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Cancer and Alzheimer's disease: an inverse relationship
Lane Simonian
Posted: Thursday, June 29, 2017 10:03 AM
Joined: 12/12/2011
Posts: 4854


Most people with cancer don't get Alzheimer's disease and most people with Alzheimer's disease don't get cancer.  This article touches upon the reason for this.

There's a striking relationship between cancer and Alzheimer's, and it could hold the key to new treatments

 

Unexpectedly, it's something researchers at the top cancer hospital in the US are looking into. While cancer and Alzheimer's seemingly don't have that much in common, there is one key link that researchers at MD Anderson think could be useful: People with a history of cancer are less likely to get Alzheimer's, while people with Alzheimer's are less likely to get cancer...

"Age is the biggest risk factor for both. But then for some reason, some people go one direction, others go another direction," Jim Ray, head of research for the Neurodegeneration Consortium at MD Anderson told Business Insider.

In the last decade the researchers have made this observational link between the development of Alzheimer's and a decreased cancer risk and vice versa. So researchers have been hypothesizing why that happens. At a very simplified level, the cause of the diseases might hold the biggest clue. "Cancer is a disease of cells that cannot die, will not die. Alzheimer's is a disease of cells that are supposed to live your entire lifetime that you can't keep alive," he said.

One of the ways researchers have been getting clues into the link is in cancer patients who have chemotherapy-related cognitive dysfunction. An estimated 75% of cancer patients have some level of cognitive impairment (memory loss, attention problems, etc.). Chemotherapy works by killing cancer cells by targeting fast-dividing cells, and in most cases, kills off some healthy cells along the way, including nerve cells in the brain. 

"It's an understudied area," Ray said. "And I think a lot of people didn't fully realize it was a problem."

It's something drug researchers have started looking into, to see if there could be a therapy that prevents the neurological damage that happens with chemotherapy. If they can figure out what's going on and how to prevent the neurological side effects for cancer patients, the same approach could hold some promise in treating Alzheimer's as well. 

Unlike some of the promising treatments that have failed in 2017 that deal with the so-called "amyloid hypothesis" (the treatments target amyloid beta deposits in the brain that accumulate in people with Alzheimer's disease), approaches that try to prevent nerve cells from dying wouldn't have any impact on that buildup. Instead of trying to clear the body of the deposits, it would just try to strengthen the nerve cells that are there.

"What we're trying to do is make your nerve cells more resistant to damage," Ray said. "It won't stop the damage, but it'd just make them more resistant longer, be more resilient."

And here is where it gets more bizarre: the same oxidant--peroxynitrite--may be responsible for both conditions.

In cancer, peroxynitrite prevents the dephosphorylation of the the phosphatidyinositol 3-kinase/Akt pathway.  This pathway leads to cell growth instead of cell death and is thought to be one of the primary pathways in various cancers.

The phosphatidylinositol 3-Kinase–AKT pathway in human cancer

But in the brain (or at least the part of the brain affected by Alzheimer's disease), peroxynitrite does the opposite, it nitrates the phosphatidlinositol 3-kinase/Akt pathway which leads to the death of neurons.

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.

The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.


Chemotherapy and radiation are used to kill cancer cells, but they can also kill neurons leading in some cases to memory problems in cancer patients.  

The oxidation, nitration, and DNA damage done by peroxynitrite is probably at the root of several other diseases as well.

https://www.ncbi.nlm.nih.gov/pubmed/17237348



Mimi S.
Posted: Thursday, June 29, 2017 10:22 AM
Joined: 11/29/2011
Posts: 7029


Well I had colon cancer and am a PWD. the cancer was caught so early I did not need chemo nor radiation.
Lane Simonian
Posted: Thursday, June 29, 2017 10:43 AM
Joined: 12/12/2011
Posts: 4854


I am glad that they caught and treated the colon cancer early, Mimi.

As with most things, the negative correlation between cancer and Alzheimer's disease is not a hard and fast rule.  But in some respects they are opposite diseases: cancer is cancer cell growth without cancer cell death and Alzheimer's disease is neuronal cell death without neuronal cell growth and yet peroxynitrite seems central to both diseases.

Peroxynitrite (ONOO) has been vastly implicated in mutagenesis and cancer development.

Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease


Lane Simonian
Posted: Friday, June 30, 2017 9:59 AM
Joined: 12/12/2011
Posts: 4854


If oxidative stress is a common mechanism in both cancer and Alzheimer's disease, then the same risk factors should be common to both and the same protective measures should be common for both.  For instance, certain pesticides such as Agent Orange (with dioxin) and Roundup (glyphosate with polyethoxylated tallow amines) increase the risk for Alzheimer's disease and non-Hodgkin lymphoma (the combination of which took the life of Gene Wilder).  A Mediterranean diet reduces the risk of both Alzheimer's disease and certain types of cancer.

If peroxynitrite inhibits the dephosphorylation of phosphatidyinositol 3 4 5 triphosphate the risk of cancer increases but the risk for Alzheimer's decreases.

PTEN [phosphatase tensin homolog] and the PI3-Kinase Pathway in Cancer

 

Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway.

 

If peroxynitrite nitrates the phosphatidylinositol 3-kinase (which inactivates it) the risk for cancer decreases but the risk for Alzheimer's disease increases.

 

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. 

 

The inhibition of phosphatidylinositol-3-kinase induces neurite retraction and activates GSK3

 

It is certainly possible to have cancer and Alzheimer's disease (due to the overactivation of phosphatidylinositol 3-kinase in one part of the body and its inhibition in the brain), but this appears to be a fairly rare occurrence.

The critical point is this: peroxynitrite can be responsible for either cancer cell growth without cancer cell death and/or it can be responsible for neuronal cell death without neuronal cell growth.  The same type of receptors when overactivated can lead to one outcome or the other and the same compounds can potentially be used to prevent and treat both various types of cancer and neurological diseases.


Keep It 100
Posted: Saturday, July 1, 2017 9:23 AM
Joined: 2/26/2017
Posts: 581


Existing cancer treatment drugs are now being tested for Alz and Parkinson's patients. This is my husband's doctor at Georgetown, and the trial he started last month.

https://www.alzdiscovery.org/news-room/view/new-clinical-trial-will-test-cancer-drug-as-alzheimers-treatment

There are other already existing cancer drugs that are likely to enter trials for Alz as well. They didn't tell me which ones, but they are gearing up for more....


Lane Simonian
Posted: Saturday, July 1, 2017 9:46 AM
Joined: 12/12/2011
Posts: 4854


Nilotinib mentioned in the article is a case in point.  Nilotinib is a platelet derived growth factor receptor antagonist--one of several receptor tyrosine kinases involved in certain forms of cancer and Alzheimer's disease.

Targeting the PDGF signaling pathway in tumor treatment

PDGF is associated with neuronal and glial alterations of Alzheimer's disease

 

For individuals in which platelet derived growth factor plays a role in their development of Alzheimer's disease, this may be a helpful treatment at least early on.  For individuals in which overactivation of other receptor tyrosine kinases or g protein-coupled receptors led to Alzheimer's disease this may be a less effective treatment.


Brdy64
Posted: Sunday, July 23, 2017 3:44 AM
Joined: 7/22/2017
Posts: 11


I have both moderate alzheimers and parotid gland cancer just diagnosised?