The successful of anti-cancer treatment are often limited by the development of drug resistance. Recent work has highlighted the involvement of non-coding RNAs, microRNAs(miRNAs) in cancer development, and their possible involvement in the evolution of drug resistance has been proposed. In this study, we combine taxol chemotherapy and miR-21 inhibitor treatment via polyamidoamine (PAMAM) dendrimers vector to evaluate the effects of combination therapy on suppression of breast cancer cells. The 50% inhibitory concentration (IC50) values for taxol were significantly decreased to a greater extent in the cells transfected with miR-21 inhibitor compared with cells treated with taxol alone. Taxol treatment also increased the percentage of apoptotic breast cancer cells in miR-21 inhibitor transfected cells compared with control cells. Furthermore, treatment of the miR-21 inhibitor-transfected cells with the anti-cancer drugs taxol resulted in significantly reduced cell viability and invasiveness compared with control cells. These results indicated that the miR-21 plays an important role in the resistance of breast carcinoma cells to chemotherapeutic drugs. Therefore, miR-21 inhibitor gene therapy combined with taxol chemotherapy might represent a promising novel therapeutic approach for the treatment of breast malignancies.
ChuD.LuJ.Novel therapies in breast cancer: What is new from ASCO 2008. J Hematol Oncol1, 16 (2008).
2.
SzakacsG.PatersonJ. K.Booth-GentheC.GottesmanM. M.Targeting multidrug resistance in cancer. Nat Rev Drug Disc5, 219–234 (2006).
3.
ChristineT.JohnC. R.ChristineM. A.Estrogen Promotes Chemotherapeutic Drug Resistance by a Mechanism Involving Bcl-2 Proto-Oncogene Expression in Human Breast Cancer Cells. Cancer Research55, 3902–3907 (1995).
4.
CsabaK.TungO. C.MarleneR. Q.Targeting the Epidermal Growth Factor Receptor in Cancer. Cancer Research63, 1–5 (2003).
5.
DouglasD. R.WeidongY.LynneV.Atypical Multidrug Resistance: Breast Cancer Resistance Protein Messenger RNA Expression in Mitoxantrone-Selected Cell Lines. Journal of the National Cancer Institute5, 429–433 (1999).
BlowerP. E.ChungJ. H.VerducciJ. S.MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther7, 1–9 (2008).
8.
BartelD. P.ChenC. Z.Micromanagers of gene expression: The potentially widespread influence of metazoan microRNAs. Nat Rev Genet5, 396–400 (2004).
9.
JenniferA. C.AnnaM. K.KennethS. K.MicroRNA-21 Is an Antiapoptotic Factor in Human Glioblastoma Cells. Cancer Res14, 6029–33 (2005).
10.
MeiM.RenY.ZhouX.YuanX. B.LiF.JiangL. H.KangC. S.YaoZ.Suppression of Breast Cancer Cells In Vitro by Polyamidoamine-Dendrimer-Mediated 5-Fluorouracil Chemotherapy Combined with Antisense Micro-RNA 21 Gene Therapy. Journal of Applied Polymer Science114, 3760–3766 (2009).
11.
LarsA.JohnJ. R.RNAi therapeutics: Principles, prospects and challenges. Advanced Drug Delivery Reviews59, 75–86 (2007).
12.
IstvánJ. M.ThommeyP. T.ChandanB. M.Poly(amidoamine) Dendrimer-Based Multifunctional Engineered Nanodevice for Cancer Therapy. Med Chem48, 5892–5899 (2005).
13.
LarsA.JohnJ. R.RNAi therapeutics: Principles, prospects and challenges. Advanced Drug Delivery Reviews59, 75–86 (2007).
14.
EmanueleA.AttwoodD.Dendrimer-drug interactions. Adv Drug Deliv Rev57, 2147–2162 (2005).
15.
ChengY. Y.XuT. W.Dendrimers as Potential Drug Carriers: Solubilization of Non-Steroidal Anti-Inflammatory Drugs in the Presence of Polyamidoamine Dendrimers. European Journal of Medicinal Chemistry40, 1188–1192 (2005).
16.
RenY.KangC. S.YuanX. B.ZhouX.XuP.HanL.WangG. X.JiaZ. F.ZhongY.YuS. Z.ShengJ.PuP. Y.Co-delivery of As-miR-21 and 5-Fu by Poly(amidoamine) Dendrimer for the Inhibition of Human Glioma Cells in vitro.Journal of Biomaterials Science: Polymer Edition. Journal of Biomaterials Science Accepted, DOI:10.1163/156856209X415828.
17.
TishaC. K.EmelyneD.WeiyuanJ. K.Developmental Toxicity of Low Generation PAMAM Dendrimers in Zebrafish. Toxicology and Applied Pharmacology225, 70–79 (2007).
18.
JonathanD. E.AnnaU. B.JolantaF. K.The use of PAMAM dendrimers in the efficient transfer of genetic material into cells. Pharmaceutical Science & Technology Today7, 232–245 (2000).
19.
HaenslerJ.SzokaF. C.Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem4, 372–379 (1993).
20.
JeremyR. G.AnnM. M.KimberlyR. H., The Protein Kinase Cß-Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts. Cancer Research65, 7462–7469 (2005).
21.
RobertN. J.FrancescaW.NormandP.ThomasP. J. G.ColinW. W.AntonyW. B.Epidermal growth factor receptor: Mechanisms of activation and signaling. Experimental Cell Research284, 31–53 (2003).
22.
GrantS.QiaoL.DentP.Roles of Erbb Family Receptor Tyrosine Kinases, and Downstream Signaling Pathways, in the Control of Cell Growth and Survival. Frontiers in Bioscience7, 376–389 (2002).
23.
RaffaellaS.DaphneW. B.DanielA. H.JeffreyS.Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways. Science305, 1163–1167 (2004).
24.
NiuG.BowmanT.HuangM.ShiversS.ReintgenD.DaudA.ChangA.KrakerA.JoveR.YuH.Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene21, 7001–7010 (2002).
OlieR.A.ZangemeisterW. U.Targeting tumor cell resistance to apoptosis induction with antisense oligonucleotides: Progress and therapeutical potential. Drug Resist Update4, 9–15 (2001).
27.
YamamotoK.IchijoH.KorsmeyerS.BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-Terminal protein kinase pathway normally activated at G2/M. Mol Cell Biol19, 8469–8478 (1999).
28.
ZhouD. J.CaseyG.ClineM. J.Amplification of human int-2 in breast cancers and squamous carcinomas. Oncogene2, 279–282 (1988).
29.
MusgroveE. A.LeeC. S.BuckleyM. F.SutherlR. L.Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. PNAS91, 8022–8026 (1994).
30.
NasredineA.ChristopheL. T.AïdaG.Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines. Cancer Chemother Pharmacol62, 305–313 (2008).
31.
StamenkovicI.Extracellular matrix remodelling: The role of matrix metalloproteinases. J Pathol200, 448–464 (2003).
