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A novel structural derivative of natural alkaloid ellipticine, MDPSQ, induces necrosis in leukemic cells

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Summary

DNA intercalating molecules are promising chemotherapeutic agents. In the present study, a novel DNA intercalating compound of pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline series having 8-methyl-4-(3 diethylaminopropylamino) side chain is studied for its chemotherapeutic properties. Our results showed that 8-methyl-4-(3 diethylaminopropylamino) pyrimido [4′,5′:4,5] selenolo(2,3-b)quinoline (MDPSQ) induces cytotoxicity in a time- and concentration-dependent manner on leukemic cell lines. Both cell cycle analysis and tritiated thymidine assays revealed that MDPSQ affects DNA replication. Treatment with MDPSQ resulted in both elevated levels of DNA strand breaks and repair proteins, further indicating its cytotoxic effects. Besides, Annexin V/PI staining revealed that MDPSQ induces cell death by triggering necrosis rather than apoptosis.

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Acknowledgements

We thank Dr. Kavitha C.V., Ms. Nishana M. and members of SCR laboratory for critical reading of the manuscript. This work was supported by Lady Tata Memorial Trust international award for leukemia research (London) for SCR. SMS is supported by DBT postdoctoral fellowship from India. MN is supported by Senior Research Fellowship from CSIR, India.

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Authors and Affiliations

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

    M. S. Shahabuddin, Mridula Nambiar, Balaji T. Moorthy, Bibha Choudhary & Sathees C. Raghavan

  2. Department of Biochemistry, Kuvempu University, Shivagangotri, Davanagere, 577002, India

    Prakruthi L. Naik & Gopal M. Advirao

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  1. M. S. Shahabuddin
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  2. Mridula Nambiar
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  7. 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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Suppl. Figure 1

Quantification of cell cycle analysis of K562 and CEM cells following treatment with MDPSQ. K562 (A,B) and CEM (D,E) cells were treated with MDPSQ as described in Fig. 3. Quantification of different cell cycle phases is shown. C. Western blot showing expression of PCNA. The α-Tubulin was used as an internal loading control (PPT 283 kb)

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Shahabuddin, M.S., Nambiar, M., Moorthy, B.T. et al. A novel structural derivative of natural alkaloid ellipticine, MDPSQ, induces necrosis in leukemic cells. Invest New Drugs 29, 523–533 (2011). https://doi.org/10.1007/s10637-009-9379-5

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