparation, characterization, and anticancer activity. J. Biosci. Bioeng., 2014, 117(6), 775-779.
[http://dx.doi.org/10.1016/j.jbiosc.2013.12.001] [PMID: 24508024]
Liu, B.; Li, W.; Zhao, J.; Liu, Y.; Zhu, X.; Liang, G. Physicochemical characterisation of the supramolecular structure of luteolin/cyclodextrin inclusion complex. Food Chem., 2013, 141(2), 900-906.
[http://dx.doi.org/10.1016/j.foodchem.2013.03.097] [PMID: 23790865]
Liu, Y.; Chen, Y. Cooperative binding and multiple recognition by bridged bis(beta-cyclodextrin)s with functional linkers. Acc. Chem. Res., 2006, 39(10), 681-691.
[http://dx.doi.org/10.1021/ar0502275] [PMID: 17042468]
Dollo, G.; Thompson, D.O.; Le Correa, P.; Chevannea, F.; Le Vergea, R. Inclusion complexation of amide-typed local anesthetics with β-cyclodextrin and its derivatives. III. Biopharmaceutics of bupivacaine-SBE7-β-CD complex following percutaneous sciatic nerve administration in rabbits. Int. J. Pharm., 1998, 164, 11-19.
Estebe, J.P.; Ecoffey, C.; Dollo, G.; Le Corre, P.; Chevanne, F.; Le Verge, R. Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine-sulphobutylether 7-beta-cyclodextrin complex in sheep. Eur. J. Anaesthesiol., 2002, 19(4), 308-310.
[http://dx.doi.org/10.1097/00003643-200204000-00015] [PMID: 12074425]
De Araujo, D.R.; Tsuneda, S.S.; Cereda, C.M.; Del, G F Carvalho, F.; Preté, P.S.; Fernandes, S.A.; Yokaichiya, F.; Franco, M.K.; Mazzaro, I.; Fraceto, L.F.; de F A Braga, A.; de Paula, E. Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex. Eur. J. Pharm. Sci., 2008, 33(1), 60-71.
[http://dx.doi.org/10.1016/j.ejps.2007.09.010] [PMID: 18036789]
Wei, Y.; Nedley, M.P.; Bhaduri, S.B.; Bredzinski, X.; Boddu, S.H. Masking the bitter taste of injectable lidocaine HCl formulation for dental procedures. AAPS PharmSciTech, 2015, 16(2), 455-465.
[http://dx.doi.org/10.1208/s12249-014-0239-z] [PMID: 25361901]
Moraes, C.; Abrami, P.; de Araujo, D.R.; Braga, A.F.A.; Issa, M.G.; Ferraz, H.G.; de Paula, E.; Fraceto, L.F. Characterization of lidocaine: hydroxypropyl-β-cyclodextrin inclusion complex. J. Incl. Phenom. Macrocycl. Chem., 2007, 57(4), 313-316.
Sakaguchi, M.; Kuroda, Y.; Hirose, M. The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor. Anesth. Analg., 2006, 102(4), 1103-1107.
[http://dx.doi.org/10.1213/01.ane.0000198330.84341.35] [PMID: 16551906]
Wang, W.T.; Chen, Y.H.; Hsu, J.L.; Leu, W.J.; Yu, C.C.; Chan, S.H.; Ho, Y.F.; Hsu, L.C.; Guh, J.H. Terfenadine induces anti-proliferative and apoptotic activities in human hormone-refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation. Naunyn Schmiedebergs Arch. Pharmacol., 2014, 387(1), 33-45.
[http://dx.doi.org/10.1007/s00210-013-0912-x] [PMID: 24048439]
Guide for the Care and Use of Laboratory Animals, 8th ed; The National Academies Press: Washington, 2011.
Brigatte, P.; Sampaio, S.C.; Gutierrez, V.P.; Guerra, J.L.; Sinhorini, I.L.; Curi, R.; Cury, Y. Walker 256 tumor-bearing rats as a model to study cancer pain. J. Pain, 2007, 8(5), 412-421.
[http://dx.doi.org/10.1016/j.jpain.2006.11.006] [PMID: 17287145]
Chang, Y.C.; Liu, C.L.; Chen, M.J.; Hsu, Y.W.; Chen, S.N.; Lin, C.H.; Chen, C.M.; Yang, F.M.; Hu, M.C. Local anesthetics induce apoptosis in human breast tumor cells. Anesth. Analg., 2014, 118(1), 116-124.
[http://dx.doi.org/10.1213/ANE.0b013e3182a94479] [PMID: 24247230]
Call, T.R.; Pace, N.L.; Thorup, D.B.; Maxfield, D.; Chortkoff, B.; Christensen, J.; Mulvihill, S.J. Factors associated with improved survival after resection of pancreatic adenocarcinoma: a multivariable model. Anesthesiology, 2015, 122(2), 317-324.
[http://dx.doi.org/10.1097/ALN.0000000000000489] [PMID: 25305092]
McCarthy, G.C.; Megalla, S.A.; Habib, A.S. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review of randomized controlled trials. Drugs, 2010, 70(9), 1149-1163.
[http://dx.doi.org/10.2165/10898560-000000000-00000] [PMID: 20518581]
Xing, W.; Chen, D.T.; Pan, J.H.; Chen, Y.H.; Yan, Y.; Li, Q.; Xue, R.F.; Yuan, Y.F.; Zeng, W.A. Lidocaine induces apoptosis and suppresses tumor growth in human hepatocellular carcinoma cells in vitro and in a xenograft model in vivo. Anesthesiology, 2017, 126(5), 868-881.
[http://dx.doi.org/10.1097/ALN.0000000000001528] [PMID: 28121635]
Schlagenhauff, B.; Ellwanger, U.; Breuninger, H.; Stroebel, W.; Rassner, G.; Garbe, C. Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma. Melanoma Res., 2000, 10(2), 165-169.
[http://dx.doi.org/10.1097/00008390-200004000-00009] [PMID: 10803717]
Wang, F.; Yang, B.; Zhao, Y.; Liao, X.; Gao, C.; Jiang, R.; Han, B.; Yang, J.; Liu, M.; Zhou, R. Host-guest inclusion system of scutellarein with 2-hydroxypropyl-beta-cyclodextrin: preparation, characterization, and anticancer activity. J. Biomater. Sci. Polym. Ed., 2014, 25(6), 594-607.
[http://dx.doi.org/10.1080/09205063.2014.884875] [PMID: 24555409]
Zhang, D.; Zhang, J.; Jiang, K.; Li, K.; Cong, Y.; Pu, S.; Jin, Y.; Lin, J. Preparation, characterisation and antitumour activity of β-, γ- and HP-β-cyclodextrin inclusion complexes of oxaliplatin. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2016, 152, 501-508.
[http://dx.doi.org/10.1016/j.saa.2015.07.088] [PMID: 26254603]
Reagan-Shaw, S.; Nihal, M.; Ahmad, N. Dose translation from animal to human studies revisited. FASEB J., 2008, 22(3), 659-661.
[http://dx.doi.org/10.1096/fj.07-9574LSF] [PMID: 17942826]
Baptista-Hon, D.T.; Robertson, F.M.; Robertson, G.B.; Owen, S.J.; Rogers, G.W.; Lydon, E.L.; Lee, N.H.; Hales, T.G. Potent inhibition by ropivacaine of metastatic colon cancer SW620 cell invasion and NaV1.5 channel function. Br. J. Anaesth., 2014, 113(Suppl. 1), i39-i48.
[http://dx.doi.org/10.1093/bja/aeu104] [PMID: 24852501]
Freeman, J.; Crowley, P.D.; Foley, A.G.; Gallagher, H.C.; Iwasaki, M.; Ma, D.; Buggy, D.J.; Buggy, D.J. Effect of perioperative lidocaine and cisplatin on metastasis in a murine model of breast cancer surgery. Anticancer Res., 2018, 38(10), 5599-5606.
[http://dx.doi.org/10.21873/anticanres.12894] [PMID: 30275177]
Piegeler, T.; Votta-Velis, E.G.; Liu, G.; Place, A.T.; Schwartz, D.E.; Beck-Schimmer, B.; Minshall, R.D.; Borgeat, A. Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Anesthesiology, 2012, 117(3), 548-559.
[http://dx.doi.org/10.1097/ALN.0b013e3182661977] [PMID: 22846676]
Tsubaki, M.; Komai, M.; Itoh, T.; Imano, M.; Sakamoto, K.; Shimaoka, H.; Takeda, T.; Ogawa, N.; Mashimo, K.; Fujiwara, D.; Mukai, J.; Sakaguchi, K.; Satou, T.; Nishida, S. By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells. Leuk. Res., 2014, 38(1), 121-130.
[http://dx.doi.org/10.1016/j.leukres.2013.10.017] [PMID: 24239173]
Hu, Y.; Qin, X.; Cao, H.; Yu, S.; Feng, J. Reversal effects of local anesthetics on P-glycoprotein-mediated cancer multidrug resistance. Anticancer Drugs, 2017, 28(3), 243-249.
[http://dx.doi.org/10.1097/CAD.0000000000000455] [PMID: 27906699]
Liu, H.; Wang, Y.; Chen, B.; Shen, X.; Li, W. Effects of lidocaine-mediated CPEB3 upregulation in human hepatocellular carcinoma cell proliferation in vitro. BioMed Res. Int., 2018, •••e8403157
Groisman, I.; Ivshina, M.; Marin, V.; Kennedy, N.J.; Davis, R.J.; Richter, J.D. Control of cellular senescence by CPEB. Genes Dev., 2006, 20(19), 2701-2712.
[http://dx.doi.org/10.1101/gad.1438906] [PMID: 17015432]
Ivshina, M.; Lasko, P.; Richter, J.D. Cytoplasmic polyadenylation element binding proteins in development, health, and disease. Annu. Rev. Cell Dev. Biol., 2014, 30, 393-415.
[http://dx.doi.org/10.1146/annurev-cellbio-101011-155831] [PMID: 25068488]
Hensler, S.; Mueller, M.M. Inflammation and skin cancer: old pals telling new stories. Cancer J., 2013, 19(6), 517-524.
[http://dx.doi.org/10.1097/PPO.0000000000000010] [PMID: 24270351]
Borish, L.C.; Steinke, J.W. 2. Cytokines and chemokines. J. Allergy Clin. Immunol., 2003, 111(2), S460-S475.
[http://dx.doi.org/10.1067/mai.2003.108] [PMID: 12592293]
Rimbäck, G.; Cassuto, J.; Wallin, G.; Westlander, G. Inhibition of peritonitis by amide local anesthetics. Anesthesiology, 1988, 69(6), 881-886.
[http://dx.doi.org/10.1097/00000542-198812000-00013] [PMID: 3195759]
Dernek, B.; Aydin, T.; Koseoglu, P.K.; Kesiktas, F.N.; Yesilyurt, T.; Diracoglu, D.; Aksoy, C. Comparison of the efficacy of lidocaine and betamethasone dipropionate in carpal tunnel syndrome injection. J. Back Musculoskeletal Rehabil., 2017, 30(3), 435-440.
[http://dx.doi.org/10.3233/BMR-150477] [PMID: 28035909]
Caracas, H.C.; Maciel, J.V.; Martins, P.M.; de Souza, M.M.; Maia, L.C. The use of lidocaine as an anti-inflammatory substance: a systematic review. J. Dent., 2009, 37(2), 93-97.
[http://dx.doi.org/10.1016/j.jdent.2008.10.005] [PMID: 19058888]
Li, P.; Liu, Q.; Wang, X.; Huang, G.; Song, S. 18F-Deoxyglucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) monitoring of dynamic growth characteristics of walker-256 tumor models in 3 different locations in rats. Med. Sci. Monit., 2019, 25, 558-564.
[http://dx.doi.org/10.12659/MSM.909286] [PMID: 30659557]
de Souza, C.O.; Kurauti, M.A.; de Fatima Silva, F.; de Morais, H.; Borba-Murad, G.R.; de Andrade, F.G.; de Souza, H.M. Effects of celecoxib and ibuprofen on metabolic disorders induced by Walker-256 tumor in rats. Mol. Cell. Biochem., 2015, 399(1-2), 237-246.
[http://dx.doi.org/10.1007/s11010-014-2250-9] [PMID: 25359170]
Wang, D.; Dubois, R.N. Eicosanoids and cancer. Nat. Rev. Cancer, 2010, 10(3), 181-193.
[http://dx.doi.org/10.1038/nrc2809] [PMID: 20168319]
Miksza, D.R.; de Souza, C.O.; de Morais, H.; da Rocha, A.F.; Borba-Murad, G.R.; Bazotte, R.B.; de Souza, H.M. Effect of infliximab on metabolic disorders induced by Walker-256 tumor in rats. Pharmacol. Rep., 2013, 65(4), 960-969.
[http://dx.doi.org/10.1016/S1734-1140(13)71077-6] [PMID: 24145090]
Cassuto, J.; Sinclair, R.; Bonderovic, M. Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol. Scand., 2006, 50(3), 265-282.
[http://dx.doi.org/10.1111/j.1399-6576.2006.00936.x] [PMID: 16480459]
Chamaraux-Tran, T.N.; Mathelin, C.; Aprahamian, M.; Joshi, G.P.; Tomasetto, C.; Diemunsch, P.; Akladios, C. Antitumor effects of lidocaine on human breast cancer cells: an in vitro and in vivo experimental trial. Anticancer Res., 2018, 38(1), 95-105.
[http://dx.doi.org/10.21873/anticanres.12196] [PMID: 29277761]
Piegeler, T.; Schläpfer, M.; Dull, R.O.; Schwartz, D.E.; Borgeat, A.; Minshall, R.D.; Beck-Schimmer, B. Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase. Br. J. Anaesth., 2015, 115(5), 784-791.
[http://dx.doi.org/10.1093/bja/aev341] [PMID: 26475807]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 11 May, 2020
Page: [588 - 598]
Pages: 11
DOI: 10.2174/1567201817666200512101448
Price: $65

Article Metrics

PDF: 17