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Investigational New Drugs

, Volume 28, Issue 1, pp 35–48 | Cite as

A novel DNA intercalator, butylamino-pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells

  • M. S. Shahabuddin
  • Mridula Nambiar
  • Bibha Choudhary
  • Gopal M. Advirao
  • Sathees C. RaghavanEmail author
PRECLINICAL STUDIES

Summary

DNA intercalators are one of the most commonly used chemotherapeutic agents. Novel intercalating compounds of pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline series having a butylamino or piperazino group at fourth position (BPSQ and PPSQ, respectively) are studied. Our results showed that BPSQ induced cytotoxicity whereas PPSQ was cytostatic. The cytotoxicity induced by BPSQ was concentration- and time-dependent. Cell cycle analysis and tritiated thymidine assay revealed that BPSQ affects the cell cycle progression by arresting at S phase. The absence of p-histone H3 and reduction in the levels of PCNA in the cells treated with BPSQ further confirmed the cell cycle arrest. Further, annexin V staining, DNA fragmentation, nuclear condensation and changes in the expression levels of BCL2/BAD confirmed the activation of apoptosis. Activation of caspase 8 and lack of cleavage of caspase 9, caspase 3 and PARP suggest the possibility of BPSQ triggering extrinsic pathway for induction of apoptosis, which is discussed. Hence, we have identified a novel compound which would have clinical relevance in cancer chemotherapeutics.

Keywords

Chemotherapy Double-strand breaks Cytotoxicity DNA damage Anticancer drug 

Notes

Acknowledgements

We thank Prof. Ambeker SY and members of the SCR laboratory for discussions and help. This work was supported by Lady Tata Memorial Trust international award for leukemia research, London; grants from DBT, India (BT/PRS129/GBD/27/7/2006), and IISc start up grant for SCR. We also thank Dr. Raghavan Varadarajan for financial assistance. SMS is supported by DBT postdoctoral fellowship from DBT, India. MN is supported by senior research fellowship from CSIR, India.

Conflict of interest statement

Authors disclose that there is no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • M. S. Shahabuddin
    • 1
  • Mridula Nambiar
    • 1
  • Bibha Choudhary
    • 2
  • Gopal M. Advirao
    • 3
  • Sathees C. Raghavan
    • 1
    Email author
  1. 1.Department of BiochemistryIndian Institute of ScienceBangaloreIndia
  2. 2.Manipal Institute of Regenerative MedicineManipal UniversityBangaloreIndia
  3. 3.Department of Studies and Research in BiochemistryKuvempu UniversityDavanagereIndia

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