Cell Biology and Toxicology

, Volume 35, Issue 5, pp 435–443 | Cite as

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

  • David J. Mallick
  • Alexander Korotkov
  • Hui Li
  • Jimmy Wu
  • Alan EastmanEmail author
Original Article


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.


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


Funding information

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Molecular and Systems BiologyGeisel School of MedicineLebanonUSA
  2. 2.Department of ChemistryDartmouth CollegeHanoverUSA
  3. 3.Norris Cotton Cancer CenterGeisel School of MedicineLebanonUSA

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