Brazilian Wasp’s Venom Kills Cancer Cells Without Harming Normal Cells...
📍Study Reveals How Wasp Venom Kills Cancer Cells: //www.medicalnewstoday.com/articles/298863.php
Wasps can be a menace, often found haunting picnics and fruit trees in the summer. However, the venom of one particular breed of wasp is known to contain a potent anticancer ingredient, and now researchers have shown precisely how the venom's toxin selectively kills cancer cells.
Venom belonging to the Brazilian social wasp Polybia paulista contains the antimicrobial peptide Polybia-MP1 (MP1), which has been demonstrated to inhibit multiple forms of cancerous cells such as prostate cancer, bladder cancer and multidrug-resistant leukemic cells.
Despite this antimicrobial peptide showing great potential as a component of anticancer treatment in humans, researchers have not fully understood exactly how MP1 kills cancer cells.
The new study, published in Biophysical Journal, now reveals how MP1 is capable of killing cancer cells while leaving normal cells unscathed: by attacking lipids on the surface of cancer cells and creating holes that allow important cell molecules to leak out.
"Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs," explains study co-senior author Paul Beales of the University of Leeds in the UK.
"This could be useful in developing new combination therapies," he adds, "where multiple drugs are used simultaneously to treat a cancer by attacking different parts of the cancer cells at the same time."
The researchers hypothesized that the mechanism behind MP1's effectiveness against cancer cells would involve the way that cancer cell membranes differ from healthy cell membranes.
One major difference is the positioning of two lipids that form part of the cell membrane: phosphatidylserine (PS) and phosphatidylethanolamine (PE).
In cancer cells, PS and PE are located in the outer cell membrane facing outward from the cell, while in healthy cells, they are situated in the inner membrane and face inward. MP1 creates pores large enough for critical molecules to easily escape cancer cells!
To test their hypothesis, the researchers created some model cell membranes. Some of these contained PS, some contained PE and some contained both. They then exposed their model membranes to MP1 and observed what happened.
Using a combination of membrane permeability assays and imaging techniques, the researchers revealed that PS increased the binding of the antimicrobial peptide to the cell membrane, while the presence of PE boosted MP1's ability to quickly disrupt the membrane and increase the size of any holes in it.
The formation of these holes was key to how MP1 kills cancer cells, as co-senior author João Ruggiero Neto, of São Paulo State University in Brazil, explains:
“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells. The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising."
Going forward, the researchers plan to experiment with adjusting MP1's amino acid sequence, enabling them to investigate how MP1's structure relates to its function, as well as potentially boosting its anticancer properties for therapeutic purposes.
"Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine," Dr. Beales concludes.
“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that."
Wasps are not the only creatures that have certain characteristics which could benefit human health. In a Spotlight feature published earlier this year, Medical News Today examined how spiders, bees, scorpions, frogs, Gila monsters and snakes could provide novel forms of treatment for human conditions.
📍Beauty In The Beasties: How Some Of The World’s Creepiest Critters May Benefit Your Health:
📍A New Breakthrough in Breast Cancer Therapy: Wasp Venom:
//curioussciencewriters.org/2017/02/12/a-new-breakthrough-in-breast-cancer-therapy-wasp-venom/ February 12, 2017
❌❌➖ In Brief:
A peptide in wasp venom called Mitoparan can kill cancer cells, but it degrades in blood and can also kill off healthy cells.
When attached to certain compounds and proteins, Mitoparan prevents degradation and targets breast cancer cell.
Wasp venom has potential for treating breast cancer. Imagine yourself strolling through a beautiful park. Surrounded by nature, you smell the fresh air and let the sun hit your face. Suddenly, you hear a familiar buzzing and immediately turn pale. You see a venomous wasp and are tempted to run away.
Research may soon cause you to reconsider how you look at wasps: their venom is being explored as a treatment for breast cancer. In lab studies, scientists discovered that when cells and wasp venom interact, the venom interrupts the cell’s energy-producing process and creates gaping holes in the cell membrane. Everything inside the cell oozes out, and the cell eventually dies.
Scientists can use the poison in wasp venom to kill cancer cells. They know, however, that using pure wasp venom presents two problems: the venom immediately degrades when it touches the body’s blood, and it will also kill off any healthy, normal cells in the body.
In the process of designing a way to use wasp venom to treat breast cancer, Spanish scientists at the Institute for Research in Biomedicine in Barcelona have solved these problems. These scientists learned that a peptide called Mitoparan in wasp venom is the culprit that kills cells.
According to Miguel Moreno, “This peptide has the ability to form pores in the cell plasma membrane, penetrate into the cell and finally, cause its death.”
To ensure that Mitoparan reaches the cancer cells, the scientists attached other molecules to the venom to preserve it as it travels through the body.
Among these molecules is a protein that specifically targets breast cancer cells. This protein allows the cell-killing venom with Mitoparan to attach only to breast cancer cells, leaving healthy cells alone.
Other teams of researchers are also investigating how wasp venom can be used to treat cancer. For example, Paul Beales from the University of Leeds notes “cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs. This could be useful in developing new combination therapies, where multiple drugs are used simultaneously to treat a cancer by attacking different parts of the cancer cells at the same time.”
The research from these and other scientists show the exciting possibilities of wasp venom as a cancer treatment. Who would have guessed that something as angry and dangerous as a wasp could help us fight breast cancer?
So next time you take a stroll through the park, pay careful attention; you might be looking at another one of Mother Nature’s powerful medicines just waiting to be discovered.
📍Delivering Wasp Venom For Cancer Therapy:
Cytolytic peptides with potential therapeutic properties have appeared during the last three decades. However, the use of these natural weapons is relatively narrow due to their non-specific cytolytic activity as well as their rapid degradation and excretion when injected in blood. In order to rescue the use of these lytic peptides, we have designed pro-cytotoxic systems based on cytotoxic peptides conjugated to poly(l-glutamic acid) PGA polymer through specific cleavage sequences that are sensitive over-expressed tumor proteases, such as the metalloproteinase-2 (MMP-2) or cathepsin B. The potent cytotoxic peptide tested here, Mitoparan, is inactive when conjugated to the polymer and then become active again once released through the tumor proteases. Furthermore, this pro-cytotoxic system was decorated by a particular targeting peptide which binds to HER2 receptors over-expressed in some types of breast tumor cells, thereby increasing the selective release of cytolytic peptides inside tumor cell with exquisite spatiotemporal control. In this way, the system would improve the maximum tolerated dose and the pharmacokinetic parameters of cytotoxic peptides in vivo.
📍Brazilian Wasp Venom Kills Cancer Cells By Opening Them Up:
September 1, 2015
The social wasp Polybia paulista protects itself against predators by producing venom known to contain a powerful cancer-fighting ingredient.
A new study reveals exactly how the venom's toxin -- called MP1 (Polybia-MP1) -- selectively kills cancer cells without harming normal cells.
MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating gaping holes that allow molecules crucial for cell function to leak out.
The social wasp Polybia paulista protects itself against predators by producing venom known to contain a powerful cancer-fighting ingredient. A Biophysical Journal study published September 1 reveals exactly how the venom's toxin -- called MP1 (Polybia-MP1) -- selectively kills cancer cells without harming normal cells. MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating gaping holes that allow molecules crucial for cell function to leak out.
“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs," says co-senior study author Paul Beales, of the University of Leeds in the UK. "This could be useful in developing new combination therapies, where multiple drugs are used simultaneously to treat a cancer by attacking different parts of the cancer cells at the same time."
MP1 acts against microbial pathogens by disrupting the bacterial cell membrane. Serendipitously, the antimicrobial peptide shows promise for protecting humans from cancer; it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.
However, until now, it was not clear how MP1 selectively destroys cancer cells without harming normal cells. Beales and co-senior study author João Ruggiero Neto of São Paulo State University in Brazil suspected that the reason might have something to do with the unique properties of cancer cell membranes.
In healthy cell membranes, phospholipids called phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.
The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1.
They used a wide range of imaging and biophysical techniques to characterize MP1's destructive effects on the membranes.
Strikingly, the presence of PS increased the binding of MP1 to the membrane by a factor of 7 to 8.
On the other hand, the presence of PE enhanced MP1's ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.
"Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells," Neto says. "The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising."
In future studies, the researchers plan to alter MP1's amino acid sequence to examine how the peptide's structure relates to its function and further improve the peptide's selectivity and potency for clinical purposes.
"Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine," Beales says. "As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that."
📍PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide with Anticancer Properties:
-MP1 (MP1) is a bioactive host-defense peptide with known anticancer properties. Its activity is attributed to excess serine (phosphatidylserine (PS) on the outer leaflet of cancer cells.
Recently, higher quantities of phosphatidylethanolamine (PE) were also found at these cells’ surface.
We investigate the interaction of MP1 with model membranes in the presence and absence of POPS (PS) and DOPE (PE) to understand the role of lipid composition in MP1’s anticancer characteristics. Indeed we find that PS lipids significantly enhance the bound concentration of peptide on the membrane by a factor of 7–8.
However, through a combination of membrane permeability assays and imaging techniques we find that PE significantly increases the susceptibility of the membrane to disruption by these peptides and causes an order-of-magnitude increase in membrane permeability by facilitating the formation of larger transmembrane pores.
Significantly, atomic-force microscopy imaging reveals differences in the pore formation mechanism with and without the presence of PE. Therefore, PS and PE lipids synergistically combine to enhance membrane poration by MP1, implying that the combined enrichment of both these lipids in the outer leaflet of cancer cells is highly significant for MP1’s anticancer action. These mechanistic insights could aid development of novel chemotherapeutics that target pathological changes in the lipid composition of cancerous cells.
The antimicrobial peptide Polybia-MP1 (IDWKKLLDAAKQIL-NH2), or simply MP1, has unexpectedly been shown to exhibit selective inhibition against several types of cancerous cells and therefore could prove advantageous in the development of novel chemotherapies.
Extracted from the Brazilian wasp Polybia paulista, MP1 has a broad spectrum of bactericidal activities against Gram-negative and Gram-positive bacteria without being hemolytic and cytotoxic (1).
Surprisingly, MP1 also selectively inhibits proliferating bladder and prostate cancer cells (2), and multidrug-resistant leukemic cells (3).
Recently, it has been observed that this peptide is cytotoxic against leukemic T lymphocytes and very selective in recognizing these cells compared to healthy lymphocytes (4).
Cancer cell membranes are now known to lose the asymmetric transmembrane distribution of phospholipids that is observed in healthy cells (5, 6).
In healthy mammalian cells, the anionic aminophospholipid PS (phosphatidylserine) is predominant in the inner membrane leaflet and zwitterionic phospholipids are predominant in outer membrane leaflet.
In such cells, the phospholipid asymmetry is maintained by a family of aminophospholipid translocases that catalyze the transport of PS from the outer to the inner membrane leaflets (7).
However, in apoptotic and cancer cells, PS is found to also be located in the outer monolayer of the plasma membrane in significant proportions (5, 6).
The molecular-scale mechanistic basis for MP1’s anticancer properties is yet to be established. Changes in the distribution and/or composition of lipids (e.g., PS) within the plasma membrane of malignant cells could be the origin of MP1’s cancer selectivity.
This is a reasonable hypothesis, based upon the well-established selectivity of antimicrobial peptides for bacterial membranes over eukaryotic membranes due to their higher anionic lipid content (8, 9, 10, 11).
Recently, the effect of PS on the pore-forming activity of MP1 was investigated by multiple techniques, namely, conductance measurements in planar bilayer lipid membranes, binding assays, and lytic activity on large unilamellar vesicles (4).
Although an increase in affinity and lytic activity of MP1 for lipid vesicles containing PS was observed, MP1’s pore-formation activity in BLM showed no difference between PC (phosphatidylcholine) and mixed PC/PS bilayers.
Significantly, it was recently reported that PE (phosphatidylethanolamine) lipids, naturally found on the inner plasma membrane of normal cells, are also externalized to the outer monolayer of the plasma membrane of apoptotic and tumor endothelial cells due to both PS and PE lipids being coregulated by the same transporters (7).
These authors observed that the exposure to the outer monolayer of one of these phospholipids leads to the exposure of the other.
Therefore, it is important for future work to establish the role of increased concentrations of both PE and PS lipids in the interaction of MP1 with membranes. In this work, we address this challenge by establishing the roles of PE and PS lipids in the effects of MP1 on the structure and permeability of model membranes.
Primarily, we study the permeability of giant unilamellar vesicles (GUVs) at the single vesicle level.
Fluorescence confocal microscopy was used to determine the size-dependent macromolecular permeability of lipid membranes in GUV model systems by analyzing the influx of three fluorescent dyes with molecular masses of 0.37, 3.0, and 10.0 kDa into these vesicles (Fig. 1).
We deconvolve the effects of PS and PE lipids by exploring their effects within DOPC (PC) membranes both separately and in combination: DOPC/POPS 80:20 (PC/PS), DOPC/DOPE 90:10 (PC/PE), and DOPC/DOPE/POPS 70:10:20 (PC/PE/PS).
These experiments are corroborated by circular dichroism (CD) spectroscopy to quantify peptide binding to the membrane, fluorescence spectroscopy experiments to establish the leakage mechanism in an ensemble system of nanoscale large unilamellar vesicles (LUVs), and atomic-force microscopy (AFM) imaging of supported lipid bilayers to reveal the nanoscale perturbations of membrane structure induced by the peptide.
By combining these approaches, we show that, while PS lipids significantly enhance MP1’s binding onto the membrane, PE lipids impart the most significant contribution to the rate and extent of membrane permeabilization by MP1, facilitating the opening of larger membrane defects than in bilayers lacking in PE.
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