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Nuphar alkaloids induce very rapid apoptosis through a novel caspase-dependent but BAX/BAK-independent pathway

Cell Biology and Toxicology volume 35, pages 435–443 (2019)Cite this article

Abstract

Nuphar alkaloids, originally isolated from water lilies, induce apoptosis in mammalian cells in less than 1 h, making them possibly the fastest known inducers. However, the mechanism by which this rapid apoptosis occurs remains unknown. We have investigated canonical aspects of apoptosis to determine how the nuphar alkaloid, (+)-6-hydroxythiobinupharidine (6HTBN), induces apoptosis. 6HTBN induced rapid apoptosis in various leukemia, lymphoma, and carcinoma cell lines, suggesting that its mechanism is cell-type independent. It also circumvented resistance of patient-derived chronic lymphocytic leukemia cells generated by co-culture on survival-promoting stroma. Intriguingly, 6HTBN failed to induce apoptosis in platelets. The mechanism of apoptosis involves activation of caspase 9 and caspase 3, but not caspase 8 as previously reported. The release of cytochrome c from mitochondria occurred even in the absence of BAX/BAK and in cells that retained mitochondrial membrane potential. These results suggest a novel mechanism of apoptosis that has previously not been reported. The molecular target of the nuphar alkaloids remains to be determined.

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Funding

This research was supported by grant RSG-13-011-01-CDD from the American Cancer Society to JW and AE, a pilot grant from the COBRE Institute for Biomolecular Targeting (P20GM113132), and an NCI Cancer Center Support Grant 5P30 CA023108 to the Norris Cotton Cancer Center.

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Authors and Affiliations

  1. Department of Molecular and Systems Biology, Geisel School of Medicine, Lebanon, NH, USA

    David J. Mallick & Alan Eastman

  2. Department of Chemistry, Dartmouth College, Hanover, NH, USA

    Alexander Korotkov, Hui Li & Jimmy Wu

  3. Norris Cotton Cancer Center, Geisel School of Medicine, Rubin Building Level 6, One Medical Center Drive, Lebanon, NH, 03756, USA

    Jimmy Wu & Alan Eastman

Authors
  1. David J. Mallick
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  2. Alexander Korotkov
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  3. Hui Li
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  4. Jimmy Wu
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  5. Alan Eastman
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Correspondence to Alan Eastman.

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Mallick, D.J., Korotkov, A., Li, H. et al. Nuphar alkaloids induce very rapid apoptosis through a novel caspase-dependent but BAX/BAK-independent pathway. Cell Biol Toxicol 35, 435–443 (2019). https://doi.org/10.1007/s10565-019-09469-5

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  • DOI: https://doi.org/10.1007/s10565-019-09469-5

Keywords

  • Nuphar alkaloids
  • BAX/BAK–independent apoptosis
  • Platelets
  • Caspase 3
  • Cytochrome c release
  • Mitochondrial membrane potential