Probing the Link between Pancratistatin and Mitochondrial Apoptosis through Changes in the Membrane Dynamics on the Nanoscale

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.

Investigating the Effect of Medium Chain Triglycerides on the Elasticity of Pulmonary Surfactant

“…Using NSE we are able to look at the bending modulus (κ), which sheds light on the elastic properties of the bilayer system in question. 56,57 Elastic properties have been reported to have significance in biological processes, such as budding, formation of stalks, and adsorption, all of which are relevant to the functionality of PS. 58,59 Our results suggest that the incorporation of MCT had an overall softening effect on the lipid-only bilayers.…”

“…Although generally described as a monolayer system, pulmonary surfactant also forms multilayers that are referred to as surfactant reservoirs. ,, These bilayers tend to form upon compression of the monolayer, which causes buckling of the film, leading to bilayer folds protruding into the water subphase of the air–water interface. Using NSE we are able to look at the bending modulus (κ), which sheds light on the elastic properties of the bilayer system in question. , Elastic properties have been reported to have significance in biological processes, such as budding, formation of stalks, and adsorption, all of which are relevant to the functionality of PS. , …”

“…NSE is a quasi-elastic neutron scattering technique that probes the membrane dynamics at the time and length scales of thermal undulations . This method has been used to investigate the dynamics and associated membrane properties of lipid vesicles by many groups. − This allows for the extraction of important information such as the effective bending modulus of PS systems, which can shed light on the compressibility of the lipid bilayer environment . For example, if MCT found in vaping solutions lowers the bending rigidity of PS systems, this may still permit for adsorption and respreading to occur; however, it can still lead to a compromised integrity of the film at the vital near-zero surface tensions …”

Determination of pancratistatin in mouse blood by ultra-liquid chromatography-tandem quadrupole mass spectrometry and its application

“…At present, pancratistatin has been proved to selectively induce apoptosis of a variety of human cancer cells, but has no significant effect on non-cancer cells [10]. Natasha Kekre studied human lymphoma cells (Jurkat), and found that pancratistatin in Jurkat cells caused early activation of caspase-3 and reversal of phosphatidylserine, and induced cancer cells to use non genomic target cells to apoptosis [11].…”

Investigating the cut-off effect of n-alcohols on lipid movement: a biophysical study

“…This scheme exploits the sensitivity of SANS between hydrogen and deuterium, allowing the time-dependent mixing to be tracked. It has been successfully employed to monitor lipid motions in lipid-additive systems that included methanol, 24 proteins/peptides, 25–28 therapeutic agents 29 lipid nanodiscs, 30 and oil–water emulsions. 31 We complement the neutron scattering experiments with structural studies using small angle X-ray scattering and molecular dynamics simulations in two resolutions: all-atomistic and coarse-grained.…”