Biomedical Microdevices

, 20:57 | Cite as

A low cost PS based microfluidic platform to investigate cell cycle towards developing a therapeutic strategy for cancer

  • Irem Ezgi Odabasi
  • Elif Gencturk
  • Sevde Puza
  • Senol Mutlu
  • Kutlu O. UlgenEmail author


Inhibition of DNA damage response pathway in combination with DNA alkylating agents may enhance the selective killing of cancer cells leading to better therapeutic effects. MDM2 binding protein (MTBP) in human has a role in G1 phase (interphase of cell cycle) and its overexpression leads to breast and ovarian cancers. Sld7 is an uncharacterized protein in budding yeast and a potential functional homologue of MTBP. To investigate the role of Sld7 as a therapeutic target, the behavior of the wild-type cells and sld7∆ mutants were monitored in 0.5 nL microbioreactors. The brightfield microscopy images were used to analyze the change in the cell size and to determine the durations of G1 and S/G2/M phases of wild type cells and mutants. With the administration of the alkylating agent, the cell size decreased and the duration of cell cycle increased. The replacement of the medium with the fresh one enabled the cells to repair their DNA. The application of calorie restriction together with DNA alkylating agent to mutant cells resulted in smaller cell size and longer G1 phase compared to those in control environment. For therapeutic purposes, the potential of MTBP in humans or Sld7 in yeast as a drug target deserves further exploration. The fabrication simplicity, robustness and low-cost of this microfluidic bioreactor made of polystyrene allowed us to perform yeast culturing experiments and show a potential for further cell culturing studies. The device can successfully be used for therapeutic applications including the discovery of new anti-microbial, anti-inflammatory, anti-cancer drugs.


Sld7 DNA damage DNA alkylating agent Cancer 



The financial support of Boğaziçi University Research Fund through project 11141 M was gratefully acknowledged.


This study was funded by Boğaziçi University Research Fund through project 11141 M.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

“This article does not contain any studies with human participants or animals performed by any of the authors.”

Supplementary material

10544_2018_302_MOESM1_ESM.docx (510 kb)
ESM 1 (DOCX 509 kb)


  1. R.C. Alver, G.S. Chadha, J.J. Blow, DNA Repair (Amst) 19, 182 (2014)CrossRefGoogle Scholar
  2. H. Araki, Genes Genet. Syst. 86, 141 (2011)CrossRefGoogle Scholar
  3. H. Becker, C. Gärtner, Electrophoresis 21, 12 (2000)CrossRefGoogle Scholar
  4. S.N. Bhatia, D.E. Ingber, Nat. Biotechnol. 32, 760 (2014)CrossRefGoogle Scholar
  5. A. Bhattacharyya, C.M. Klapperich, Lab Chip 7, 876 (2007)CrossRefGoogle Scholar
  6. D. Boos, M. Yekezare, J.F.X. Diffley, Science 340, 981 (2013)CrossRefGoogle Scholar
  7. B.J. Brewer, E. Chlebowicz-Sledziewska, W.L. Fangman, Mol. Cell. Biol. 4, 2529 (1984)CrossRefGoogle Scholar
  8. B. Brujins, A. van Asten, R. Tiggelaar, H. Gardeniers, Biosensors 6, 1 (2016)CrossRefGoogle Scholar
  9. I. Caffa, V. D’Agostino, P. Damonte, D. Soncini, M. Cea, F. Monacelli, P. Odetti, A. Ballestrero, A. Provenzani, V.D. Longo, A. Nencioni, Oncotarget 6, 11820 (2015)CrossRefGoogle Scholar
  10. Y. Cao, J. Bontrager-Singer, L. Zhu, J. Micromech. Microeng. 25, 065005 (2015)CrossRefGoogle Scholar
  11. A. Chandrasekaran, N. Kalashnikov, R. Rayes, C. Wang, J. Spicer, C. Moraes, Lab Chip 17, 2003 (2017)CrossRefGoogle Scholar
  12. C.-S. Chen, D.N. Breslauer, J.I. Luna, A. Grimes, W.C. Chin, L.P. Lee, M. Khine, Lab Chip 8, 622 (2008)CrossRefGoogle Scholar
  13. H. Chen, W. Yao, Q. Chu, R. Han, Y. Wang, J. Sun, D. Wang, Y. Wang, M. Cao, Y. He, Cancer Lett. 369, 97 (2015)CrossRefGoogle Scholar
  14. M.M. Crane, I.B.N. Clark, E. Bakker, S. Smith, P.S. Swain, PLoS One 9, 1 (2014)Google Scholar
  15. I.E. Dayan, K.Y. Arga, K.O. Ulgen, Omi. A J. Integr. Biol. 21, 100 (2017)CrossRefGoogle Scholar
  16. S. Di Biase, C. Lee, S. Brandhorst, B. Manes, R. Buono, C. Cheng, M. Cacciottolo, A. Martin-Montalvo, R. de Cabo, M. Wei, T.E. Morgan, V.D. Longo, Cancer Cell 30, 136 (2016)CrossRefGoogle Scholar
  17. S. Di Talia, J.M. Skotheim, J.M. Bean, E.D. Siggia, F.R. Cross, Nature 448, 947 (2007)CrossRefGoogle Scholar
  18. F. Ferrezuelo, N. Colomina, A. Palmisano, E. Garí, C. Gallego, A. Csikász-Nagy, M. Aldea, Nat. Commun. 3, 1012 (2012)CrossRefGoogle Scholar
  19. E. Gencturk, S. Mutlu, K.O. Ulgen, Biomicrofluidics 11, 051502 (2017)CrossRefGoogle Scholar
  20. B.C. Grieb, X. Chen, C.M. Eischen, Mol. Cancer Res. 12, 1216 (2014)CrossRefGoogle Scholar
  21. P. Groth, S. Ausländer, M.M. Majumder, N. Schultz, F. Johansson, E. Petermann, T. Helleday, J. Mol. Biol. 402, 70 (2010)CrossRefGoogle Scholar
  22. J.I. Hahm, Langmuir 30, 9891 (2014)CrossRefGoogle Scholar
  23. S. Halldorsson, E. Lucumi, R. Gómez-Sjöberg, R.M.T. Fleming, Biosens. Bioelectron. 63, 218 (2015)CrossRefGoogle Scholar
  24. D. Hanway, J.K. Chin, G. Xia, G. Oshiro, E.A. Winzeler, F.E. Romesberg, Proc. Natl. Acad. Sci. U. S. A. 99, 10605 (2002)CrossRefGoogle Scholar
  25. R.W. Hart, A. Turturro, Environ. Health Perspect. 105, 989 (1997)Google Scholar
  26. Z.X. He, Z.H. Sun, W.Z. Yang, K.A. Beauchemin, S.X. Tang, C.S. Zhou, X.F. Han, M. Wang, J.H. Kang, Z.L. Tan, J. Anim. Sci. 92, 4856 (2014)CrossRefGoogle Scholar
  27. T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R.A. Sharma, Nat. Rev. Cancer 8, 193 (2008)CrossRefGoogle Scholar
  28. X. Hu, Y. Dong, Q. He, H. Chen, Z. Zhu, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 990, 96 (2015)CrossRefGoogle Scholar
  29. R.M. Jones, E. Petermann, Biochem. J. 443, 13 (2012)CrossRefGoogle Scholar
  30. P. Jorgensen, J.L. Nishikawa, B. Breitkreutz, M. Tyers, Science 297, 395 (2002)CrossRefGoogle Scholar
  31. N. Kim, S.N. Huang, J.S. Williams, Y.C. Li, A.B. Clark, J. Cho, T.A. Kunkel, Y. Pommier, S. Jinks-Robertson, Science 332, 1561 (2011)CrossRefGoogle Scholar
  32. R. Kodzius, K. Xiao, J. Wu, X. Yi, X. Gong, I.G. Foulds, W. Wen, Sensors Actuators B Chem. 161, 349 (2012)CrossRefGoogle Scholar
  33. K. Köhler, P. Ferreira, B. Pfander, D. Boos, Springer, Chapter 22 (2016)Google Scholar
  34. G.S. Kopeina, V.V. Senichkin, B. Zhivotovsky, Biochim. Biophys. Acta. 1867, 29 (2017)Google Scholar
  35. O.V. Leontieva, M.V. Blagosklonny, Aging (Albany NY) 3, 1078 (2011)CrossRefGoogle Scholar
  36. D. Mcintosh, J.J. Blow, Cold Spring Harb. Perspect. Biol. 4, a012955 (2012)CrossRefGoogle Scholar
  37. M. Mehling, S. Tay, Curr. Opin. Biotechnol. 25, 95 (2014)CrossRefGoogle Scholar
  38. R. Milo, R. Philips, Cell biology by the numbers, 1st edn. (Garland Science, 2015)Google Scholar
  39. V.C. Miranda, M.I. Braghiroli, L.D. Faria, G. Bariani, A. Alex, J.E. Bezerra Neto, F.C. Capareli, J. Sabbaga, J.F. Lobo dos Santos, P.M. Hoff, R.P. Riechelmann, Clin. Colorectal Cancer 15, 321 (2016)CrossRefGoogle Scholar
  40. A.G. Paulovich, L.H. Hartwell, Cell 82, 841 (1995)CrossRefGoogle Scholar
  41. F. Pietrocola, J. Pol, E. Vacchelli, S. Rao, D.P. Enot, E.E. Baracco, S. Levesque, F. Castoldi, N. Jacquelot, T. Yamazaki, L. Senovilla, G. Marino, F. Aranda, S. Durand, V. Sica, A. Chery, S. Lachkar, V. Sigl, N. Bloy, A. Buque, S. Falzoni, B. Ryffel, L. Apetoh, F. Di Virgilio, F. Madeo, M.C. Maiuri, L. Zitvogel, B. Levine, J.M. Penninger, G. Kroemer, Cancer Cell 30, 147 (2016)CrossRefGoogle Scholar
  42. S. Puza, E. Gencturk, I.E. Odabasi, E. Iseri, S. Mutlu, K.O. Ulgen, Biomed. Microdevices 19 (2017)Google Scholar
  43. R. Ralhan, J. Kaur, J. Expert Opin. Ther. Patents 17, 1061 (2007)CrossRefGoogle Scholar
  44. C. Santocanale, J.F. Diffley, Nature 395, 615 (1998)CrossRefGoogle Scholar
  45. F. Sherman, Encycl. Mol. Biol. Mol. Medicine 6, 302 (1997)Google Scholar
  46. K. Shirahige, Y. Hori, K. Shiraishi, M. Yamashita, K. Takahashi, C. Obuse, T. Tsurimoto, H. Yoshikawa, Nature 395, 618 (1998)CrossRefGoogle Scholar
  47. K. Sun, Y. Xie, D. Ye, Y. Zhao, Y. Cui, F. Long, W. Zhang, X. Jiang, Langmuir 28, 2131 (2012)CrossRefGoogle Scholar
  48. S. Tanaka, R. Nakato, Y. Katou, K. Shirahige, H. Araki, Curr. Biol. 21, 2055 (2011a)CrossRefGoogle Scholar
  49. T. Tanaka, T. Umemori, S. Endo, S. Muramatsu, M. Kanemaki, Y. Kamimura, C. Obuse, H. Araki, EMBO J. 30, 2019 (2011b)CrossRefGoogle Scholar
  50. M. Tehranirokh, A.Z. Kouzani, P.S. Francis, J.R. Kanwar, Biomicrofluidics 7, 51502 (2013)CrossRefGoogle Scholar
  51. J.A. Tercero, J.F.X. Diffley, Nature 412, 553 (2001)CrossRefGoogle Scholar
  52. P.M. van Midwoud, A. Janse, M.T. Merema, G.M.M. Groothuis, E. Verpoorte, Anal. Chem. 84, 3938 (2012)CrossRefGoogle Scholar
  53. M. Werner, F. Merenda, J. Piguet, R.P. Salathé, H. Vogel, Lab Chip 11, 2432–2439 (2011)CrossRefGoogle Scholar
  54. M. Yekezare, B. Gomez-Gonzalez, J.F.X. Diffley, J. Cell Sci. 126, 1297 (2013)CrossRefGoogle Scholar
  55. L.Y. Yeo, H.C. Chang, P.P. Chan, J.R. Friend, Small 7(1), 12–48 (2011)CrossRefGoogle Scholar
  56. E.W.K. Young, E. Berthier, D.J. Guckenberger, E. Sackmann, C. Lamers, I. Meyvantsson, A. Huttenlocher, D.J. Beebe, Anal. Chem. 83, 1408 (2011)CrossRefGoogle Scholar
  57. E.B. Yucel, S. Eraslan, K.O. Ulgen, FEBS J. 281, 1281 (2014)CrossRefGoogle Scholar
  58. P. Zegerman, J.F.X. Diffley, Nature 467, 474 (2010)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Irem Ezgi Odabasi
    • 1
  • Elif Gencturk
    • 1
  • Sevde Puza
    • 1
  • Senol Mutlu
    • 2
  • Kutlu O. Ulgen
    • 1
    Email author
  1. 1.Department of Chemical Engineering, Biosystems Engineering LaboratoryBogazici UniversityIstanbulTurkey
  2. 2.Department of Electrical and Electronics Engineering, BUMEMS LaboratoryBogazici UniversityIstanbulTurkey

Personalised recommendations