Dear Harikrishna Reddy, it would be great to target either glycolysis, which is typical for cancer cells, or to target high glucose demand, what we are trying to do… Warburg suggests that cancer cell have about 200 times higher glucose demand and overexpresion of GLUT transporters. Best, Tomek

Hmm that would mean blocking respiration selectively, cbd.run from the cure.

Blocking of respiration in mitochondria results in mitochondria dysfunction. ..which results to decreased of ATP production results in cell death.

Am I correct Blazej Niewiadosmki.

I don't think this relation is that simple. More of all, tumor environment is usually acidic, which may one way or else speaking about anaerobic respiration too ( several past reference on that). I can only speak for this. But one thing is there, the death receptor pathway is to some extent mitochondria dependent.....But again, I don't think this is also linearly related.

In cancer mitochondria are already changed - retarded. They are either blocked or their metabolism is changed, slowed down or switched to protein production. The main source of cancer cells energy comes from glycolysis (low efficiency but no oxygen). This is called Warburg effect (Nobel prize), and has already been employed in cancer diagnosis – PET tomography (2-deoxy glucose with positron emitting fluorine isotope).

thanks a lot for your valuable information. Tomasz

Dear Harikrishna Reddy, it would be great to target either glycolysis, which is typical for cancer cells, or to target high glucose demand, what we are trying to do… Warburg suggests that cancer cell have about 200 times higher glucose demand and overexpresion of GLUT transporters. Best, Tomek

Hi - remember that cancer cells typically display glycolysis rather than mitochondrial respiration so I'm not sure if targeting mitochondria would be a good strategy.

The Mitochondria plays a central role in cancerous cells and is responsible for many of the hallmarks of cancer; including altered metabolism and resistance to apoptosis.

Recent research has shown that genetic alterations in mitochondria lead to the dysfunction typically found in cancerous cells.

http://www.targeting-mitochondria.com/alerts-on-mitochondria/discoveries-in-mitochondria-open-new-field-of-cancer-research

Mitochondria are critical source of cellular ROS and scavenging of mitochondrial superoxide kills cancer (see ref. bellow). Inhibition of mitochondrial function is cytotoxic and represents "old dogma". Targeting mitochondrial ROS is not cytotoxic for non-malignant cells and can be used to attenuate and treat cancer.

Does scavenging of mitochondrial superoxide attenuate cancer prosurvival signaling pathways? Nazarewicz RR, Dikalova A, Bikineyeva A, Ivanov S, Kirilyuk IA, Grigor'ev IA, Dikalov SI. Antioxid Redox Signal. 2013 Aug 1;19(4):344-9.

One must keep in mind that normal stem cells (which have well functional mitochondria) in the body also rely heavily on glycolysis similar to cancer cells, so the Warburg effect may not be so specific for cancer cells. Therefore, targeting high glucose demand may target the stem cells too, which would not be good. An interesting discussion on this topic could be found here:

http://www.news-medical.net/news/20111116/Human-pluripotent-stem-cells-rely-heavily-on-glycolysis-to-drive-their-metabolic-activities.aspx

When we can bring the therapy specifically to the cancer cells, leaving all other dividing cells including stem cells alone, it would not matter what the killer is, as long as the mechanism of death does not lead to toxicity to neighboring healthy cells (like necrosis). How about finding cell surface markers specific to cancer cells? Then drugs conjugated antibody therapy is the way forward.

It is a huge challenge to investigate the role of mitochondia in cancer. Is the dysregulation of mitochondria a cause of cancer development or a consequence? How can we preserve normal cells when targetting mitochondria? Will we kill all the cancerogenic cells when targetting mitochondria and does all the tumor cells have the same mitochondrial behaviour? So many questions with conflicting answers in the litterature. I know that pharmaceutical companies usually discard the compounds affecting mitochondria when screening for anticancer drugs, and little is known about the effect of such compounds on a human organism.

What, in my opinion, is really important when considering the role of mitochondria in cancer, is that the symbiosis between a cell and its mitochondria is impaired. The most important challenge may be to understand how this relationship is modified.

Targetting mitochondria may affect normal cells too or may affect differentially the cancer cells' population leading to huge side effects or an incomplete response.

As in many relationships which are impaired, the major cause may be a matter of communication. There is a cross talk between mitochondria and the cells they belong and a dysregulation in that communication is a hallmark of cancerous cells. It can be a dysregulation in the apoptotic signaling, the energetic signaling, or else, but understanding how this is modified in cancer cells may help to design specific targets in cancer cells. Restoring a normal communication between cells and their mitochondria (and may be with the endoplasmic reticulum and Golgi apparatus too) may contribute to stop cancer progression.

That said, I didn't help too much, so to answer the question:"is it better to target mitochondria in cancer cells?", I would say:

The type of cancer matters! When considering a virally or bacterially induced cancer may not be the same than some cancers coming from genetic mutations.

First of all you got to ensure that, in your system (type of cancer), the mitochondrial metablolism is significantly affected and affected the same way in the different cancer samples you want to investigate. Afterwhat you can study the impact of targetting mitochondrial activity in your cancer cells. You can use oxamate or 2deoxyglucose to block glycolysis or rotenone to block OXPHOS and see if you significantly affect cell proliferation, survival or motility depending on your routine studies.

But be carefull, blocking glucose supply may be hard to translate in vivo, and drugs as rotenone are known (thanks to Monsanto) to induce parkingson disease in humans by inducing specific cell death in dopaminergic neurons.

The challenge will be here to design experiments to investigate this in vivo, may be glucose deprivation can partially be obtained with a special diet, and perhaps a partial deprivation is sufficient to modify tumor development, but it has to be measured.

The last part should be a long time treatment and a good histopathology analysis to predict unwanted side effect related to the experiment.

Regards.

Mitochondria are also the site of beta oxidation (fatty acid degradation). If mitochondria are inhibited by some new therapy, this could inhibit growth of normal and tumor cells. Lipogenesis is a new hallmark of cancer. So, we need more proof that lipogenesis rate in tumor cells is much greater than that of normal cells. Once we get such evidence, one can target speific lipogenic enzymes to selectively kill tumor cells (without affecting normal cells). Hope this helps!

Thanks a lot sir..venil I'm following Your updates.

Mitochondria play an important role during programmed cell death especially during apoptosis. The mitochondrial and receptor pathways are two main pathways of apoptotic cell death.