PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy

Document Type : Original Article

Authors

1 Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran

2 Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran

3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

5 Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s):Multidrug resistance (MDR) of cancer cells is a major obstacle to successful chemotherapy. Overexpression of breast cancer resistance protein (BCRP) is one of the major causes of MDR. In addition, it has been shown that PI3K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI3K/Akt signaling pathway using LY294002 (LY) to re-sensitize breast cancer MCF7 cell line to mitoxantrone (MTX) chemotherapy.
Materials and Methods: Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF7 cells using MTT cytotoxicity assay and flow cytometry analysis of cell cycle distribution and apoptosis induction.
Results: MTT and apoptosis assays showed that both MTX and LY inhibited cell proliferation and induced apoptosis in MCF7 cells. Results indicated that inhibition of BCRP by siRNA or PI3K/Akt signaling pathway by LY significantly increased sensitivity of MCF7 cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G2/M arrest, whereas LY induced G0/G1 arrest in cell cycle distribution of MCF7 cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF7 cells in the G2/M phase of cell cycle.
Conclusion: Combination of MTX chemotherapy with BCRP siRNA and PI3K/Akt inhibition can overcome MDR in breast cancer cells. This study furthermore suggests that novel therapeutic approaches are needed to enhance anticancer effects of available drugs in breast cancer

Keywords

References

1. Arafa el-SA, Zhu Q, Shah ZI, Wani G, Barakat BM, Racoma I, et al. Thymoquinone up-regulates PTEN expression and induces apoptosis indoxorubicin-resistant human breast cancer cells. Mutat Res 2011; 706:28–35.
2. Momtazi-borojeni AA, Behbahani M, Sadeghi-aliabadi H. Antiproliferative activity and apoptosis induction of crude extract and fractions of Avicennia Marina. Iran J Basic Med Sci 2013; 16:1203-1208.
3. Liu C, Zhao G, Liu J, Ma N, Chivukula P, Perelman L, et al. Novel bio degradable lipid nano complex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel. J Control Release 2009; 140:277–283.
4. Ee PL, He X, Ross DD, Beck WT. Modulation of breast cancer resistance protein (BCRP/ABCG2) gene expression using RNA interference. Mol Cancer Ther 2004; 3:1577-1584.
5. Choi BH, Kim CG, Lim Y, Shin SY, Lee YH. Curcumin down-regulates the multidrug resistance mdr1b gene by inhibiting the PI3K/Akt/NFjB pathway. Cancer Lett 2008; 259:111–118.
6. Dai CL, Liang YJ, Wang YS, Tiwari AK, Yan YY, Wang F, et al. Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer lett 2009; 279:74-83.
7. Chen Z, Liu F, Ren Q, Zhao Q, Ren H, Lu S, et al. Suppression of ABCG2 inhibits cancer cell proliferation. Int J Cancer 2010; 126:841–851.
8. Steinbach D, Sell W, Voigt A, Hermann J, Zintl F, Sauerbrey A. BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia 2002; 16:1443–1447.
9. Su Y, Lee SH, Sinko PJ. Inhibition of efflux transporter ABCG2/BCRP does not restore mitoxantrone sensitivity in irinotecan-selected human leukemia CPT-K5 cells: Evidence for multifactorial multidrug resistance. Eur J Pharm Sci 2006; 29:102–110.
10. Aliabadi HM, Landry B, Mahdipoor P, Hsu CY, Uludag H. Effective down-regulation of breast cancer resistance protein (BCRP) by siRNA delivery using lipid-substituted aliphatic polymers. Eur J Pharm Biopharm 2012; 81:33–42.
11. Ganjalikhani hakemi M, Hashemi M. siRNA delivery improvement by co-formulation of different modified polymers in erythroleukemic cell line K562. Iran J Basic Med Sci 2013; 16:973-978.
12. Hegedus C, Truta-Feles K, Antalffy G, Brozik A, Kasza I, Nemet K, et al. PI3-kinase and mTOR inhibitors differently modulate the function of the ABCG2 multidrug transporter. Biochem Biophys Res Commun 2012; 420:869–874.
13. Barancik M1, Bohacova V, Sedlak J, Sulova Z, Breier A. LY294002, a specific inhibitor of PI3K/Akt kinase pathway, antagonizes P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci 2006; 29:426-434.
14. Nicholson KM, Quinn DM, Kellett GL, Warr JR. LY294002, an inhibitor of phosphatidylinositol-3-kinase, causes preferential induction of apoptosis in human multidrug resistant cells. Cancer Lett 2003; 190:31-36.
15. Song N, Wu X, Gao Z, Zhou G, Zhang WJ, Liu W. Enhanced expression of membrane transporter and drug resistance in keloid fibroblasts. Hum Pathol 2012; 43:2024–2032.
16. Lv H, He Z, Liu X, Yuan J, Yu Y, Chen Z. Reversal of BCRP-mediated multidrug resistance by stable expression of small interfering RNAs. J Cell Biochem 2007; 102:75–81.
17. Seifrtova M, Havelek R, Chmelarova M, Cmielova J, Muthna D, Stoklasova A, Zemankova S, Rezacova M. The effect of ATM and ERK1/2 inhibition on mitoxantrone-induced cell death of leukaemic cells. Folia Biol (Praha) 2011; 57:74-81.
18. Abdul-Ghani R, Serra V, Gyorffy B, Jurchott K, Solf A, Dietel M, et al. The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. Oncogene 2006; 25:1743–1752.
19. Jiang H, Fan D, Zhou G, Li X, Deng H. Phosphatidylinositol 3-kinase inhibitor (LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo. J Exp Clin Cancer Res 2010; 29:34.
20. YangJiong X, Ping Z,  MingHui H, Fei C, JiWu C, WenXin Q. Diverse effects of two kinds of PI3K inhibitors on drug-resistant human breast cancer MCF-7/MIT cells. Tumor 2009; 29:620-625.
21. Gong C, Liao H, Wang J, Lin Y, Qi J, Qin L, et al. LY294002 induces G0/G1 cell cycle arrest and apoptosis of cancer stem-like cells from human osteosarcoma Via Down-regulation of PI3K activity. Asian Pac J Cancer Prev 2012; 13:3103-3107.

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