Document Type

Article

Publication Date

6-6-2022

Publication Title

Molecular Pharmaceutics

Volume

19

Issue

6

First Page

1839

Keywords

Anticancer drugs, Apoptosis, Cancer, Lipid membranes, Molecular dynamics, Nanomedicine, Natural compounds, Neutron spin-echo, Small angle neutron scattering, Small angle X-ray scattering, Vesicles

Last Page

1852

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.

DOI

10.1021/acs.molpharmaceut.1c00926

ISSN

15438384

E-ISSN

15438392

PubMed ID

35559658

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