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

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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.

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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.

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Authors disclose that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India

    M. S. Shahabuddin, Mridula Nambiar & Sathees C. Raghavan

  2. Manipal Institute of Regenerative Medicine, Manipal University, Bangalore, 560 071, India

    Bibha Choudhary

  3. Department of Studies and Research in Biochemistry, Kuvempu University, Shivagangotri, Davanagere, 577 002, India

    Gopal M. Advirao

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  1. M. S. Shahabuddin
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  2. Mridula Nambiar
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  3. Bibha Choudhary
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  4. Gopal M. Advirao
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  5. Sathees C. Raghavan
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Correspondence to Sathees C. Raghavan.

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M. S. Shahabuddin and Mridula Nambiar contributed equally to the work.

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Shahabuddin, M.S., Nambiar, M., Choudhary, B. et al. A novel DNA intercalator, butylamino-pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells. Invest New Drugs 28, 35–48 (2010). https://doi.org/10.1007/s10637-008-9212-6

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