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Tumor Biology
Published in: Tumor Biology 3/2015

01-03-2015 | Review

Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal

Authors: Suoyuan Li, Wei Sun, Hongsheng Wang, Dongqing Zuo, Yingqi Hua, Zhengdong Cai

Published in: Tumor Biology | Issue 3/2015

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Abstract

Osteosarcoma (OS) is the most common and aggressive primary malignant type of bone cancer in children and adolescents. Chemotherapy is one of the most important treatments for OS. Although cancer therapy has improved over the past few decades, survival outcomes for OS patients remain unsatisfactory. One of the primary reasons for the failure of current treatments is that patients with stage IV cancer often develop resistance to anticancer agents. This article will review multidrug resistance (MDR) mechanisms of OS and strategies for overcoming resistance.
Literature
1.
2.
Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol. 2008;26(4):633–8.PubMedCrossRef
3.
4.
5.
6.
Lourda M, Trougakos IP, Gonos ES. Development of resistance to chemotherapeutic drugs in human osteosarcoma cell lines largely depends on up-regulation of clusterin/apolipoprotein J. Int J Cancer. 2007;120(3):611–22.PubMedCrossRef
7.
8.
Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495–502.PubMedCrossRef
9.
Tiwari KA, Sodani K, Dai C-L, Ashby RC, Chen Z-S. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 2011;12(4):570–94.PubMedCrossRef
10.
11.
Keppler D. Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Drug Transporters. Springer; 2011;299–323.
12.
Rajkumar T, Yamuna M. Multiple pathways are involved in drug resistance to doxorubicin in an osteosarcoma cell line. Anticancer Drugs. 2008;19(3):257–65.PubMedCrossRef
13.
Serra M, Pasello M, Manara MC, Scotlandi K, Ferrari S, Bertoni F, et al. May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int J Oncol. 2006;29(6):1459.PubMed
14.
Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS. Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: a pilot study. Cancer. 2012;118(7):1856–67. doi:10.​1002/​cncr.​26472.PubMedCrossRef
15.
Baldini N, Scotlandi K, Barbanti-Bròdano G, Manara MC, Maurici D, Bacci G, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med. 1995;333(21):1380–5.PubMedCrossRef
16.
Han L, Wang YF, Zhang Y, Wang N, Guo XJ, Yang JK, et al. Increased expression and function of P-glycoprotein in peripheral blood CD56+ cells is associated with the chemoresistance of non-small-cell lung cancer. Cancer Chemother Pharmacol. 2012;70(3):365–72. doi:10.​1007/​s00280-012-1915-x.PubMedCrossRef
17.
Brambilla D, Zamboni S, Federici C, Lugini L, Lozupone F, Milito AD, et al. P-glycoprotein binds to ezrin at amino acid residues 149–242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma. Int J Cancer. 2012;130(12):2824–34.PubMedCrossRef
18.
Matherly LH, Diop-Bove N, Goldman ID. Biological role, properties, and therapeutic applications of the reduced folate carrier (RFC-SLC19A1) and the proton-coupled folate transporter (PCFT-SLC46A1). Targeted Drug Strategies for Cancer and Inflammation. Springer; 2011;1–34.
19.
Patiño-García A, Zalacaín M, Marrodán L, San-Julián M, Sierrasesúmaga L. Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. J Pediatr. 2009;154(5):688–93.PubMedCrossRef
20.
Matherly LH, Hou Z, Deng Y. Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev. 2007;26(1):111–28.PubMedCrossRef
21.
Ifergan I, Meller I, Issakov J, Assaraf YG. Reduced folate carrier protein expression in osteosarcoma: implications for the prediction of tumor chemosensitivity. Cancer. 2003;98(9):1958–66. doi:10.​1002/​cncr.​11741.PubMedCrossRef
22.
Serra M, Reverter-Branchat G, Maurici D, Benini S, Shen J-N, Chano T, et al. Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells. Ann Oncol. 2004;15(1):151–60.PubMedCrossRef
23.
Fine RL, Chambers TC, Sachs CW. P-glycoprotein, multidrug resistance and protein kinase C. Stem Cells. 1996;14(1):47–55.PubMedCrossRef
24.
Liao C-L, Lai K-C, Huang A-C, Yang J-S, Lin J-J, Wu S-H, et al. Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways. Food Chem Toxicol. 2012;50(5):1734–40.PubMedCrossRef
25.
Hong SH, Osborne T, Ren L, Briggs J, Mazcko C, Burkett S, et al. Protein kinase C regulates ezrin–radixin–moesin phosphorylation in canine osteosarcoma cells. Vet Comp Oncol. 2011;9(3):207–18.PubMedCrossRef
26.
Bulut G, Hong S, Chen K, Beauchamp E, Rahim S, Kosturko G, et al. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene. 2011;31(3):269–81.PubMedPubMedCentralCrossRef
27.
Yu C, Zhongliang D. Effect of protein kinase C on multidrug resistance in human osteosarcoma cells and its underlying mechanism [J]. J Third Mil Med Univ. 2011;18:005.
28.
Onishi Y, Kawamoto T, Kishimoto K, Hara H, Fukase N, Toda M, et al. PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma. Int J Oncol. 2012;40(6):1839.PubMed
29.
Azarova AM, Lyu YL, Lin C-P, Tsai Y-C, Lau JY-N, Wang JC, et al. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci. 2007;104(26):11014–9.PubMedPubMedCentralCrossRef
30.
31.
Brown GA, McPherson JP, Gu L, Hedley DW, Toso R, Deuchars KL, et al. Relationship of DNA topoisomerase IIα and β expression to cytotoxicity of antineoplastic agents in human acute lymphoblastic leukemia cell lines. Cancer Res. 1995;55(1):78–82.PubMed
32.
Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010;17(5):421–33.PubMedCrossRef
33.
Nguyen A, Lasthaus C, Guerin E, Marcellin L, Pencreach E, Gaub MP, et al. Role of Topoisomerases in pediatric high grade osteosarcomas: TOP2A gene is one of the unique molecular biomarkers of chemoresponse. Cancers (Basel). 2013;5(2):662–75. doi:10.​3390/​cancers5020662.CrossRef
34.
Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47):7369–75.PubMedCrossRef
35.
Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res. 1994;54(16):4313–20.PubMed
36.
Uozaki H, Horiuchi H, Ishida T, Iijima T, Imamura T, Machinami R. Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase π, heat shock protein 27, and lung resistance-related protein) in osteosarcoma. Cancer. 1997;79(12):2336–44.PubMedCrossRef
37.
Wei L, Song X, Wang X, Li M. Expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcoma and their correlation with chemotherapy resistance. Zhonghua zhong liu za zhi [Chin J Oncol]. 2006;28(6):445–8.
38.
Bruheim S, Bruland OS, Breistol K, Maelandsmo GM, Fodstad Ø. Human osteosarcoma xenografts and their sensitivity to chemotherapy. Pathol Oncol Res. 2004;10(3):133–41.PubMedCrossRef
39.
Pasello M, Michelacci F, Scionti I, Hattinger CM, Zuntini M, Caccuri AM, et al. Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma. Cancer Res. 2008;68(16):6661–8.PubMedCrossRef
40.
Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS. Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma. Cancer. 2012;118(7):1856–67.PubMedCrossRef
41.
42.
Yang L-M, Li X-H, Bao C-F. Glutathione S-transferase P1 and DNA polymorphisms with the response to chemotherapy and the prognosis of bone tumor. Asian Pac J Cancer Prev. 2012;13(11):5883–6.PubMedCrossRef
43.
Murata T, Haisa M, Uetsuka H, Nobuhisa T, Ookawa T, Tabuchi Y, et al. Molecular mechanism of chemoresistance to cisplatin in ovarian cancer cell lines. Int J Mol Med. 2004;13(6):865–8.PubMed
44.
Wu X, Cai Z-D, Lou L-M, Zhu Y-B. Expressions of p53, c-MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients. Cancer Epidemiol. 2012;36(2):212–6.PubMedCrossRef
45.
Nedelcu T, Kubista B, Koller A, Sulzbacher I, Mosberger I, Arrich F, et al. Livin and Bcl-2 expression in high-grade osteosarcoma. J Cancer Res Clin Oncol. 2008;134(2):237–44.PubMedCrossRef
46.
Fu H-L, Shao L, Wang Q, Jia T, Li M, Yang D-P. A systematic review of p53 as a biomarker of survival in patients with osteosarcoma. Tumor Biol. 2013;34(6):3817–21.CrossRef
47.
Wong RPC, Tsang WP, Chau PY, Tsang TY, Kwok TT. p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3. Mol Cancer Ther. 2007;6(3):1054–61.PubMedCrossRef
48.
Tsuchiya H, Mori Y, Ueda Y, Okada G, Tomita K. Sensitization and caffeine potentiation of cisplatin cytotoxicity resulting from introduction of wild-type p53 gene in human osteosarcoma. Anticancer Res. 1999;20(1A):235–42.
49.
Ozger H, Eralp L, Atalar AC, Toker B, Ates LE, Sungur M, et al. The effect of resistance-related proteins on the prognosis and survival of patients with osteosarcoma: an immunohistochemical analysis. Acta Orthop Traumatol Turc. 2004;43(1):28–34.CrossRef
50.
51.
52.
53.
Song B, Wang Y, Titmus MA, Botchkina G, Formentini A, Kornmann M, et al. Research molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer. 2010;9:96.PubMedPubMedCentralCrossRef
54.
Zhou Y, Huang Z, Wu S, Zang X, Liu M, Shi J. miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST. J Exp Clin Cancer Res CR. 2014;33(1):12.PubMedCrossRef
55.
56.
57.
Fung H, Demple B. A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells. Mol Cell. 2005;17(3):463–70.PubMedCrossRef
58.
Wang D, Luo M, Kelley MR. Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition. Mol Cancer Ther. 2004;3(6):679–86.PubMed
59.
Caronia D, Patino-Garcia A, Milne R, Zalacain-Diez M, Pita G, Alonso M, et al. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J. 2009;9(5):347–53.PubMedCrossRef
60.
Biason P, Hattinger CM, Innocenti F, Talamini R, Alberghini M, Scotlandi K, et al. Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy. Pharmacogenomics J. 2011;12(6):476–83.PubMedPubMedCentralCrossRef
61.
Hao T, Feng W, Zhang J, Sun Y-J, Wang G. Association of four ERCC1 and ERCC2 SNPs with survival of bone tumour patients. Asian Pac J Cancer Prev. 2012;13(8):3821–4.PubMedCrossRef
62.
63.
Fishel ML, Kelley MR. The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target. Mol Asp Med. 2007;28(3):375–95.CrossRef
64.
Yang J, Yang D, Cogdell D, Du X, Li H, Pang Y, et al. APEX1 gene amplification and its protein overexpression in osteosarcoma: correlation with recurrence, metastasis, and survival. Technol Cancer Res Treat. 2010;9(2):161–9.PubMedCrossRef
65.
Wang D, Zhong ZY, Li MX, Xiang DB, Li ZP. Vector-based Ape1 small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo. Cancer Sci. 2007;98(12):1993–2001.PubMedCrossRef
66.
Vangipuram SD, Wang ZJ, Lyman WD. Resistance of stem-like cells from neuroblastoma cell lines to commonly used chemotherapeutic agents. Pediatr Blood Cancer. 2010;54(3):361–8.PubMedCrossRef
67.
68.
Tirino V, Desiderio V, d’Aquino R, De Francesco F, Pirozzi G, Galderisi U, et al. Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One. 2008;3(10):e3469.PubMedPubMedCentralCrossRef
69.
Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR, et al. CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res. 2010;70(11):4602–12.PubMedPubMedCentralCrossRef
70.
Fujii H, Honoki K, Tsujiuchi T, Kido A, Yoshitani K, Takakura Y. Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int J Oncol. 2009;34(5):1381–6.PubMed
71.
Gangemi R, Paleari L, Orengo AM, Cesario A, Chessa L, Ferrini S, et al. Cancer stem cells: a new paradigm for understanding tumor growth and progression and drug resistance. Curr Med Chem. 2009;16(14):1688–703.PubMedCrossRef
72.
Di Fiore R, Santulli A, Drago Ferrante R, Giuliano M, De Blasio A, Messina C, et al. Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment. J Cell Physiol. 2009;219(2):301–13.PubMedCrossRef
73.
Germann UA, Ford PJ, Shlyakhter D, Mason VS, Harding MW. Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP. Anticancer Drugs. 1997;8(2):141–55.PubMedCrossRef
74.
Minderman H, O’Loughlin KL, Pendyala L, Baer MR. VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin Cancer Res. 2004;10(5):1826–34.PubMedCrossRef
75.
Wang Z, Xia Q, Cui J, Diao Y, Li J. Reversion of P-glycoprotein-mediated multidrug resistance by diallyl trisulfide in a human osteosarcoma cell line. Oncol Rep. 2014;31(6):2720–6.PubMed
76.
Yang X, Yang P, Shen J, Osaka E, Choy E, Cote G et al. Prevention of multidrug resistance (MDR) in osteosarcoma by NSC23925. British Journal of Cancer. 2014.
77.
78.
Fleuren ED, Versleijen-Jonkers YM, Roeffen MH, Franssen GM, Flucke UE, Houghton PJ, et al. Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models. Int J Cancer. 2014;135(12):2770–82. doi:10.​1002/​ijc.​28933.PubMedCrossRef
79.
Wagner LM, Fouladi M, Ahmed A, Krailo MD, Weigel B, DuBois SG et al. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Children’s Oncology Group. Pediatric Blood & Cancer. 2014.
80.
Moriceau G, Ory B, Mitrofan L, Riganti C, Blanchard F, Brion R, et al. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. Cancer Res. 2010;70(24):10329–39.PubMedPubMedCentralCrossRef
81.
Pasello M, Manara MC, Michelacci F, Fanelli M, Hattinger CM, Nicoletti G, et al. Targeting glutathione-S transferase enzymes in musculoskeletal sarcomas: a promising therapeutic strategy. Anal Cell Pathol. 2011;34(3):131–45.CrossRef
82.
83.
Mei J, Zhu X, Wang Z, Wang Z. VEGFR, RET, and RAF/MEK/ERK pathway take part in the inhibition of osteosarcoma MG63 cells with sorafenib treatment. Cell Biochem Biophys. 2014;69(1):151–6.PubMedCrossRef
84.
Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S, et al. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer. 2009;8(1):118.PubMedPubMedCentralCrossRef
85.
Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, et al. Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma. PLoS One. 2010;5(5):e10764.PubMedPubMedCentralCrossRef
86.
Duan Z, Brakora KA, Seiden MV. Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol Cancer Ther. 2004;3(7):833–8.PubMed
87.
Rousseau J, Escriou V, Perrot P, Picarda G, Charrier C, Scherman D, et al. Advantages of bioluminescence imaging to follow siRNA or chemotherapeutic treatments in osteosarcoma preclinical models. Cancer Gene Ther. 2010;17(6):387–97.PubMedCrossRef
88.
Fu Z, Deng B, Liao Y, Shan L, Yin F, Wang Z, et al. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer. 2013;13(1):580.PubMedPubMedCentralCrossRef
89.
Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313–21.PubMedCrossRef
90.
He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell. 2009;137(6):1100–11.PubMedCrossRef
91.
Zhang D-W, Shao J, Lin J, Zhang N, Lu B-J, Lin S-C, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325(5938):332–6.PubMedCrossRef
92.
Dhule SS, Penfornis P, Frazier T, Walker R, Feldman J, Tan G, et al. Curcumin-loaded γ-cyclodextrin liposomal nanoparticles as delivery vehicles for osteosarcoma. Nanomedicine: Nanotechnol Biol Med. 2012;8(4):440–51.CrossRef
Metadata
Title
Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal
Authors
Suoyuan Li
Wei Sun
Hongsheng Wang
Dongqing Zuo
Yingqi Hua
Zhengdong Cai
Publication date
01-03-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 3/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3181-0

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