Mitocans induce lipid flip-flop and permeabilize the membrane to signal apoptosis
Stuart R Castillo1, Michael H L Nguyen1, Mitchell DiPasquale1
1Department Chemistry and Biochemistry, University of Windsor, Windsor, Canada.
Abstract:
Pancratistatin (PST) and narciclasine (NRC) are natural therapeutic agents that exhibit specificity toward the mitochondria of cancerous cells and initiate apoptosis. Unlike traditional cancer therapeutic agents, PST and NRC are effective, targeted, and have limited adverse effects on neighboring healthy, noncancerous cells. Currently, the mechanistic pathway of action for PST and NRC remains elusive, which in part inhibits PST and NRC from becoming efficacious therapeutic alternatives. Herein, we use neutron and x-ray scattering in combination with calcein leakage assays to characterize the effects of PST, NRC, and tamoxifen (TAM) on a biomimetic model membrane. We report an increase in lipid flip-flop half-times (t1/2) (≈12.0%, ≈35.1%, and a decrease of ≈45.7%) with 2 mol percent PST, NRC, and TAM respectively. An increase in bilayer thickness (≈6.3%, ≈7.8%, and ≈7.8%) with 2 mol percent PST, NRC, and TAM, respectively, was also observed. Lastly, increases in membrane leakage (≈31.7%, ≈37.0%, and ≈34.4%) with 2 mol percent PST, NRC, and TAM, respectively, were seen. Considering the maintenance of an asymmetric lipid composition across the outer mitochondrial membrane (OMM) is crucial to eukaryotic cellular homeostasis and survival, our results suggest PST and NRC may play a role in disrupting the native distribution of lipids within the OMM. A possible mechanism of action for PST- and NRC-induced mitochondrial apoptosis is proposed via the redistribution of the native OMM lipid organization and through OMM permeabilization.
Insights
Pancratistatin (PST) and narciclasine (NRC) disrupt cancer cell mitochondria by altering lipid distribution and increasing membrane permeability, suggesting a novel apoptosis mechanism. These natural agents show targeted efficacy with fewer side effects.
Area of Science:
- Biochemistry
- Cell Biology
- Membrane Biophysics
Background:
- Pancratistatin (PST) and narciclasine (NRC) are natural compounds targeting cancer cell mitochondria to induce apoptosis.
- Their precise mechanism of action is not fully understood, hindering their therapeutic application.
- Understanding their interaction with mitochondrial membranes is crucial for developing novel cancer therapies.
Purpose of the Study:
- To investigate the effects of PST and NRC on biomimetic model membranes.
- To elucidate the biophysical mechanisms underlying PST and NRC-induced apoptosis.
- To compare the effects of PST and NRC with tamoxifen (TAM) on membrane properties.
Main Methods:
- Neutron and X-ray scattering techniques were employed to analyze membrane structure.
- Calcein leakage assays were used to assess membrane permeability.
- A biomimetic model membrane system was utilized to mimic the outer mitochondrial membrane.
Main Results:
- PST and NRC significantly increased lipid flip-flop half-times and bilayer thickness.
- Both compounds, along with TAM, induced substantial increases in membrane leakage.
- These changes suggest disruption of the native lipid organization in the outer mitochondrial membrane.
Conclusions:
- PST and NRC may induce apoptosis by altering the lipid asymmetry and increasing the permeability of the outer mitochondrial membrane.
- The findings propose a novel mechanism of action for PST and NRC involving the disruption of mitochondrial membrane integrity.
- Further research into these natural compounds could lead to more effective and targeted cancer treatments.
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