Another complication added to the whole scene is that by the time tumor is detected, it is too late and it might have under gone metastasis. The inner core of tumor mass "loves"  hypoxic condition that helps it generate HIF1alpha, HIF2alpha (endothelial and cancer stem cells) and  HIFbeta.  These HIFs help produce VEGF for angiogenesis.  Hypoxia also leads to the production of reactive oxygen species..most tumors tolerate certain amount of ROS.

The cancer stem cells, may not be affected by any treatment due to an excellent Bcl-2 system, presence of ABCG2 type of pumps for multidrug resistance, being in Go phase of cell cycle etc.  Friends this is great discussion on the complexity of cancer and why it is so diffficult to plan a perfect treatment.

Dear colleague, I suppose that there can not be one definite and universal strategy. This situation comes from cancer pathogenesis. On the one hand, oxidative stress can potentially lead to cancer due to ROS-induced DNA damage. At the other hand, ROS are required for cell cycle and apoptosis regulation, consequently, their impairment may also lead to carcinogenesis.

That is why therapeutists have to turn to the principles of personalized medicine. Particularly, in every patient "basal" antioxidant system activity needs to be estimated. Based on the results of this analysis, the oxidant/antioxidant therapy may be prescribed. However, the methodology for this analysis needs to be improved.

I hope that my subjective view on this problem may help you.

Hi Dear Tinkov, I appreciate and thank you for your subjective view.

Effect of oxidative stress  in cancer cells will depend on the degree of stress.  Hence, a double edged sword. Small amount of stress will lead to PARP activation and repair DNA with minimal loss of energy.  However, excessive oxidative stress can lead to three scenerios (1) apoptosis (2) Necrosis due to depleletion of too much ATP that is used in PARP related repair (3) mutations and more carcinogenesis.  Please aldso note that tumor cells are highly glycolytic  and have a well defined pentose phosphate cycle.  Hence, they can also produce large amounts of glutathione to overcome oxidative stress.

As previously mentioned, there are groups who work on both sides of ROS. I guess it would depend on how much oxidative stress the cells are undergoing, and if it is promoting tumorigenesis or killing cells. Some healthy cells also have high levels of ROS (eg, melanocytes) so targeting ROS alone might not be the right strategy.

Moreover, the problem of possible affection of "healthy" cells may be solved by the direct delivery of the chemical agent into the tumor.

Another complication added to the whole scene is that by the time tumor is detected, it is too late and it might have under gone metastasis. The inner core of tumor mass "loves"  hypoxic condition that helps it generate HIF1alpha, HIF2alpha (endothelial and cancer stem cells) and  HIFbeta.  These HIFs help produce VEGF for angiogenesis.  Hypoxia also leads to the production of reactive oxygen species..most tumors tolerate certain amount of ROS.

The cancer stem cells, may not be affected by any treatment due to an excellent Bcl-2 system, presence of ABCG2 type of pumps for multidrug resistance, being in Go phase of cell cycle etc.  Friends this is great discussion on the complexity of cancer and why it is so diffficult to plan a perfect treatment.

There has been a lot of work on this topic and it has been clearly shown that increased ROS in and around a tumor is immunosuppressive. ROS kills T cells and NK cells. So a strategy to eliminate ROS should improve outcomes when using immune-stimulating treatments, like IL-2 or including checkpoint inhibitors. This has been proven in clinical trials using histamine as a way to block ROS production by macrophages and monocytes in tumors, plus low dose IL-2. In stage 4 melanoma, the combination improved survival 6-fold in patients with liver metastases (published in JCO) and the combination is approved in Europe as a remission maintenance therapy in AML. In the randomized trial, the number of patients in life long remission was doubled. If you search Kristoffer Hellstrand, you will find much of this work. The AML trial was published in Blood. Many of these papers can be downloaded from my RG page.

Just to add another short note on glycolysis: Tumor cell glycolysis can be about 200 times higher than normal cells. Plus GLUT1, GLUT4 are over expressed in tumors.  Glycolysis via Pentose phosphate pathway also provides sugars for nucleic acid synthesis in fast growing cells.

Mitochondrial contribution can not be completely ruled out. Some of the recent publications have shown that in tumors there is a truncated Krebs cycle where glutamine is fed into the cycle via glutamate and alpha keto glutarate, which is sufficient to meet energy demands of highly proliferative cells.. Hence, glutaminanse is also an interesting theraperutic target. Here are some useful citations:

Cell Research (2013) 23; 724-727

Genes Dev.(2012). 26: 877-890

Molecular Cancer (2013) 12:152

some other factors can also hamper the process of apoptosis. fat deposits in cells can result in the production of some chemicals that can block the death of abnormal cells/initiated cells via apoptosis.

Interesting question with no simple answer. All cells can tolerate some ROS levels since their production is a natural product of cellular respiration. Not all cells have the same capacity to generate or tolerate the consequences of ROS, or other reactive species, that can damage nucleic acids, lipids and proteins and so also affect cell fate. Moreover, not all cells that tolerate high levels of ROS do so by using the same “system”. This is a really great example of the fundamental importance of considering cellular context in understanding biology.

Many cytotoxic drugs and other antineoplastic therapeutic interventions act by increasing ROS and other reactive species above cells’ respective abilities to detoxify. Antioxidants can often reduce the efficacy of interventions that do so.

Not only is the capacity to manage stress determined by the cancer cells themselves, and varies with the cellular heterogeneity evident among solid cancer cell populations, but it is likely also affected by the nature of the tumor microenvironment. We likely still have a lot to learn about a very basic component of cell metabolism and response to stress.

There is no simple answer here. The real answer is "It depends". It depends on the antioxidant and it depends on the type of chemotherapy. For example, the use of cysteine-rich glutathione precursors have the effect of down-regulating glutathione in cancer cells and up-regulating them in "normal" cells. A good clinical study looking at this approach in lung cancer patients receiving chemo/radiotherapy can be found here: http://online.liebertpub.com/doi/pdf/10.1089/ars.2007.1919

Yes the answer is not that simple. Cancer cells possess a different oxidative homeostasis whereby the ROS levels are high and so the redox defense system any alteration will disrupt this balance and can succumb cancer cells to death. ROS is required by the cancer cells to proliferate and survive in conditions with high glycolysis. Hence if we increase the ROS levels with Pro-oxidants it will cause deleterious effects on cancer cells selectively. However  normal cells possess different oxidative homeostasis and hence are not affected by pro-oxidants. On the contrary cancer stem cells have low ROS levels in comparison to other tumor cells. hence its difficult to judge but pro-oxidants are considered to be selective and have given satisfactory results in chemotherapy.

I would have to agree with Alaaeldin A. Hamza, above. ROS can have different roles in cancer cells. Hence,  in cancer cells, antioxidants can either lead to cell death or protect them and lead to enhanced proliferation. I have observed both vitamin C and N-acetyl cysteine to kill leukemia cells either alone, or with chemotherapeutic agents in an additive manner. On the other hand, both antioxidants protected prostate cancer cells from the effects of chemotherapeutic agents. So, again, it depends on the cell and on the role of ROS in the cells. There are a lot of reports on the dual role of ROS in cancer including killing of leukemia cells with antioxidants since these cells rely on ROS for their growth and survival. On the other hand, pushing these cells over  a certain threshold with pro-oxidants, can also lead to cell death. Bottom line, it depends, it depends...This is why cancer treatment is so complex.

Good question but difficult to answe due to complex cancer metabolomics.

According to the latest literature (see attachment), I think it is the sword of Damocles. 

It may be due to the drug time-window, and the status of pro-oxidant or anti-oxidant drugs should be re-considered in different time-points after using different treatment regimens.

I've just read the following on the topic: The promise and perils of antioxidants for cancer patients. Chandel NS, Tuveson DA. NEJM 371:177, 2014. I think it can be useful to this discussion

Ask yourself: Is there any widely accepted literature on vitamins like vitamin C or E as anti-oxidant reducing cancer growth or prevalence with a high yield? To the best of my knowledge the answer is no, especially not for cancer growth in established cancer. For prevalence there is a tendency for positive influences.

In bulky NSCLCs we see sometimes intratumoral abscess formation which parallels the increase of ROS content of such tumor: If patients survive such an event, the tumour appears to be reduced in volume sometimes. In that understanding of biology I would expect that the increase of ROS intratumoral could be a therapeutic option.

Of note is the fact that there is an increase in literature about exercise (18mets /w, divided over several events per day) as treatment option in established cancer, very well shown with a high impact of tumor-related OS for mCRC and breast cancer. One of the pathways could be the HIFalpha which is influenced negatively by an AUC of higher pO2-levels - even intratumoral.

very interesting topic especially in regards to tumor related  mOS 

To read:

Holmes et al, JAMA 2005, 293: 2479-86

Tan et al. Clin Cancer Research 2009; 15(22)

Meyerhardt JA et al., JCO (2006)24: 3527-34

Haydon AMM et al.: GUT (2006)55: 62-67

Kind regards,

Wolfgang

It has been a good number of years since the subject of antioxidants' effects on chemotherapy had been addressed. Here is a 2007 meta analysis which clearly suggests that antioxidants are a good complimentary approach. http://www.ncbi.nlm.nih.gov/pubmed/17283738

Hi Jimmy,

this is a non-selective meta, partly observational..- why are non of these results are in current guidelines even 7 years later? I do not know any repeatedly convincing non-observational study of large volume using antioxidants as therapeutic factor in regards to tumor related mOS improval. If so, they should be in the guidelines.. Of course we have the general suggestion of mediterranean food but this counts as well for cardiovascular health ... for any kind of health...

On the other hand, there is as well literature that supplementation of vit. E for instance enhances tumor prevalence..

Thanks for the link, if you have this as original, I would ask you if you can send me this as pdf: [email protected]

MANY THANKS

Wolfgang

For me, it shuld be both, a pro and anti-oxidant 

Very interesting discussion.

Most of chemotherapies induce free radical  production, which is not good for healthy cells. The problem is to induce oxidative stress only in cancer cells.

And some works show that this can be done by changing the membrane potential of cancer cells and their mitochondria (which are hyperpolarized) and this bring back natural oxidative stress (which can be helped by a targeted and reasonable chemotherapy). Terpenes and molecules in essential oils are molecules that can do this membrane changes which permit apoptosis again.

Antioxidant is interesting in preventing cancer as it is probably linked to a chronic oxidation of DNA (with chronic inflammation).

It can also helped I think at any time as everything that can boost the antioxidant status (in particular glutathione and increasing the activity of SOD) and immune system should be good. My personal view: you don't heal a patient by a single hard molecule, you provide him  arms to fight with his own defenses.

Concerning the antioxidant studies in general, why do they use only one antioxidant , for ex vitamine E (and not with minerals + polyphenols +  glutathione precursors) and why in only one chemical form ..?  When there are more than 30 isomers of vitamin E. Studies with antioxidant in fruits and vegetables work better.

A very complex topic indeed. The balance between endogenous pro-oxidant and anti-oxidant species is key to maintaining cellular homeostasis. Our experience screening compounds with pro-oxidant and/or anti-oxidant properties on various individual cell lines and in vivo tumor models suggests that the anti-oxidant and/or pro-oxidant effect of certain compounds is more to do with the nature of the chemical (antioxidant) in question. Activation of key intracellular antioxidant signaling pathways such as NRF-2 for example does not directly correlate with enhanced cellular survival or resistance to simulated oxidative stress environment. Modulation of XCT- receptors enhancing cystine uptake which upregulates GSH production can also paradoxically increase free radical generation and stimulate apoptotic cell death. We see varying degree of cytotoxicity or cytoprotection with pro-oxdants/antioxidants respectively in cell lines exposed to various insults generating free radical formation such as hydrogen peroxide, cobalt chloride, serum dperivation, various mitochondrial toxins, light of different wavelengths and many other models. Of much interest are the sulphur antioxidants having unique properties such as modulating the cells own endogenous antioxidant defense architecture and  their redox status. In animal tumor models we see a decrease in tumor volume after treatment with certain concentration range of antioxidants. Certain concentrations can shift the balance to promote and accelerate tumor growth and metastasis to a certain point. This have been reflected in the antioxidant status of the animal model in question. Often seen in these models a positive response to a particular antioxidant treatment is not directly correlated with serum antioxidant status of the animals. Other factors such as nutritional status, tumor volume etc. can also influence the tissue redox state.  

There will not be a simple answer to the question. One example from Nature in 2011 is quoted below that invokes the role for immune function. The recent review in Current Biology provides a great "big picture" view in their Fig. 1 to explain the conundrum.

DeNicola et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature (2011) vol. 475 (7354) pp. 106-9

Schieber and Chandel. ROS Function in Redox Signaling and Oxidative Stress. CURBIO (2014) vol. 24 (10) pp. R453-R462

The effects of oxidative stress on cancer cell biology might be strictly related to the stage of the tumourigenesis. In simple words, while in very early stages ROS might contribute to malignant transformation, in advanced stages the cancer cells need to adapt their anti-oxidant defense to cope with very high ROS level to avoid cell death. Consequentially, anti-oxidant/pro-oxidant compounds might have contradictory effects when used at different stages. The master regulator of oxidative response, Nrf2 was considered in the past a canonical tumour suppressor for its antioxidant ability. Recent evidence have instead highlighted that expression of Nrf2 and its target genes in cancer cells sustain proliferation because they neutralize the toxic effects of ROS.

I suggest this interesting review article Gorrini C. et al, Nature Reviews Drug Discovery 12, 931–947 (2013).