Polybia paulista isolate Polybia MP1 as an anti-oncogenic agent -
Polybia Paulista is a social wasp found in Brazil. It was discovered that a protein
derived from this wasp's venom now known as Polybia MP1 selectively attacks and
kills cancer cells in a laboratory environment.1 Polybia MP1 was initially isolated and
studied as an antimicrobial agent where it had bactericidal effects on a number of
Gram positive and negative bacteria. It also was not cytotoxic or haemolytic.2 It was
also discovered that MP1 can selectively attack prostate cancer cell membranes.
This was shown by a team of scientists who, in 2008 incubated normal mouse
fibroblasts and prostate cancer cell lines with the MP1 protein. They then used a
scanning electron microscope to view the effects of the polybia MP1 on prostate
cancer cells and mouse fibroblasts. The results of this are shown in Figure 1.
Figure 1: (A) shows a prostate cancer before MP1 application and (B) following
treatment with MP1. (C) shows a mouse fibroblast before MP1 addition with (D)
showing the mouse fibroblast afterwards.3
The figure shows that there is significant damage to the membrane of the prostate
cancer cell with no effect on the fibroblast. The scientists also determined that
bladder cancer cell lines were also killed by polybia MP1.3 Originally the mechanism
for this selectivity and for the disruption of the cell membrane was unclear. Now it is
believed that two phospholipids known as phosphatidylethanolamine and
phosphatidylserine are what allows MP1 to selectively attack the membranes of
cancer cells.4 It has been shown previously that phosphatidylserine, which is
normally distributed on the inside leaflet of the cell membrane, is found on the
outside of cancer cells and other pathological cells (such as apoptotic cells). 5 This
provides evidence for why cancer cells are targeted by MP1 as the cancer cells are
the only cells that have phosphatidylserine and phosphatidylethanolamine accessible
to the protein. To test the hypothesis the scientists created giant unilamellar vesicles
(GUVs) with varying amounts of phosphatidylethanolamine and phosphatidylserine
and then exposed them to MP1. They then exposed these model membranes to 3
fluorescent dyes of varying molecular mass Then using fluorescence microscopy
they were able to view the GUVs they had created and see which dyes had entered
the GUVs thus allowing them to determine the size of the pores created. They then
used multiple other processes to corroborate the results from the first experiment.
This resulted in the discovery that phosphatidylserine significantly increases the
bound concentration of lipid to MP1 (by a factor of 7-8) while
phosphatidylethanolamine increased the permeability of the membrane by allowing
MP1 to create larger pores.5
However it must be noted that just because MP1 selectively attacks cancer cells in a
laboratory environment it does not mean that MP1 is a clinically viable cancer
treatment. To be clinically viable the protein would need to be proved safe for use in
the human body and more studies would be needed to reach this conclusion. In
addition the breakdown of the cell membrane causes cell death through important
molecules exiting the cell. These molecules include RNA and different varieties of
proteins.6 This is a mode of cell death can be described as necrosis and any material
within the cell could well diffuse out of it. This would include any substances that may
be harmful when outside of the cells such as lysosomes. In addition to this the
presence of these dead necrotic cells would induce an inflammatory response from
the body’s immune system which could cause further complications.7
One of the professors instead suggests that the two phospholipids targeted by MP1
could provide new target for combination therapies where multiple drugs are used in
combination to help attack the tumour. This would be useful as any drug developed
that targets this molecule would be a new class of anticancer drug.6 Combination
therapies were developed with the idea that using multiple drugs with multiple
mechanisms of action would be a very efficient way of treating cancer. 8 Due to this
having a whole new mode of action and being a whole new class of drugs this could
be very useful for using with other existing drugs in combination chemotherapy.
Polybia MP1 has also not been tested with all the cell types in the human body.
Since human somatic cells have a huge variety of different cell surface markers
involved in many different processes it cannot be proved that MP1 will not react with
any of these other surface markers without extensive testing.9 If MP1 were to react
with other molecules this could mean it is not clinically viable as it could pose a
severe risk to the patient's health. Need to consider exploring this further. What
about differential sensitivities of cancer cells? Do all cancer cells repond in the same
way?
In conclusion the MP1 protein is clearly an anti-oncogenic agent because it attacks
and kills cancer cells and has been shown to inhibit the growth of a variety of
different cancers. However this does not necessarily mean it can be used as a
treatment for cancer in humans due to a variety of different reasons outlined in this
report. To determine whether it would be an effective cancer treatment extensive
testing of the drug would need to be carried out both on cell cultures and through
other methods. The MP1 protein’s specificity to the phospholipids
phosphatidylethanolamine and phosphatidylserine presents an opportunity for the
creation of new drugs that target these molecules that can be found on the surface of
cancer cells. This could lead to a variety of new treatments derived from the protein
MP1. So, to summarise, Polybia MP1 is an anti-onconogenic agent in the sense that
it kills cancer cells however it may not be suitable for treatment of cancer within
human patients.
References:
1. Sciencedaily. Sciencedaily.com. [Online]. Available from:
http://www.sciencedaily.com/releases/2015/09/150901134941.htm [Accessed
1 December 2015].
2. De souza, B.M, Da silva, A.V, Arcuri, H.A, Palma, M.S, Neto, J.R. et al
Characterization of two novel polyfunctional mastoparan peptides from the
venom of the social wasp Polybia paulista. Peptides. 2009;30(8): 1387–1395.
3. Wang K, Zhang B, Zhang W, Yan J, Li J, Wang R et al. Antitumor effects, cell
selectivity and structure–activity relationship of a novel antimicrobial peptide
polybia-MPI. Peptides. 2008;29(6):963-968.
4. Leite N, Aufderhorst-Roberts A, Palma M, Connell S, Neto J, Beales P et al.
PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide
with Anticancer Properties. Biophysical Journal. 2015;109(5):936-947.
5. 3. Zwaal R, Comfurius P, Bevers E. Surface exposure of phosphatidylserine
in pathological cells. CMLS, Cell Mol Life Sci. 2005;62(9):971-988.
6. Phys.org. Brazilian wasp venom kills cancer cells by opening them up
[Internet]. 2015 [cited 3 December 2015]. Available from:
http://phys.org/news/2015-09-brazilian-wasp-venom-cancer-cells.html
7. Cabana E. Modes of Cell Death [Internet]. mozcom. 2015 [cited 3 December
2015]. Available from: http://www2.mozcom.com/~emcdvm/path02.html
8. Chabner B, Thompson E. Combination Cancer Therapy - Cancer [Internet].
MSD Manual. 2015 [cited 3 December 2015]. Available from:
http://www.msdmanuals.com/home/cancer/prevention-and-treatment-ofcancer/combination-cancer-therapy
9. Cooper G. The Cell: A Molecular approach. 2nd ed. Sunderland (MA):
Sinauer Associates; 2015. Available
from:http://www.ncbi.nlm.nih.gov/books/NBK9898/