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Repositioning antispasmodic drug Papaverine for the treatment of chronic myeloid leukemia

Pharmacological Reports volume 73, pages 615–628 (2021)Cite this article

Abstract

Background

Papaverine is a benzylisoquinoline alkaloid from the plant Papaver somniferum (Opium poppy). It is approved as an antispasmodic drug by the US FDA and is also reported to have anti-cancer properties. Here, Papaverine's activity in chronic myeloid leukemia (CML) is explored using Saccharomyces cerevisiae, mammalian cancer cell lines, and in silico studies.

Methods

The sensitivity of wild-type and mutant (anti-oxidant defense, apoptosis) strains of S. cerevisiae to the drug Papaverine was tested by colony formation, spot assays, and AO/EB staining. In vitro cytotoxic effect was investigated on HCT15 (colon), A549 (lung), HeLa (cervical), and K562 (Bcr-Abl positive CML), and RAW 264.7 cell lines; cell cycle, mitochondrial membrane potential, ROS detection analyzed in K562 cells using flow cytometry and apoptotic markers, Bcr-Abl signaling pathways examined by western blotting. Molecular docking and molecular dynamics simulation of Papaverine against the target Bcr-Abl were also carried out.

Results

Investigation in S. cerevisiae evidenced Papaverine induces ROS-mediated apoptosis. Subsequent in vitro examination showed that CML cell line K562 was more sensitive to the drug Papaverine. Papaverine induces ROS generation, promotes apoptosis, and inhibits Bcr-Abl downstream signaling. Papaverine acts synergistically with the drug Imatinib. Furthermore, the docking and molecular dynamic simulation studies supported that Papaverine binds to the allosteric site of Bcr-Abl.

Conclusion

The data presented here have added support to the concept of polypharmacology of existing drugs and natural compounds to interact with more than one target. This study provides a proof-of-concept for repositioning Papaverine as an anti-CML drug.

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Acknowledgements

The authors would like to thank Dr. Kitlangki Suchiang for his critical reading of the manuscript and thank Saswat Kumar Mohanty and Anasooya P. Balakrishnan for their assistance.

Funding

This work was financially supported by the Department of Biotechnology, India, as a DBT-BUILDER project (BT/PR14554/INF/22/125/2010).

Author information

Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, India

    Phani Krishna Parcha, S. J. Sudharshan, Madhu Dyavaiah & Baskaran Rajasekaran

  2. DBT-Interdisciplinary Program in Life Sciences, School of Life Sciences, Pondicherry University, Puducherry, India

    Phani Krishna Parcha, S. J. Sudharshan, Madhu Dyavaiah & Baskaran Rajasekaran

  3. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, 605014, India

    Sailu Sarvagalla & Mohane Selvaraj Coumar

  4. Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, 605014, India

    Cheemala Ashok

Authors
  1. Phani Krishna Parcha
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  2. Sailu Sarvagalla
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  3. Cheemala Ashok
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  4. S. J. Sudharshan
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  5. Madhu Dyavaiah
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  7. Baskaran Rajasekaran
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Contributions

PK, MC, and BR conceived and designed the experiments. PK performed in vitro experiments with contributions from CA and SSJ. SS performed computational studies. PK wrote the manuscript and corrected it by MC.

Corresponding author

Correspondence to Mohane Selvaraj Coumar.

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The authors declare no competing interests.

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This article is dedicated to the loving memory of Dr. R. Baskaran, who passed away on 2nd June 2018.

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Parcha, P.K., Sarvagalla, S., Ashok, C. et al. Repositioning antispasmodic drug Papaverine for the treatment of chronic myeloid leukemia. Pharmacol. Rep 73, 615–628 (2021). https://doi.org/10.1007/s43440-020-00196-x

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  • DOI: https://doi.org/10.1007/s43440-020-00196-x

Keywords

  • Papaverine
  • Saccharomyces cerevisiae
  • Chronic myeloid leukemia
  • K562
  • Bcr-abl
  • Docking
  • Drug repositioning