Evaluation of the Synergism Mechanism of Tamoxifen and Docetaxel by Nanoparticles

Author(s): Zhihong Zhu, Hao Pan*, Yuenan Li, Weisan Pan*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 16 , 2019

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Graphical Abstract:


Background: Our previous studies have shown that Docetaxel (DTX) and Tamoxifen (TMX) loaded nanoparticles(Co-NPs) could exhibit a synergistic effect on estrogen receptor positive cell lines. In the current study,we have studied the synergistic effect of Co-NPs and underlying possible molecular mechanism.

Methods: Cell apoptosis assay, pharmacokinetic experiment and immunohistochemistry experiment were used to explore the synergistic effect and underlying possible mechanism in vitro and in vivo.

Results: Cell apoptosis assay revealed that Co-NPs could mediate cell sensitization to a cytotoxic agent, resulting in remarkable cell apoptosis. In addition, pharmacokinetic experiment research showed that Co-NPs have longer circulation time in vivo, which could prolong the treatment time of the chemotherapeutic drugs. Immunohistochemistry experiment revealed that the Co-NPs could downregulate the expression of P-gp level to reduce the drugs’ efflux.

Conclusion: The possible mechanism of the synergistic effect of DTX and TMX by Co-NPs was attributed to the longer in vivo circulation time, significantly increased rate of cell apoptosis and downregulated expression of P-gp level to the tumor cells.

Keywords: P-glycoprotein, combination therapy, tamoxifen, docetaxel, cell apoptosis, nanoparticles.

Peter, M.; Ellis, E.T.V.; Yee, C. Ung, Immune checkpoint inhibitors for patients with advanced nonesmall-cell lung cancer: A systematic review. Clin. Lung Cancer, 2017, 18(5), 444-459.
[http://dx.doi.org/10.1016/j.cllc.2017.02.001] [PMID: 28416123]
(a) Visconti, R.; Grieco, D. Fighting tubulin-targeting anticancer drug toxicity and resistance. Endocr. Relat. Cancer, 2017, 24(9), T107-T117.
[http://dx.doi.org/10.1530/ERC-17-0120] [PMID: 28808045]
(b) Barbara, T.; McGrogan, B.G.; Desmond, N.C.; McCann, A. Taxanes, microtubules and chemoresistant breast cancer. Biochim. Biophys. Acta, 2008, 2008(1785), 96-132.
Azzoli, C.G.; Baker, S., Jr; Temin, S.; Pao, W.; Aliff, T.; Brahmer, J.; Johnson, D.H.; Laskin, J.L.; Masters, G.; Milton, D.; Nordquist, L.; Pfister, D.G.; Piantadosi, S.; Schiller, J.H.; Smith, R.; Smith, T.J.; Strawn, J.R.; Trent, D.; Giaccone, G. American Society of Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J. Clin. Oncol., 2009, 27(36), 6251-6266.
[http://dx.doi.org/10.1200/JCO.2009.23.5622] [PMID: 19917871]
Choudhury, B.G.; Pandeya, M.; Kumbharc, S.A.; Tekaded, R.K.; Iyere, A.K.; Kesharwani, P. Recent advances in TPGS-based nanoparticles of docetaxel for improved chemotherapy. Int. J. Pharm., 2017, 2017(529), 506-522.
(a) Jain, A.K.; Sanyog Jain, K.T. Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: Implications on oral bioavailability, antitumor efficacy and drug induced toxicit. Mol. Pharm.,2013, 2013(10), 3459-3474. (b Shien, T.; Iwata, H.; Aogi, K.; Fukutomi, T.; Inoue, K.; Kinoshita, T.; Takahashi, M.; Matsui, A.; Shibata, T.; Fukuda, H. Tamoxifen versus tamoxifen plus doxorubicin and cyclophosphamide as adjuvant therapy for node-positive postmenopausal breast cancer: Results of a Japan Clinical Oncology Group Study (JCOG9401). Int. J. Clin. Oncol., 2014, 19(6), 982-988.
[http://dx.doi.org/10.1007/s10147-013-0657-z] [PMID: 24395447]
Ikeda, H.; Taira, N.; Nogami, T.; Shien, K.; Okada, M.; Shien, T.; Doihara, H.; Miyoshi, S. Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer. Cancer Sci., 2011, 102(11), 2038-2042.
[http://dx.doi.org/10.1111/j.1349-7006.2011.02050.x] [PMID: 21801281]
Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res., 2010, 70(2), 440-446.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
Zhu, Z.Y.L.; Yang, X.; Pan, W.; Pan, H. The reversion of anti-cancer drug antagonism of tamoxifen and docetaxel by the hyaluronic acid-decorated polymeric nanoparticles. Pharmacol. Res., 2017, 126, 84-96.
Zhu, Z.D.L.; Li, Y.; Yang, X.; Pan, W. In vitro-in vivo evaluation of hyaluronic acid-based amphiphilic copolymers for tumour targeted delivery: The role of hydrophobic groups. RSC Advances, 2017, 2017(7), 23942-23953.
Wang, X.S.; Kong, D.J.; Lin, T.Y.; Li, X.C.; Izumiya, Y.; Ding, X.Z.; Zhang, L.; Hu, X.C.; Yang, J.Q.; Gao, S.G.; Lam, K.S.; Li, Y.P. A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer. Acta Pharmacol. Sin., 2017, 38(6), 931-942.
[http://dx.doi.org/10.1038/aps.2017.43] [PMID: 28552907]
Wang, X.; Zhang, M.; Zhang, L.; Li, L.; Li, S.; Wang, C.; Su, Z.; Yuan, Y.; Pan, W. Designed synthesis of lipid-coated polyacrylic acid/calcium phosphate nanoparticles as dual pH-responsive drug-delivery vehicles for cancer chemotherapy. Chemistry, 2017, 23(27), 6586-6595.
[http://dx.doi.org/10.1002/chem.201700060] [PMID: 28218434]
Khan, M.; Khan, M.; Al-Marri, A.H.; Al-Warthan, A.; Alkhathlan, H.Z.; Siddiqui, M.R.; Nayak, V.L.; Kamal, A.; Adil, S.F. Apoptosis inducing ability of silver decorated highly reduced graphene oxide nanocomposites in A549 lung cancer. Int. J. Nanomedicine, 2016, 11, 873-883.
[PMID: 27022256]
Swerts, K.; de Moerloose, B.; Dhooge, C.; Noens, L.; Laureys, G.; Benoit, Y.; Philippé, J. Comparison of two functional flow cytometric assays to assess P-gp activity in acute leukemia. Leuk. Lymphoma, 2004, 45(11), 2221-2228.
[http://dx.doi.org/10.1080/10428190412331272767] [PMID: 15512810]
Li, Q.; Zhang, F.; Zhang, S.; Sheng, X.; Han, X.; Weng, Q.; Yuan, Z. Seasonal expression of androgen receptor, aromatase, and estrogen receptor alpha and beta in the testis of the wild ground squirrel (Citellus dauricus Brandt). Eur. J. Histochem., 2015, 59(1), 2456.
[http://dx.doi.org/10.4081/ejh.2015.2456] [PMID: 25820559]
Yu, S.G.T.; Liu, D.; Yang, X. Pan, W. Nanostructured lipid carrier (NLC)-based novel hydrogels as potential carriers for nepafenac applied after cataract surgery for the treatment of inflammation: Design, characterization and in vitro cellular inhibition and uptake studies. RSC Advances, 2017, 2017(7), 16668-16677.
(a) Zhang, X.; Du, F.; Huang, J.; Lu, W.; Liu, S.; Yu, J. Fabrication of biodegradable micelles with reduction-triggered release of 6-mercaptopurine profile based on disulfide-linked graft copolymer conjugate. Colloids Surf. B Biointerfaces, 2012, 100, 155-162.
[http://dx.doi.org/10.1016/j.colsurfb.2012.04.043] [PMID: 22766292]
(b) Saravanakumar, G.; Choi, K.Y.; Yoon, H.Y.; Kim, K.; Park, J.H.; Kwon, I.C.; Park, K. Hydrotropic hyaluronic acid conjugates: Synthesis, characterization, and implications as a carrier of paclitaxel. Int. J. Pharm., 2010, 394(1-2), 154-161.
[http://dx.doi.org/10.1016/j.ijpharm.2010.04.041] [PMID: 20438818]
(a) Tardi, P.G.; Dos Santos, N.; Harasym, T.O.; Johnstone, S.A.; Zisman, N.; Tsang, A.W.; Bermudes, D.G.; Mayer, L.D. Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo. Mol. Cancer Ther., 2009, 8(8), 2266-2275.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0243] [PMID: 19671743]
(b) Harasym, T.O.; Liboiron, B.D.; Mayer, L.D. Drug ratio-dependent antagonism: A new category of multidrug resistance and strategies for its circumvention. Methods Mol. Biol., 2010, 596, 291-323.
[http://dx.doi.org/10.1007/978-1-60761-416-6_13] [PMID: 19949929]
(c) Tan, G.R.; Feng, S.S.; Leong, D.T. The reduction of anti-cancer drug antagonism by the spatial protection of drugs with PLA-TPGS nanoparticles. Biomaterials, 2014, 35(9), 3044-3051.
[http://dx.doi.org/10.1016/j.biomaterials.2013.12.033] [PMID: 24439415]
Tu, Z.; Ma, Y.; Akers, W.; Achilefu, S.; Gu, Y. Therapeutic effect of the treatment for colorectal cancer with adenoviral vectors mediated estrogen receptor β gene therapy combined with thermotherapy. J. Cancer Res. Clin. Oncol., 2014, 140(4), 623-632.
[http://dx.doi.org/10.1007/s00432-014-1611-9] [PMID: 24531912]

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Year: 2019
Page: [1991 - 2000]
Pages: 10
DOI: 10.2174/1871520619666190702120829
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