Find the answer and we will all be grateful! (and you may publish a well-cited article). In the meantime, we know that in the absence of an immune system, it does not matter much which way they die. See "Chemotherapy induces tumor clearance independent of apoptosis", Jennifer L. Guerriero,1 Dara Ditsworth,2 Yongjun Fan,3 Fangping Zhao,2 Howard C. Crawford,4 and Wei-Xing Zong, Cancer Res. 2008 December 1; 68(23): 9595–9600. http://cancerres.aacrjournals.org/content/68/23/9595.long

To me apoptosis may be better than necrosis since it will not induce inflammation which may generate more damage. But, i may be wrong since inflammation itself has been shown to help controlling cancer progression.

Yes I agree with Ru-Jeng. However apoptosis should be cancer cell specific, are else the therapeutic drug would be too toxic.

Hi, John, apotosis is a better way, but only in the case if poptosis is strictly specifci for cancer cell only. But it is not the case, otjher cells (not cancer one) may also affected by this way, may be little less manner.

Inhibition of apoptosis seemed a good approach. But, even after 2 decades of drugs which promote apoptosis, we have chemo-resistant and radio-resistant cells which meatstasize. Drugs causing apoptosis may actually permit the cancer stem cells to grow better (because the other competing cells have died of apoptosis!). So, we need drugs which can specifically target cancer stem cells. Hope this helps!

Apoptosis may attract and/or induce polarization of M2 macrophages thus creating an immune permissive pro invasive microenvironment. Similarly, apoptotic bodies by inhibit cytotoxic T-cell responses. Thus, it seem not to be a black and white answer.

I am not sure if it is always possible to induce apoptosis in cancer cells. The problem is that cancer cells often have evolved strategies to avoid normal removal through apoptotic cell death, thus these pathways may be significantly disrupted in the cancer cells. In this case it might only be possible to kill the cancer cells through either alternative programmed death pathways or through massive disruption of essential cellular processes to the point where the cell breaks apart.

I don't think it is well understood yet how "apoptotically competent" cancer cells are at this point. Adding to this, with the advent of programmed necrotic death we may also need to consider how "necrotically competent" cancer cells are as well.

Find the answer and we will all be grateful! (and you may publish a well-cited article). In the meantime, we know that in the absence of an immune system, it does not matter much which way they die. See "Chemotherapy induces tumor clearance independent of apoptosis", Jennifer L. Guerriero,1 Dara Ditsworth,2 Yongjun Fan,3 Fangping Zhao,2 Howard C. Crawford,4 and Wei-Xing Zong, Cancer Res. 2008 December 1; 68(23): 9595–9600. http://cancerres.aacrjournals.org/content/68/23/9595.long

There are other ways to kill cells besides the aforementioned ones as tumor cell senescence but their efficacy in the clinic has to be still proven.

Collado M, Serrano M. Senescence in tumours: evidence from mice and humans.

Nat Rev Cancer. 2010 Jan;10(1):51-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672965/

Necrosis leads to local inflammation which leads to extravasation followed by the leaking out of the cells of the immune system to the site of injury/inflammation. In case of cancer this is not good for 2 reasons.

1. Cancer cells know how to evade the immune system (one of their emerging hallmarks) which means that the lymphocytes flowing to the site of inflammation will do no good.

2. Inflammation always leads to increase in the diameter of the blood vessels close to the site to allow a greater amount of these lymphocytes to go to the site and control the infection/injury. The greater the amount of blood that reaches the site of tumor, the more the amount of nutrients provided to the cells and they will proliferate with renewed vigor.

So we normally prefer to kill the cells by apoptosis and not necrosis. And this is precisely the reason why chronic inflammation is avoided as it can cause the mutated cells to pick up their proliferation rate.

I hope the answer helps you.

As for miRNAs, they are known to regulate about 60% of our genes, so they are a fantastic regulatory control. But I doubt if they can be used therapeutically for cancer because of their short half-life.

I guess whichever the method we advocate the one can control cancer progression or even cure the cancer is the one we want. Theoretic benefit may not translate into clinical efficacy until we obtain the real proof.

Yes apoptosis is the best therapeutic way of killing cancerous cell rather than by Narcosis because it causes inflammation that can cause further distress or injury within the body.

I think this is important to respond to Ru-Jeng Te's point because it gets at the heart of how I believe we should teach people to do research. The reason to consider what to shoot for in these types of experiments is that you may hit what you aim for. And if the experiment does not work out the way you expect then you learn something new and can build upon that knowledge. If you have no expectations every result is equally likely and whatever happens you do not learn very much. This is because there is no foundation to build upon if you approach research this way. If you have a working model then you can continue to improve it and in this way your understanding and knowledge grows much faster than if you are open to anything.

Apoptosis has been claimed as the clean way to kill the cells!! Of course, it is the best way to die instead of necrosis that induces an inflammatory status. Nowadays, it represents a really delicate mechanism balanced with other mechanisms like autophagy and necroptosis. Only some compounds can induce apoptosis straight away. The majority of compounds determine a broad spectrum of effects causing partial cell demise processes that need to be elucidated. Of course miRNAs are strongly onvolved in these processes by modulating pro and antiapoptotic factors.

Indeed, as mentioned by an earlier contributor, cancer cells have evolved strategies to avoid apoptotic cell death. These include the inactivation of tumor supressor genes (notably p53) and/or the activation of oncogenes which signal cell survival eg thru the PI 3-kinase/ AKT pathway. New strategies are being devised which can feed into the death pathways beyond the point at which the genetic blockades occur in cancer cells eg the MDM2 antagonist nutlin 3a (Vassilev et al), which will activate p53 directly; or ABT737, a bcl-2 antagonist =BH3-mimetic; Cragg et al Nat Rev Cancer 9: 321; 2009) which will neutralize bcl-2's powerful anti-apoptotic action directly, independent of upstream pathways. Many tumor supressor/ oncogene mechanisms impact on global cellular metabolism via the LKB/ AMPK tumor supressor pathway. The well-known anti-diabetic drug metformin reverses these metabolic effects and induces cancer cell apoptosis. There is immense recent interest in using this well-known and safe drug in cancer therapy ( (Alessi et al; Ann Rev Biochem 75: 137; 2006; Riedmaier et al: trends in Pharmacological sciences 34: 126; 2013). I hope these points are of some interest.

Inflammation would help to go angaisnt cancer cells since immunology has been used agaisnt cancer cells. It is the more natural and self-control by the body. Stimulation of apoptosis is a dream taht will not solve the problem as no inflammation meant no immune response agaisnt tumor cells.

Apoptosis is a dogma for cell death invented by dreamers who do not remember that apoptosis is a normal way controling growth during embryology and cell death in healthty tissues, removing the death cells without creating a havoc in the organ or tissues.

Apoptosis death is only found in cell culture induced death, only in specific conditions and shall never be a defense against cancer. It is better to create a peroxidation through medications (i.e. Apatone) to kill cancer cells in vitro and in vivo and inducing no side effects.

in my opinions, the apoptosis was better pathway to eliminate the cancer cell. But it would be better if the cancer cells have not experienced excessive metastases. if metastasis has occurred, there will be inflammation that could initiate the recruitment of antibody cells that was expected to control the cancer cells.

Soni makes a good point. Most cancer patients die due to metastases. if one can block this, actual lives will be saved (as Ru-Jeng says). Unfortunately, metastases is linked with other complex processes like hypoxia and angiogenesis--so its not easy to block!

apoptosis is the best studied mechanism by which many anticancer cells induce cell death. However many of these agents and new drugs induce cytostatic effects (long term-effects, i.e. cell cycle arrest), and other cause autophagy

Till now the apoptosis is considered the best way for killing cancer cells. Human always tries to restricted himself/herself by artificial boundaries he/she has created it in sometime. The scientific media now sticking on the apoptosis as the only and best access to app[roach cell death. I think we must fell free in seeking for further access for cell death. Personally concerning cancer cell I found the draw cells for suicide is a good method for cancer cell killing. This can be achieved by different methods, one of them is trying to support the weak cancer cell sub-clones to be dominated and those cells can be drawn for death by different simple methods rather than apoptosis. Gene therapy by using powerful bacterial exotoxins may give nice result to kill cells as well.

Christina is correct that immunology is key here. A strong immune system will foster normal human cells and either ignore or starve out abnormal cells. In that sense the mitochondrial/DNA/ATP axis will do the work that conventional medicine is attempting to do, and will do it better, in our observations.

Ying-Xin, this is exactly what I've been saying and I appreciate your position here. Thank you.

I totally agree with John's response. As a scientist we do not to come up with a hypothesis to work with. Either to prove the concept is right or unfortunately to prove it is wrong. I have no doubt that John raise a very important question for all of us to discuss about. As to my orevious comment, I may jump to the practicality too quick. However, I will not try to "define" one way is better than the other before we build up the hypothesis otherwise we lose our objectivity. As true scientist we need to be unbiased to conduct the experiemnt to prove our concept or hypothesis. But, also as a clinician I have to concern about the final outcome to my patients. One of my studies in extremely prematutre infants (all less than 25 weeks of gestation) suffered from severe lung disease never submit was the effect was so effective but most patient died for some other problems (severe bleeding in head, bowel necrosis, severe infection) or parents just withdrew life support for other morbidity." The treatment was very successful but all of the treated patients die". I have been criticized by some reviewers that the drug dose I used to study my model was too low but they apparently forget about the huge dose previous publications used will literally kill all the patients in days. We all need to be cautious about defining the "better method".

Apoptosis, or not apoptosis. It seems trivial to me. Key question is how to deliver whatever toxin to the cancer cells and not to any other cell. During delivery the toxin should remain harmless and should be activated only after delivery. Science or fiction?

I also want to address that strong immune response may not always be a good thing. Say autoimmune diseases or some transfusion related disorders. Strong immune response may do more harm than good in some situations.

no because with apoptosis there is no immune stimulation.

Autoschizis is better through peroxidative attack

Apoptotic cancer cells have been shown to release mitogens that stimulate compensatory proliferation of surviving cancer cells which repopulate the tumour. Apoptosis may not be such a straight forward therapeutic strategy to kill cancer cells.

Great discussion. Now we have evidence to support both teams and how are we going to "define" the better way? We should go back to the drawing borad, propose the better method, and prove it by solid evidence.

In my mention of immunology, my thought is that we support immunology of the body by fostering a rise in cellular pH, increase of oxygen, and making sure all deficient nutrients, including hyrdration and removal of substances detrimental to health including heavy metals are accounted for. Then, the body's response will play a stronger role in promotion of good cells and destruction of abnormal ones. Leaving the body in the state in which cancer became a proliferating factor and attempting to induce cell death to the cancer seems an incomplete approach. The goal, in my thinking, is to change the entropy of the cells to a positive mode and the patient's body can start doing the heavy lifting of recovery.

Trial of reducing the telomeres of cancer cell chromosome may lead for cell death. This can be performed if the action of the telomerasde enzyme is stopped.

There would negative and positive benefits to each pathway. I would also imagine that the stage of the cancer and type would influence the nature of the therapeutic.

Generally speaking, apoptosis is the preferred pathway for cell death.

Necrosis causes tissue damage in association with cell death of the tumor and has an inflammatory side effect; not necessarily ideal for those with cancer; typically it is accidental.

However, from a therapeutic stand point necrosis may be easier to induce and autophagy may not be effective in aggressive forms of cancer.

Nahi, the telomere angle on the cancer cells is an interesting one. I generally think of telomeres of our DNA and mitochondrial DNA, but had not delved into the cancer cells telomeres. Please, tell us more on your observations on telomeres on cancer cells--how one would go about in practical terms weakening the telomeres of cancer without weakening proportionately the same on good cells.

Hi Max ,

Many studies reported the elongation of telomeres in cancer cell. As much as telomeres are long as much cells stay alive. One of the most factors affecting aging is the shortening of telomeres. Living organisms with long ages show long telomeres on their chromosomes. Hence , one of cancer cells tricks is to keep the telomeres long to guarantee their living state. Molecular studies on telomeres can offer promising approach to kill cancer cells by approaching an access to shorten the telomeres in cancer cell.

For Max and Nahi, Many telomerase inhibitors were tested in pre-clinical models. But, these drugs also kill normal cells( because they have same telomerase and telomere structure). Remaining normal cells may age faster because their telomeres get shorter! So, Telomere length is the main difference between normal and tumor cells....its not enough to get selective death of tumor cells. Lack of selectivity is the main problem with other types of cancer drugs (tyrosine kinase inhibitors, and drugs which induce cell death). That is why we are having this discussion!

Yes, and I am wondering if by one strengthening their health by change of diet to organic, predominantly fresh fruits and vegetables, correction of any and all subclinical infections, appropirate hydration, and abstaining from all irritants or toxicants to the cells, including all possible medications, if such a change would make the normal cells less likely to die during the therapy aimed at the abnormal cells. This has been our experiences, but other than case histories we have no hard data behind such an approach.

Hi Ying-Xin: I personally think this topic is one of the best for the past several months. Everybody put in his/her belief and thought to the bottom of the discussion. I always belief life has its way out so if you bring down one thing the other things will come up so life keeps going. How many times we read a fantastic paper and try to reproduce it in another model then came back the totally opposite way around? Scientists need to keep an open mind so that we will be able to find the truth. Biology is not straight math that will have only one answer, at least in this moment.

Cancer cells exposed to the action of chemotherapeutic drugs and potential anticancer agents can undergo mitotic catastrophe, programmed cell death - autophagy, apoptosis and /or necrosis, and also differentiation or senescence.

Max,

I would not assume that nutrition etc that supports non-cancerous cells won't also support the survival of cancer cells. Cancer cells are, after all, derived from normal cells. IMO, supportive treatment which hopes to lessen side effects also needs to evaluate cancer cell survival and patient PFS & OS.

For example, some thought that fish oil might be helpful during chemo:

http://www.ncbi.nlm.nih.gov/pubmed/21360698

and http://www.ncbi.nlm.nih.gov/pubmed/21328326

but a contrary view from a lab experiment is this:

http://meetinglibrary.asco.org/content/79921-102

(to be fair, there are counterarguments to that, too, e.g., http://lifeovercancerblog.typepad.com/life-over-cancer-blog/2011/09/fish-oil-and-chemotherapy-the-bigger-picture.html)

Or another example: I have a wild speculation that people on EGFR+ inhibitors should not overindulge in green smoothies because a diet extraordinarily high in vitamin K (broccoli, parsley, leafy greens, etc.) might override the drug as described in some research (mainly for vitamin K3 but also an order of magnitude less for K1, per various citations leading to clinical trials of topical K3 and K1 to control skin side effects of EGFR+ inhibitors like erlotinib & gefitinib). I do not know if that K effect is too transient to matter in people, but it seems a consideration. (FYI, some other driving mutations like ALK might also leverage EGFR activity to circumvent inhibitors, too, though it is not known whether that usually matters enough.)

Just offering "food" for thought on your point. ;-)

Teng, I agree completely. One thing that has made this such a good discussion is scientists and clinicians (and these can be one in the same as my philosophy is that we should all be practitioner researchers where it is possible to be so) is that participants have been so considerate of different viewpoints and levels of understanding. An open mind on topics of great import is how we learn and raise awareness.

And Craig raises excellent points on nutrition during chemotherapeutic treamtents. I am aware of the caution on fish oil, but have tried to get to the bottom of whether this caution comes from studies that did not differentiate between commercial (mercury laden and nutrient deficient) forms and that from wild forms and in a well-preserved delivery system (cold processed)? Until the research on such matters differentiates it is difficult to take it as seriously. I've given examples of other nutrients where the researchers disregarded the wide array of forms of a given nutrient, yet painted all with the same broad brush--Vitamin E, for instance has a wide range of qualities (in tocotrienals, tocopherals in organic form) that must be specified in the study but rarely is.

Same with what we call Vitamin D which resembles little the kind of vitamin D the body makes and uses. I think the Vitamin K caution is more straightforward, though, because of its action in almost any form. Synthetic vitamin E and most Gingko Biloba might also fall into that category. But these are things that the scientific community can sort out so that the cautions that go out to the larger population of professionals is more nuanced and accurate. Great discussion, everyone!

Thinking of cancer as a metabolic disease, once the point of no return is reached ( redifferentiation cannot be attained), I believe apoptosis is a very atractive therapeutic intervention.

Max: Well said. We do need view points from both sides or even from multiple angles. As a clinician I have seen so many mishap in my career. Vit E used to be claimed to be the magic bullet but turn out to be no so right. Not long ago I even heard about intentionally to contaminate brain tumorduring surgery to prolong patient's life. It may all sound crazy in some point but they all come from some belief. A long way to go in biologic science.

Teng, Max Vitamin E is a general name for every tocopherol molecule (ther are 8!), as Max stated many studies are not clear what form they have used. Alpha-Tocopherol is the main source found in supplements and in the European diet, where the main dietary sources are olive and sunflower oils, while gamma-tocopherol is the most common form in the American diet due to a higher intake of soybean and corn oil. In addition there are synthetic forms which are the ones mostly used in the studies.

Michael: Thanks for pointing it out. Yes, I do know there are several kinds of vitamin E. One time it was believe that alpha-tocopherol will prevent cancer and cardiovascular disease but the results were not so convincing. It was also believe to prevent intraventricluar hemorrhage and retinopathy of prematurity in premature infants but opposite results popped up. Yes, we do need to have vit E in diet but to simplfy the belief into take pure vit E (a-tocopherol as you like) can prevent diseases will be dangerous. Remember, there must have some other antioxidants in diet to pass down the poteintial otherwise vit E itself will become a potent oxidant when it accept the electron.

I think that to provoke differentiation is the better tratment to study better in the future.

Dear Teng In relation to the studies using vitamin E supplementation, most negative studies use the wrong form or the wrong dose...but your point of the importance of diet is well taken, in addition that each clinical case should be evaluated individually when Nutrients in pharmacological doses. Another important point you mention is the synergistic action of nutrients, specially the vitamin E complex.

Dear Mike:Thanks for pointing out previous studies all used the wrong vitamin E. Hope to see your positive results soon so we can apply to patient treatment.

This is a very interesting topic and a wonderful discussion, so just adding my comments. At first instance and having worked with apoptosis, I would think apoptosis would be a preferred choice as its programmed cell death and specific genes involved in apoptosis may be targeted. But also its known now that cancer cells do develop resistance to apoptosis. It has been shown now that necrosis may be programmed too. Although differences exist we know, particularly in cell shrinkage, DNA degradation patterns, membrane changes and phagocytosis of apoptotic cells in contrast to lysis in necrosis, but molecular mechanisms show that death receptor pathways may be triggered in both. Also stress pathways, eg ROS may trigger both. So, specific tumours may be targeted using necrosis as resistance to apoptosis develops. Furthermore, it is also thought apoptosis to necrosis may be a continuum process occurring in a dose dependent manner, Nicely reviewed by Craig Thompson

http://genesdev.cshlp.org/content/20/1/1.full

http://clincancerres.aacrjournals.org/content/13/24/7271.full

About microRNA, it is another fascinating area for research now, affecting epigenetic mechanisms. MicroRNAs modulate many cellular processes by post transcriptional modification of gene expression leading to translational silencing. They are particularly known to be targets in the p53 pathway, which is frequently mutated in human tumours. MicroRNAa are found to be reduced in many tumours. Mirna Therapeutics clinical candidate mimics MicroR34, affecting genes such as Myc, Bcl2. Recent studies also show the effect of MicroRNA34 on expression of CD44 expressed in cancer stem cells (shown in prostate cancer) inhibiting both tumour development and inhibition of metastasis in animal models.

http://www.mirnarx.com/___Pipeline/Pipeline_MRX34.aspx

http://www.genomeweb.com/rnai/qa-md-andersons-dean-tang-talks-mir-34a-and-its-role-prostate-cancer

Apoptosis has taken a central position in cell death research. However, it becomes more and more clear that cells can also die by non-apoptotic mechanisms, such as autophagy and /or programmed necrosis. Mitotic catastrophe, cell differentiation and senescence should be also taken into consideration as processes occurring during chemotherapy.

"Pathways of apoptotic and non-apoptotic death in tumour cells", Nature Reviews /Cancer, 2004

"Apoptosis and non-apoptotic deaths in cancer development and treatment response" Cancer Treatment Reviews, 2008

It's a great discussion. I've learned a lot from this discussion, especially liked the posts of Ru-Jeng Teng.

Dear Teng I work with Vitamin C but here are some interesting literature on Vitamin E. We have used the Vitamin E complex succesfully in our Clinic fo ra myriad of circulatory diseases such as intermmitent claudication and atherosclerosis.

http://lpi.oregonstate.edu/ss02/blumberg.html

http://orthomolecular.org/resources/omns/v06n25.shtml

http://www.clinchem.org/content/46/9/1401.full.pdf

http://www.doctoryourself.com/shute_protocol.html

http://orthomolecular.org/resources/omns/v01n01.shtml

I would like to introduce some evolutionary perspectives of the cell death and its impact on the genome (rather than genes or specific pathway or bio-reaction) into the discussion.

Following papers can provide an outline of our genome based ideas.

http://www.ncbi.nlm.nih.gov/pubmed/23548436

http://www.ncbi.nlm.nih.gov/pubmed/21716293

The point of treatment is to stop the cancer cells from doing what it is that makes them cancerous-- proliferation, to the point of developing from a squatter in a new location to a usurper of its resources and changer of the environment. A choice of how to stop the proliferation can work better on some cell types rather than others, and you can poison (especially differential uptake during mitosis), incinerate, remove, nuke, microwave, encapsulate, starve, chill or freeze-- but the " best" mode is the one that will harm the surrounding tissues or system the least while changing the balance of the fight to favor the natural immune system and natural waste clearance (lysosomal content shouldn't be dumping into the environment, BTW-- in degenerating tadpole tail, although outside it may look like a mess, at the cellular level everything is neatly packaged and there is no extracellular debris, you are repurposing at the molecular level).

The relative value of a method to stop proliferation is entirely dependent on the nature of the tumor and its stage-- when advanced, extirpation is almost always done-- you don't threaten a million-strong invading army with economic sanctions. Of course we would expect it to be a nicer outcome if we could convince the army to go on a self-imposed hunger strike and slowly waste away in place without any bother to anyone, just desiccating and evaporating without any fuss (apoptosis). However, natural apoptosis, such as in the hand paddle during finger formation, takes serious developmental time (two weeks for a human embryo), a luxury you may not have in combatting a tumor; plus the programming is highly dependent on signals from the natural surrounding tissues, and tumor cells are like children with their fingers stuck in their ears.

But this is not to say that exploiting apoposis isn't a great means of controlling the embedded secret agents of the army-- the many cell seeds that can be triggered under the right circumstances. I suspect this can be the effectiveness of various topical medications for skin rashes and lupus.

Dear Michael:

I am glad to read those information and they are interesting althougfh they are not RCTs. I read the most recent meta-analysis including more than 219 RCTs about this topic and interesting.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0056803

The meta-analysis from recent Cochrane showed

Farina N, Isaac MGEKN, Clark AR, Rusted J, Tabet N. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD002854. DOI: 10.1002/14651858.CD002854.pub3. -

See more at: http://www.thementalelf.net/publication-types/systematic-review/new-cochrane-review-says-that-vitamin-e-should-not-be-used-to-treat-dementia/#sthash.JcezxblP.dpuf

Regarding Vit E in ROP, it seems promising but for some reason we are still not using it as standard of care for:

"Vitamin E therapy has also been reported in association with a greater incidence of intraventricular hemorrhage in the premature infant. Additional study is necessary to determine the possible efficacy of vitamin E in preventing ROP."

The most recent Cochrane review said:

Giving extra vitamin E to preterm babies can provide some benefits, but it increases the risk of life-threatening infections. Preterm babies (born before 37 weeks) can develop a range of problems because their organs are not mature. Vitamin E may be able to help prevent or limit some of these problems, but it can potentially also have harmful effects. Breast milk of a woman who has given birth prematurely has higher than usual levels of vitamin E. Preterm babies can be given extra vitamin E as vitamin drops, in vitamin E-enriched formula, in intravenous fluids, or by injection into their muscles. This review of studies of vitamin E supplements found that while extra vitamin E reduces the chances of some complications (including disease of the retina), the risk of life-threatening infection is increased. The risk of bleeding in the brain is increased when extra vitamin E is given by vein but decreased when the extra vitamin E is given by other routes. - See more at: http://summaries.cochrane.org/CD003665/vitamin-e-supplementation-for-prevention-of-morbidity-and-mortality-in-preterm-infants#sthash.fiMfsJXD.dpuf

When we treat patients in certain way we also need to consider the context. If we only focus on one benefit and literally ignore the potential harm when treating patients then it becomes dangerous. But I still want to congratulate you for your success. I have no doubt that appropriate level of vitamin E in our body is vital for health but in our practice when multivitamin is given very early on in life I proably will be very cautious about providing extra vitamin E.

I would be in favor necrosis (programmed one or not), rather than apoptosis, because there is an inverse relationship between apoptosis (basal apoptotic rate before chemotherapy) and patient prognosis, according to our and the others' studies (Ulukaya E, Lung Cancer, 2007; Haas EC, Neoplasia, 2010; Koelink PJ, BMC Cancer 2011, etc). This is a really interesting phenomenon!. The better apoptosis, the poorer survival!?... I would appreciate the comments on this interesting result!. All the best...

Ulukaya,

Your bring up an interesting point.

After further investigation, i hypothesis that this is due to the limitations in current cancer therapeutics that induce apoptosis in cancerous and non-carcerous cells.

More apoptosis producing factors, more increased risk for healthy tissue damage, and thus a lower life expectancy for cancer patients.

Potentially molecular targets may be developed to avoid this side effect.

Indeed, chemotherapy lead to adversary when not selective to the cancer cells. As far as I know necrosis is highly toxic, so I think the best way is to bring apoptotic agents specifically to the cancer cells and not to other dividing cells.

Dear Tang we off the topic here, but two landmark studies published in the New England Journal of Medicine [1][2] followed a total of 125,000 men and women health care professionals for a total of 839,000 person study-years. It was found that those who supplement with at least 100 IU of vitamin E daily reduced their risk of heart disease by 59 to 66%. The studies were adjusted for life-style differences (smoking, physical activity, dietary fiber intake, aspirin use) in order to determine the heart effect of vitamin E supplementation alone. Because a diet high in foods containing vitamin E as compared to the average diet further showed only a slight heart-protective effect, the authors emphasized the necessity of vitamin E supplementation.Researchers at Cambridge University [3] in England reported that patients who had been diagnosed with coronary arteriosclerosis could lower their risk of having a heart attack by 77% by supplementing with 400 IU to 800 IU per day of the natural (d-alpha tocopherol) form of vitamin E.

Among other things, vitamin E supplementation:

* reduces the oxygen requirement of tissues. [4]

* gradually melts fresh clots, and prevents embolism. [5]

* improves collateral circulation. [6]

* prevents scar contraction as wounds heal. [7]

* decreases the insulin requirement in about one-forth of diabetics. [8]

* stimulates muscle power. [9]

* preserves capillary walls. [10]

* reduces C-reactive protein and other markers of inflammation [11]

* Epidemiological evidence also suggests that a daily supplement of vitamin E can reduce the risk of developing prostate cancer and Alzheimer's disease. [12, 13].

References

[1] Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444-1449.

[2] Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328:1450-1456.

[3] Stephens, Nigel G., et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). The Lancet, Vol. 347, March 23, 1996, p 781-86.

[4] Hove, Hickman, and Harris (1945) Arch. Biochem. 8:395.

[5] Shute, Vogelsang, Skelton and Shute (1948) Surg., Gyn. and Obst. 86:1.

[6] Enria and Fererro (1951) Arch. per Ia Scienze Med. 91:23.

[7] Shute, Vogelsang, Skelton and Shute (1948) Surg., Gyn. and Obst. 86:1.

[8] Butturini (1950) Gior. di Clin. Med. 31:1.

[9] Percival (1951) Summary 3:55.

[10] Ames, Baxter and Griffith (1951) International Review of Vitamin Research 22:401.

[11] Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine, 2000;342:836-843.

[12] Ni J, Chen M,Zhang Y,Li R,Huang J and Yeh S. Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery. Biochem Biophys Res Commun 2003 Jan 10;300 (2):357-63.

[13] Morris M C,Evans D A,Bienias J L,Tangney C C et al.Dietary intake of antioxidant nutrients and the risk of incident Alzheimer's disease in a biracial community study. JAMA 287(24):3230-3237.

Dear Tang you mention that when we treat patients in certain way we also need to consider the context. If we only focus on one benefit and literally ignore the potential harm when treating patients then it becomes dangerous. That describes what conventional medicine does especially in cancer treatment .We are very cautious about providing any type of therapy, always thinking in what will be of more benefit and less toxicity to the patient. Its been a great discussion with you, thank you for your time and now I have a new friend and collegue!

Hi Michael: Again, I would like to point out there is always two-side story. Yes, there were numerous field studies showing the benefit of vitamin E. I have no doubt it is going to benefit certain type of patients. I raise the issue simply trying to express there are so many things we do not know. RCT is considered a most resonable way to prove the hypothesis clinically whereas meta-analysis is the considered the best analysis for clinical trials. We just need to be cautiouis about how to interpret the results. Serious discussion can always help us to understand better science. Feeling is the same for me.

In my opinion there is no a single answer, as always happens with Cancer. We should try to combine clinical data with pathology and cell biology data. There are cancer types where is "absolutely" normal and expected by the pathologist to have a 15%-30% of necrosis, and they take this as a sign of enhanced malignancy or aggressiveness (e. g. Pancreatic Ca.). Other cancer types do not present necrosis, nor a single indication of apoptosis and they are described by this (e.g. Thyroid Ca, PTC).

Thus, the different effectiveness of the cancer therapies we use in the clinics empirically is reflecting different biological mechanisms in cancer-"s".

What is really interesting is: a similar type of cancer use to present a group of common characteristics (% necrosis, % apoptosis, % mitosis) in all patients (of course within a range).

I respectfully disagree with Engin, necrosis is too uncontrolled, traumatic and sort of unregulated, while apoptosis is more controlled, regulated and less traumatic. I'm not sure what survival your refer to.

Could you be so kind to send me an electronic version of your study?

[email protected]

Thank you!

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478976/pdf/1479-5876-10-162.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276978/?report=printable

Dear Teng I concur totally with your excellent comments! Keep in touch!

[email protected]

Teng and Michael, my two cents on the metastudies on Vitamin E, we find problems with most of the studies as they treat all forms of Vitamin E as if equal. By including the studies featuring synthetics or even the inferior and questionable commercial forms of "natural" d-alpha tocopherol (which is essentially ruined by over-processing or storage problems) with the higher quality and more complete tocopherol/tocotrienals essentially negates the meta analyses' results. This is why I've called for researchers to carefully define what they are studying rather than lumping all forms together as if equal. It seems--and this not meant to be a reflection on any particular researcher but a is practical matter--we have a long way to go in educating scientists who conduct such studies to know that only the bioavailable forms are worth our time in studying. The dead, sterile, and synthetic forms might might good controls, though, as they represent the majority of wha tthe public takes today. Getting back to the question at hand (apoptosis vs necrosis) I concur fully with Michael on the conrollability factor of Apoptosis, and also that it is critical to note the context, or the larger organism, in this case. In deciding efficacy in cancer treatments, it is just as important or more to understand how the normal cells will respond when the aim is to kill the abnormal cells. Thanks to all of you for a great discussion!

Max those two cents went a long way! Were those 1943 steel pennies? Its been a great discussion forum! Thank you for this opportunity!

We're in New Zealand visiting family and I still don't have the exchange rate figured out!

Recently, three types of programmed cell death, namely apoptosis, necrosis, and authophagy have been distinguished. Different therapeutic drugs and potential anticancer agents can induce programmed cell death. Cancer cells can undergo apoptotic, necrotic, and/or autophagic cell death.

Hi Michael (and to the others as well),

Thanks for your reply/comment (sent the paper to you as well). However, i meant the basal apoptosis before the chemotherapy (nothing to do with the treatment). The paper you mentioned refers to the apoptosis after chemotherapy (but i do not agree with that paper at all). Why i prefer necrosis (now this time i mean the necrosis following chemotherapy) to apoptosis is that to kill the tumor cell together with its microenvironment may be more important than killing the tumor cell only. To achieve this, massive cell killing effect (using necrotic agents!) against whole tumor mass may be more appropriate. But of course, in this scenario, the drug should spesifically be directed to the tumor tissue, sparing the other organs. Saying again, i just wanted to give a spesific and short comment to the original question brought up by John. In brief, inducing necrosis across the tumor mass seems, to me, a better idea for some reasons including the provocation of immun system as well. Kind regards...

Dear Engin I see your point! Your point of view is valid if you consider cancer a genetic disease. I still see cancer as a metabolic disease in which mitochondria would be key either to redifferentiate the malignant state (revert the cancer cell back to normal)or induce apoptosis(eliminate the cancer cell).

Ulukaya,

Some studies due indicate that basal apoptosis levels correlates with sensitivity to proapoptotic stimuli during treatment(attached); making treatment less effective in killing tumor cells. Treatment with proapoptotic stimuli in these cases may lead to more damage to the underlying tissue.

You are right, in cases were basal apoptosis levels are extremely high, necrotic induced treatment maybe more effective to protect the integrity of the immune system.

However, in cancers with Low BAR, assisting the immune system via pro apoptotic stimuli would probably be more effective method of cell death.

Thus, BAR should be a paramount factor when deciding cancer treatment.

http://www.ncbi.nlm.nih.gov/pubmed/20630997

After application newly synthesized potential anticancer agents, leukemia cells undergo mitotic catasptrophe, differentiation, and programmed cell death - apoptosis, necrosis and autophagy. The antileukemic activity is dependent on the agent tested and its dose, the time intervals after the agen application, and the leukemia cell line used.

FWIW, from the point of view of patients the answer might be "all of the above and simultaneously if not fatally intolerable." Choosing one might matter to a choice of what agents and processes you research, but ideally patients need to kill or control (1 year+) every cancer cell possible, not just a majority which responds to one or another approach.

Hello John, Hello all, I am ignorant however besides killing cells I made a synapses to what Prof Bonnie Bassler of Princeton does. She talks about signaling harmful bacteria to stop they work. I know many drugs try to signal cells but her work may seem an alternative to killing

Excellent work, too, Jose. The body's own immune sytem also signals in that fashion, but in cases of acidosis or where oxygen is low, it cannot, and harmful bacteria (and abnormal cells) thrive.

Thanks Max ! It reminds me also words of Dr. Marti Bosch talking about the usual acid environment of tumours and the basic PH inside of them. Prof. Bassler achieves to silence a group of bacteria that stop shining which is the normal behaviour. The point here would be to mislead cancer cells so they either stop to divide or stop signalling other cells as they usually do in Hodgkin lymphoma for example.

We seem to be straying a bit from the original topic, but FWIW I thought cancer cells are usually slightly more alkaline inside than normal cells, and it is only their exterior environment that is somewhat acidic (due to pumping out the acid): https://www.researchgate.net/post/Why_do_cancer_tumor_cells_have_lower_pH_and_higher_temperature

Fans of the so-called alkaline diet fans don't like hearing that (and that blood pH can't be change outside a narrow range without causing death).

Craig read this article:

http://www.metadocs.com/pdf/publications/0707_minich.pdf

Michael -- That article seems off-topic because it doesn't mention cancer let alone the internal pH of cancer cells vs. non-cancerous cells. IMHO, most of the article seems to talk about how to change the pH of urine through dietary choices, which isn't measuring blood pH but just what the body is successfully removing to maintain blood pH in its optimal narrow range 7.35-7.45.

Uthe,

The title of the article is "preclinical and clinical estimates of the basal apoptotic rate of a cancer patient predicts the amount of apoptosis induced by subsequent proapoptotic stimui"

It is relevant to a cancer discussion of apoptosis versus necrosis induced cell death in cancers.

Michael -- Is it possible you provided the wrong link? The link you gave goes to "Acid-Alkaline Balance: Role in Chronic Disease and Detoxification."

Craig, the link that Michael Gonzalez gave for http://www.metadocs.com/pdf/publications/0707_minich.pdf was indeed on the acid increase in the modern (US) diet that has fostered an increase in metabolic disease, including cancers. I am not familiar with the article to which Michael Mannen referred, but am familiar with the concepts he describes.

..and on your comment on cancer cells being more alkaline, our findings are that cancer cells are always more acidic than normal cells and have to mutate to even grow with oxygen..so as Micheal Gonzalez' pointed out, metabolism mechanisms are critical to any viable cancer treatment regimen. Such is disregarded at peril of the patient's chances of changing the entropy of their body's cells back to normal status.

You are quite right, Max, that my last two comments were regarding Gonzalez's recent link, not Mannen's older comment from days earlier. Thank you for clearing that up.

Regarding relative acidity of cancer cells, I must defer back to the discussion I referred to at https://www.researchgate.net/post/Why_do_cancer_tumor_cells_have_lower_pH_and_higher_temperature

regarding the need to distinguish between intracellular vs. extracellular pH of cancer cells relative to other cells. Based on that discussion, I assume some common tests reflect the pH outside the cancer cells or some kind of average after breaking open cells rather than specifically intracellular pH.

I see what you're talking about, Craig. Just a cursory review of the answers I looked at, Christine and Felipe's appeared to be sound answers. I was glad to see Christine mention the Kreb's Cycle, which is the intra/extra cellular mechanism that really matters and differentiates normal and abnormal cells. pH at the cellular level is not a static state, but a rapid cycling issue. Theoretically, we are not supposed to see healthy appearing patients walk in with 6.8 blood pH, but we do in our clinic quite often, actually. Likewise, we have determined that a cell that drops under 7.0 before self-correction is an abnormal cell and the blood pH is also exceptionally low (meaning it cannot draw enough calcium--or bicarbonate--quickly enough to keep up with the pH needs of the cells--this seems inevitably to encourage abnormal cell growth. We feel as Michael Gonzalez and his colleagues that metabolism plays THE major role in the development of abnormal cells, and the best correction always begins by metabolic correction. Without metabolic correct, treatments for cancer are futile and prolong the suffering and cost of care immensely.

PS- one does not make their body more alkaline through eating more alkaline foods, as you pointed out. Our bodies require a mix of acidic and alkaline foods and it corrects itself in the metabolism process. The blood is not quite as stable in pH as many have supposed, either, we see huge swings in blood pH at the clinical level, and often wonder aloud how one can maintain their pH when they have lost a sizable portion of their bone calcium stores, as we in advanced osteoporosis cases. But Michael and his colleagues are correct that diet is the most important factor, both in causing acidic states and in overcoming chronic disease, but again we rarely see this considered in current maisntream practice around us.

The point that I wanted to make is that even subtle pH changes can have a metabolic impact. I concur with Craig's comment on differences in intracellular and extracellular pH that may add to the confusion. We have also seen cancer cells as acidic due to their high use of anaerobic glucose as energy source. In short it is related to its high glycolitic activity that maintains a high metabolic rate and the production of lactic acid.

Here's the link to the article referred by Mannen:

http://clincancerres.aacrjournals.org/content/early/2010/08/20/1078-0432.CCR-10-0859.full.pdf

Dear All, a great discussion has been ongoing here! I benefit a lot. Thanks. Just yesterday, what we have observed is that metabolic activity of cancer stem cells seems to be lower than cancer cells. I cannot give you the details right now but this is our suspect... Any comment on the metabolism of cancer stem cells in comparison with the cancer cells would be appreciated...

High rates of glycolysis, glutaminolysis, and acidic nature of cancer cells have been known for awhile. Now, we know that tumor cells also are lipogenic. But, what are the consequences of these metabolic changes?? Changes in pH are discussed above..but what damage or molecular changes result from it? Afterall, tumor cells manage well under hypoxia--perhaps they can do so with pH swings as well? SO, we need a cause-effect data linking metabolic changes with a changed tumor cell phenotype!

Ulukaya,

Embryonic and adult stem cells exhibit reduced mitochondrial activity and are more dependent on glycolysis. It would make sense, therefore, that cancer stem cells exhibit similar characteristics when compared to other cancer cells. I am wondering how the metabolic rate in CSCs compare to their traditional SCs counterparts. This area shows some promise for devising cancer therapeutics.

http://www.ncbi.nlm.nih.gov/pubmed/24030970

Pointing to the differentiation of malignant vs normal and so targeting molecular treatments or avoiding side effects or even targeting metabolic changes, the review work of Brescia P, Richichi C, Pelicci G (2011) Identification of Glioma Stems cells: what is already known and how far do we still need to go? The biomarkers dilemma doi: 10.4172/2157-2518.S1-003. Remind us that either there is no clear differentiation or we are still learning to differentiate them. The point of Max about reverting or reprogramming the cancer cells is connected to what Bonnie Bassler does. I would dare recommend you to contact her.

In cancer cells, the shift to a sugar-busting metabolism is known as the Warburg effect. The Warburg effect sets in motion the biochemical activities that provide the fuel and materials required for rapid tumor cell growth and division.

The Warburg effect in embryonic cells, may serve a similar function in preparation for the dramatic burst of embryonic growth of division without diferentiation.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583110/pdf/IJCB2013-805975.pdf

I'm glad you bought up Warburg's Hypothesis, Michael, as more and more research is vindicating his original research going back to 1924 and reiterated in 1966 found at http://healingtools.tripod.com/primecause1.html/ for anyone that would like to read it. Further, we see evidences of everything he described many years ago and wonder why this is not common knowledge in the oncology field today.

Here are some interesting papers:

https://www.researchgate.net/publication/229325765_The_bio-energetic_theory_of_carcinogenesis

http://www.nutritionandmetabolism.com/content/7/1/7

http://www.ncbi.nlm.nih.gov/pubmed/11601863

Article The bio-energetic theory of carcinogenesis

Apoptosis is one of the target however, a) starvation and killing 2) linking metabolomic biomarker data to proteomic and transcriptomics may prove good to understand best targets to kill cancer cells as they display anoxygeny, lipogeny, differential polyamine...... . metabolism

That depends on many factors like-

1)location of the cancerous cells

2) type of the cell

3) stage of the cell (has it acquired malignancy?)

Surely killing a cell through apoptosis would be better option as it would reduce many other unwanted side-effects related to untimely cell death or necrosis.