Impact of Combination Therapy with Chemical Drugs and Megavoltage X-ray Exposure on Breast Cancer Stem Cells’ Viability and Proliferation of MCF-7 and MDA-MB-231 Cell Lines


Cite item

Full Text

Abstract

Background::Breast Cancer (BC) is a serious malignancy among women. However, chemotherapy is an important tool for cancer treatments, but the long-term use of chemotherapy drugs may lead to drug resistance and tumor recurrence. Since Breast Cancer Stem Cells (BCSCs) can be the main factor to induce BC treatment resistance and recurrence, investigation of BCSCs signaling pathways can be an effective modality to enhance cancer treatment efficiency.

Objective::In this study, the effect of metformin, SB203580, and takinib alone or in combination with radiotherapy on MCF-7 and MDA-MB-231 breast cancer cell lines was evaluated.

Methods::MCF-7 and MDA-MB-231 breast cancer cell lines were treated with metformin, SB203580, and takinib for 24 or 48 hours, followed by X-ray exposure. The MTT assay and flow cytometry analysis were performed to assess cell growth inhibition and cellular death, CXCr4 expression, and BCSCs, respectively.

Results::The results showed the combination of takinib/SB203580 with radiotherapy to remarkably reduce the CXCR4 expression and BCSCs levels in the MCF-7 cell line. Also, the concurrent administration of takinib/metformin/radiotherapy significantly reduced BCSCs and CXCR4 metastatic markers in the MDA-MB- 231 cells. Since the MAPK signaling pathway has an important role in inducing drug resistance and cell proliferation, the use of SB203580 as an inhibitor of p38 MAPK can improve breast cancer treatment. Furthermore, metformin and ionizing radiation by suppression of the mTOR signaling pathway can control AMPK activation and cellular proliferation.

Conclusion::Anti-cancer and cytotoxic effects of metformin can be effective in this strategy. In conclusion, the combination of conventional chemotherapeutic drugs, including SB203580, metformin, and takinib with X-ray exposure can be a new approach to diminish the drug resistance of breast cancer.

About the authors

Fatemeh Banisharif Dehkordi

Cellular & Molecular Research Center, Shahrekord University of Medical Sciences

Email: info@benthamscience.net

Mahdi Ghatrehsamani

Cellular and Molecular Research Center, Shahrekord University of Medical Sciences

Email: info@benthamscience.net

Maryam Abdolvand

Cellular and Molecular Research Center, Shahrekord University of Medical Sciences

Email: info@benthamscience.net

Amin Soltani

Cellular and Molecular Research Center, Shahrekord University of Medical Sciences

Email: info@benthamscience.net

Seyed Hossein Masoumi

Medical Physics School of Allied Medical Sciences, Shahrekord University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

References

  1. Huang SW, Chyuan IT, Shiue C, Yu MC, Hsu YF, Hsu MJ. Lovastatin-mediated MCF-7 cancer cell death involves LKB1-AMPK-p38MAPK-p53-survivin signalling cascade. J Cell Mol Med 2020; 24(2): 1822-36. doi: 10.1111/jcmm.14879 PMID: 31821701
  2. Chang-Qing Y, Jie L, Shi-Qi Z, et al. Recent treatment progress of triple negative breast cancer. Prog Biophys Mol Biol 2020; 151: 40-53. doi: 10.1016/j.pbiomolbio.2019.11.007 PMID: 31761352
  3. Grantzau T, Overgaard J. Risk of second non-breast cancer after radiotherapy for breast cancer: A systematic review and meta-analysis of 762,468 patients. Radiother Oncol 2015; 114(1): 56-65. doi: 10.1016/j.radonc.2014.10.004 PMID: 25454172
  4. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005; 366(9503): 2087-106. doi: 10.1016/S0140-6736(05)67887-7 PMID: 16360786
  5. Han J, Jeong HJ, Lee HN, et al. Erythro-austrobailignan-6 down-regulates HER2/EGFR/integrinβ3 expression via p38 activation in breast cancer. Phytomedicine 2017; 24: 24-30. doi: 10.1016/j.phymed.2016.11.009 PMID: 28160858
  6. Tong CWS, Wu M, Cho WCS, To KKW. Recent advances in the treatment of breast cancer. Front Oncol 2018; 8: 227. doi: 10.3389/fonc.2018.00227 PMID: 29963498
  7. Sun X, Zhou T, Wei C, et al. Antibacterial effect and mechanism of anthocyanin rich Chinese wild blueberry extract on various foodborne pathogens. Food Control 2018; 94: 155-61. doi: 10.1016/j.foodcont.2018.07.012
  8. Bai X, Ni J, Beretov J, Graham P, Li Y. Cancer stem cell in breast cancer therapeutic resistance. Cancer Treat Rev 2018; 69: 152-63. doi: 10.1016/j.ctrv.2018.07.004 PMID: 30029203
  9. Dittmer J. Breast cancer stem cells: Features, key drivers and treatment options. Seminars in cancer biology: 2018. Elsevier 2018; pp. 59-74. doi: 10.1016/j.semcancer.2018.07.007
  10. Palomeras S, Ruiz-Martínez S, Puig T. Targeting breast cancer stem cells to overcome treatment resistance. Molecules 2018; 23(9): 2193. doi: 10.3390/molecules23092193 PMID: 30200262
  11. Roy S, Roy S, Kar M, et al. Role of p38 MAPK in disease relapse and therapeutic resistance by maintenance of cancer stem cells in head and neck squamous cell carcinoma. J Oral Pathol Med 2018; 47(5): 492-501. doi: 10.1111/jop.12707 PMID: 29575240
  12. Xu M, Wang S, Wang Y, et al. Role of p38γ MAPK in regulation of EMT and cancer stem cells. Biochim Biophys Acta Mol Basis Dis 2018; 1864(11): 3605-17. doi: 10.1016/j.bbadis.2018.08.024 PMID: 30251680
  13. Huang BP, Lin CH, Chen HM, Lin JT, Cheng YF, Kao SH. AMPK activation inhibits expression of proinflammatory mediators through downregulation of PI3K/p38 MAPK and NF-κB signaling in murine macrophages. DNA Cell Biol 2015; 34(2): 133-41. doi: 10.1089/dna.2014.2630 PMID: 25536376
  14. Mukhopadhyay H, Lee NY. Multifaceted roles of TAK1 signaling in cancer. Oncogene 2020; 39(7): 1402-13. doi: 10.1038/s41388-019-1088-8 PMID: 31695153
  15. Thirupathi A, Chang YZ. Role of AMPK and its molecular intermediates in subjugating cancer survival mechanism. Life Sci 2019; 227: 30-8. doi: 10.1016/j.lfs.2019.04.039 PMID: 31002918
  16. Jalving M, Gietema JA, Lefrandt JD, et al. Metformin: Taking away the candy for cancer? Eur J Cancer 2010; 46(13): 2369-80. doi: 10.1016/j.ejca.2010.06.012 PMID: 20656475
  17. Rehman Ju, Ahmad N, Khalid M. Intensity modulated radiation therapy: A review of current practice and future outlooks. J radi res appl sci 2018; 11(4): 361-7.
  18. Purdy JA. Dose to normal tissues outside the radiation therapy patient’s treated volume: A review of different radiation therapy techniques. Health Phys 2008; 95(5): 666-76. doi: 10.1097/01.HP.0000326342.47348.06 PMID: 18849701
  19. Samani RK, Tavakoli MB, Maghsoudinia F, Motaghi H, Hejazi SH, Mehrgardi MA. Trastuzumab and folic acid functionalized gold nanoclusters as a dual-targeted radiosensitizer for megavoltage radiation therapy of human breast cancer. Eur J Pharm Sci 2020; 153: 105487. doi: 10.1016/j.ejps.2020.105487 PMID: 32707173
  20. Bridges HR, Jones AJY, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 2014; 462(3): 475-87. doi: 10.1042/BJ20140620 PMID: 25017630
  21. Kelly B, Tannahill GM, Murphy MP, O’Neill LAJ. Metformin inhibits the production of reactive oxygen species from NADH: Ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J Biol Chem 2015; 290(33): 20348-59. doi: 10.1074/jbc.M115.662114 PMID: 26152715
  22. Vial G, Detaille D, Guigas B. Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol 2019; 10: 294. doi: 10.3389/fendo.2019.00294 PMID: 31133988
  23. Carnero A, Garcia-Mayea Y, Mir C, Lorente J, Rubio IT, LLeonart ME. The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev 2016; 49: 25-36. doi: 10.1016/j.ctrv.2016.07.001 PMID: 27434881
  24. Bhat-Nakshatri P, Appaiah H, Ballas C, et al. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer 2010; 10(1): 411. doi: 10.1186/1471-2407-10-411 PMID: 20691079
  25. Di Maggio FM, Minafra L, Forte GI, et al. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm 2015; 12(1): 14. doi: 10.1186/s12950-015-0058-3 PMID: 25705130
  26. Sonnemann J, Kahl M, Siranjeevi PM, et al. Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing’s sarcoma cells: Resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity. J Cancer Res Clin Oncol 2016; 142(1): 17-26. doi: 10.1007/s00432-015-1994-2 PMID: 26055805
  27. Fatehi D, Soltani A, Ghatrehsamani M. SRT1720, a potential sensitizer for radiotherapy and cytotoxicity effects of NVB-BEZ235 in metastatic breast cancer cells. Pathol Res Pract 2018; 214(6): 889-95. doi: 10.1016/j.prp.2018.04.001 PMID: 29653746
  28. Bishop RT, Marino S, Carrasco G, et al. Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis. Cancer Lett 2020; 488: 27-39. doi: 10.1016/j.canlet.2020.05.021 PMID: 32474152
  29. Wu X, Wu MY, Jiang M, et al. TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells. Cancer Cell Int 2017; 17(1): 13. doi: 10.1186/s12935-017-0382-1 PMID: 28127258
  30. Xing D, Orsulic S. Modeling resistance to pathway-targeted therapy in ovarian cancer. Cell Cycle 2005; 4(8): 1004-6. doi: 10.4161/cc.4.8.1869 PMID: 15970711
  31. Ohta T, Ohmichi M, Hayasaka T, et al. Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology 2006; 147(4): 1761-9. doi: 10.1210/en.2005-1450 PMID: 16396982
  32. Gotlieb WH, Saumet J, Beauchamp MC, et al. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol 2008; 110(2): 246-50. doi: 10.1016/j.ygyno.2008.04.008 PMID: 18495226
  33. Kuo MT, Liu Z, Wei Y, et al. Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling. Oncogene 2002; 21(13): 1945-54. doi: 10.1038/sj.onc.1205117 PMID: 11960367
  34. Lee S, Choi EJ, Jin C, Kim DH. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 2005; 97(1): 26-34. doi: 10.1016/j.ygyno.2004.11.051 PMID: 15790433
  35. Mogavero A, Maiorana MV, Zanutto S, et al. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep 2017; 7(1): 15992. doi: 10.1038/s41598-017-16149-z PMID: 29167573
  36. Zhang T, Guo P, Zhang Y, et al. The antidiabetic drug metformin inhibits the proliferation of bladder cancer cells in vitro and in vivo. Int J Mol Sci 2013; 14(12): 24603-18. doi: 10.3390/ijms141224603 PMID: 24351837
  37. Kato K, Gong J, Iwama H, et al. The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther 2012; 11(3): 549-60. doi: 10.1158/1535-7163.MCT-11-0594 PMID: 22222629
  38. Zhou J, Wulfkuhle J, Zhang H, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci 2007; 104(41): 16158-63. doi: 10.1073/pnas.0702596104 PMID: 17911267
  39. Eyler CE, Foo WC, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN. Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 2008; 26(12): 3027-36. doi: 10.1634/stemcells.2007-1073 PMID: 18802038
  40. Hill R, Wu H. PTEN, stem cells, and cancer stem cells. J Biol Chem 2009; 284(18): 11755-9. doi: 10.1074/jbc.R800071200 PMID: 19117948
  41. Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle 2010; 9(6): 1057-64. doi: 10.4161/cc.9.6.10994 PMID: 20305377
  42. Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010; 11(5): 390-401. doi: 10.1016/j.cmet.2010.03.014 PMID: 20444419
  43. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res 2010; 3(9): 1066-76. doi: 10.1158/1940-6207.CAPR-10-0055 PMID: 20810672
  44. Rocha GZ, Dias MM, Ropelle ER, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res 2011; 17(12): 3993-4005. doi: 10.1158/1078-0432.CCR-10-2243 PMID: 21543517
  45. Sanli T, Rashid A, Liu C, et al. Ionizing radiation activates AMP-activated kinase (AMPK): A target for radiosensitization of human cancer cells. Intern J Radiat Oncol 2010; 78(1): 221-9.
  46. Rashid A, Liu C, Sanli T, et al. Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways. Radiat Oncol 2011; 6(1): 144. doi: 10.1186/1748-717X-6-144 PMID: 22029423
  47. Zannella VE, Cojocari D, Hilgendorf S, et al. AMPK regulates metabolism and survival in response to ionizing radiation. Radiother Oncol 2011; 99(3): 293-9. doi: 10.1016/j.radonc.2011.05.049 PMID: 21715037
  48. Song CW, Lee H, Dings RPM, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep 2012; 2(1): 362. doi: 10.1038/srep00362 PMID: 22500211

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2024 Bentham Science Publishers