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  Probing the link between pancratistatin and mitochondrial apoptosis through changes in the membrane dynamics on the nanoscale

Castillo, S. R., Rickeard, B. W., DiPasquale, M., Nguyen, M. H. L., Lewis-Laurent, A., Doktorova, M., et al. (2022). Probing the link between pancratistatin and mitochondrial apoptosis through changes in the membrane dynamics on the nanoscale. Molecular Pharmaceutics, 19(6), 1839-1852. doi:10.1021/acs.molpharmaceut.1c00926.

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 Creators:
Castillo, Stuart R., Author
Rickeard, Brett W., Author
DiPasquale, Mitchell, Author
Nguyen, Michael H. L., Author
Lewis-Laurent, Aislyn, Author
Doktorova, Milka, Author
Kav, Batuhan1, Author              
Miettinen, Markus S.2, Author              
Nagao, Michihiro, Author
Kelley, Elizabeth G., Author
Marquardt, Drew, Author
Affiliations:
1Thomas Weikl, Theorie & Bio-Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863330              
2Markus Miettinen, Theorie & Bio-Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_3070372              

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Free keywords: Cancer; Lipid membranes; Vesicles; Anticancer drugs; Apoptosis; Natural compounds; Nanomedicine; Neutron spin−echo; Small angle X-ray scattering; Small angle neutron scattering; Molecular dynamics
 Abstract: Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity toward cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent. Herein, we use neutron spin–echo (NSE) spectroscopy, molecular dynamics (MD) simulations, and supporting small angle scattering techniques to study PST’s effect on membrane dynamics using biologically representative model membranes. Our data suggests that PST stiffens the inner mitochondrial membrane (IMM) by being preferentially associated with cardiolipin, which would lead to the relocation and release of cytochrome c. Second, PST has an ordering effect on the lipids and disrupts their distribution within the IMM, which would interfere with the maintenance and functionality of the active forms of proteins in the electron transport chain. These previously unreported findings implicate PST’s effect on mitochondrial apoptosis.

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Language(s): eng - English
 Dates: 2022-05-132022
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: DOI: 10.1021/acs.molpharmaceut.1c00926
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Title: Molecular Pharmaceutics
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 19 (6) Sequence Number: - Start / End Page: 1839 - 1852 Identifier: ISSN: 1543-8384