Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity towards cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed and has previously been shown to induce targeted apoptotic action on various human cancer cell lines, such as breast, colon, and neuroblastoma, while having minimal effects on healthy cell lines. However, due to the lack of experimental evidence for its mechanism of action, the use of PST has yet to be advanced as an efficacious cancer treatment. Above all, the mechanistic pathway must first be elucidated to advance PST as an alternative to the current ineffective treatments available. To investigate this, we use techniques such as use neutron spin-echo (NSE) spectroscopy, very small angle neutron scattering (vSANS), and supporting small angle scattering techniques to study PST’s effect on membrane dynamics using biologically representative model membranes. Our data obtained from NSE suggests that PST stiffens the inner mitochondrial membrane (IMM) mimic by preferentially associating with cardiolipin. Secondly, scattering techniques demonstrate that 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. Combined, these results shed light on PST’s effects on the mechanical properties of biomimetic systems with the hopes of advancing PST as an alternative to the current limited treatments available. Furthermore, membranes play a significant role in regulating physiological processes such as signalling and apoptosis. Mitochondrial membranes have a high degree of spatial organization, specifically lipid packing within lipid bilayers is key to the physiochemical features of membranes and has been shown to be involved in many processes. Unfortunately, this feature proves difficult to study with traditional approaches as the inherit complexity of cellular membranes poses a challenge to resolution. By using NSE, the bending rigidity of cancerous and non-cancerous mitochondrial membrane extracts from colon cell lines were investigated. These results revealed key differences between both samples, potentially linking their structural differences to mitochondrial apoptosis, further giving insight into the nanoscopic workings of healthy and diseased mitochondria.

Investigating the role of pancratistatin in mitochondrial apoptosis via neutron scattering

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