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Membrane perturbation through novel cell-penetrating peptides influences intracellular accumulation of imatinib mesylate in CML cells

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Abstract

Chronic myeloid leukemia is a stem cell disease with the presence of Philadelphia chromosome generated through reciprocal translocation of chromosome 9 and 22. The use of first- and second-generation tyrosine kinase inhibitors has been successful to an extent. However, resistance against such drugs is an emerging problem. Apart from several drug-resistant mechanisms, drug influx/efflux ratio appears to be one of the key determinants of therapeutic outcomes. In addition, intracellular accumulation of drug critically depends on cell membrane fluidity and lipid raft dynamics. Previously, we reported two novel cell-penetrating peptides (CPPs), namely, cationic IR15 and anionic SR11 present in tryptic digest of Abrus agglutinin. Here, the potential of IR15 and SR11 to influence intracellular concentration of imatinib has been evaluated. Fluorescent correlation spectroscopy and lifetime imaging were employed to map membrane fluidity and lipid raft distribution following peptide-drug co-administration. Results show that IR15 and SR11 are the two CPPs which can modulate membrane fluidity and lipid raft distribution in K562 cells. Both IR15 and SR11 significantly reduce the viability of CML cells in the presence of imatinib by increasing the intracellular accumulation of the drug.

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Acknowledgements

Authors acknowledge Central Research Facility of IIT Kharagpur, DST, DBT, and Government of India for the financial and infrastructure support. D. Mukherjee acknowledges CSIR and Government of India for “Senior Research Fellowship.”

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Authors and Affiliations

  1. Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India

    Devdeep Mukherjee, Birendra Behera & Tapas Kumar Maiti

  2. Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, India

    Niloy Kundu & Nilmoni Sarkar

  3. Department of Haematology, Nil Ratan Sircar Medical College and Hospital, Kolkata, India

    Lopamudra Chakravarty & Prantar Chakrabarti

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  1. Devdeep Mukherjee
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  2. Niloy Kundu
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  3. Lopamudra Chakravarty
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  4. Birendra Behera
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  5. Prantar Chakrabarti
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  6. Nilmoni Sarkar
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  7. Tapas Kumar Maiti
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Correspondence to Tapas Kumar Maiti.

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Bone marrow samples were collected from the informed patients attending Medical College, Kolkata, after written consent. This study was approved by the Ethical Committee of Medical College, Kolkata, and was performed according to the guidelines of Indian Council of Medical Research, IIT, Kharagpur, and the Helsinki Declaration.

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The authors declare that they have no conflict of interest.

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Mukherjee, D., Kundu, N., Chakravarty, L. et al. Membrane perturbation through novel cell-penetrating peptides influences intracellular accumulation of imatinib mesylate in CML cells. Cell Biol Toxicol 34, 233–245 (2018). https://doi.org/10.1007/s10565-017-9414-9

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  • DOI: https://doi.org/10.1007/s10565-017-9414-9

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