I'm currently working on a compound that I had isolated which exhibited anticancer activity. It has a therapeutic index of more than 3 and so I'm interested to know its mechanism of action. Based on my current findings, it seems that the compound causes necrosis instead of apoptosis. I was told before by my colleague that apoptosis is a preferred mode of action. However, is it really bad for a compound to have good therapeutic index to kill cancer cells through necrosis?
Hi Daniel
I would be interessted to see how your compound reacts in a concentration dependent manner and if it induces necrosis only at higher concentrations this would give you already some informations regarding the mode of action, interessting topic best luck and
best regards
The above comment is right. It could also be secondary necrosis. Check at an early time point say 8hrs to see if it indeed induces apoptosis. Necrosis is acceptable as long as it doesn't cause tumor lysis syndrome (necrosis of all/most tumor cells at once, which leads to shock and death of animal in pre-clinical studies). At lower doses it may induce proper apoptosis. Do a dose response study to detect, apoptosis versus necrosis quantitatively using FACS. See my papers for methods https://www.researchgate.net/publication/292615481_Mitochondrial_oligomers_boost_glycolysis_in_cancer_stem_cells_to_facilitate_blebbishield-mediated_transformation_after_apoptosis?_iepl%5BviewId%5D=Mfirvd8JgPE0MfBptbzAjfOcWcIIrdS1Ia0l&_iepl%5Bcontexts%5D%5B0%5D=prfhpi&_iepl%5Bdata%5D%5BstandardItemCount%5D=4&_iepl%5Bdata%5D%5BuserSelectedItemCount%5D=5&_iepl%5Bdata%5D%5BtopHighlightCount%5D=1&_iepl%5Bdata%5D%5BstandardItemIndex%5D=3&_iepl%5Bdata%5D%5BstandardItem3of4%5D=1&_iepl%5BtargetEntityId%5D=PB%3A292615481&_iepl%5BinteractionType%5D=publicationTitle
Article Mitochondrial oligomers boost glycolysis in cancer stem cell...
I agree with my colegues, at a lower dose it may produce apoptosis. The only problem is that it is highly possible that it will produce necrosis also in not malignant cells.
Remember Paracelsus' paradigm drugs that at a low dose cure at a high dose they may become a poison.
I agree with Tomas; the effect on normal cells needs to be excluded. In the end, the mode of cell death of malignant cells does not matter. The important endpoint is cell death.
W
Necrosis could be problematic in some types of tumors, some sensitive organs -like brain- can be seriously affected by necrosis products -even when normal cells are not directly affected.
I agree with the colleagues you need to perform a dose-response study. But if you are interested in its molecular mechanism, molecular modeling and docking against suspected targets could be helpful.
There is NOT ANY indication that apoptosis is a preferred mode of death of cancer cells. A dead cancer cell - by which ever way - is a good thing!!!
WD
I also align my thoughts with Wolfgang's. Cancer cell death by either way is desirable.
Certainly, a dead cancer cell is a good thing, but for the surrounding tissue it is not always that simple. The necrosis- induced inflammation isn’t necessarily beneficial with the tumor cells leaking its contents during necrosis. The outcome depends on multiple factors including type of cancer, size of the tumor, percentage of tumor necrosis, and nature of immune response (which could be good as stated above, or favoring disease progression). Actually necrosis is a problem in treatment of brain tumors for example, radiation do kill the cancer cells, but TUMOR necrosis was related to lower patient survival (let aside radiation induced necrosis of normal tissues).
One of the main strategies of cancer genome is the inhibition of apoptosis in cancer cells. Simultaneously, the back door (as necrosis) could relatively easily be opened. It would be critically important to control levels of inflammation, which will accompany necrosis.
- Badges
- Science topic
- Similar topics
- Medicine
- Oncology
- Cancer Research
- Cancer Biology
- Cancer Cells