Month: August 2017

This is a continuation of cancer as a metabolic disease due to mitochondrial dysfunction.  We will discuss our initial work on the Mitochondrial Organelle Transplantation.

I stated on the last post about cancer as a metabolic disease and some of the results of our mitochondrial organelle transplantation would be presented. I am sorry I am a little late in posting this but I have been on a research trip to discuss collaboration with Hebert Weissbach, PhD,  at Florida Atlantic University. 

When I initially thought that mitochondria as bacteria could be isolated from normal cells, I told my research associates what I wanted to do about isolating normal mitochondria to see if they might enter cancer cells in cell culture. They first thought that I was dreaming about something that was probably never going to happen; however, Mr. Jiang agreed to order a mitochondrial isolation kit and we decided to go ahead and isolate mitochondria from a normal human mammary epithelial cell line. We stained the cells before isolation with a stain that is a vital stain that the mitochondria will not take up unless they are functioning well. That stain is called JC-1. When Mr. Jiang initially isolated the mitochondria, and incubated them with some cancer cells lines he immediately after he looked at this under a fluorescent microscope came to get me to come into the lab to observe. We were extremely excited that yes, normal mitochondria could be isolated, stained with a vital stain JC-1, co-incubate with cancer cells and ENTER the cancer cells. This was proven by fluorescent microscopy. I next postulated that possibly if normal mitochondria would enter cancer cells they possibly may reverse their metabolism from glycolysis to oxidative phosphorylation which is normal cellular respiration. Possibly inhibit proliferation. In so doing might even make these cancer cells more responsive to chemotherapy agents.

The next procedure we did was to incubate the normal mitochondria with cancer cell lines and test for inhibited cellular proliferation. That requires a proliferation assay that requires radioactive thymidine which is involved in DNA synthesis. The final results are obtained in a radiation scintillation counter by certain amounts of counts. Knowing if you have a high count you have a lot of cellular proliferation and DNA synthesis. If you have low counts you have inhibited the proliferation. Mr. Jiang set up the procedure and as I came in one Saturday morning to do the normal Saturday morning work I decided to go into the lab to see if anything had come off of the scintillation counter and I found a large strip of data. I read the results of this data and although I do not do this very much and have not been technically associated with this procedure, it looked to me as if proliferation in the cancer cells after being co-cultured with normal mitochondria and the mitochondria entering the cancer cells had definitely inhibited proliferation. I went home that day quite excited and it was almost too hard to believe and could not wait for Monday morning to come to talk with Mr. Jiang. I left a message for him to get in touch with me Monday morning as soon as he came in.

We looked at the data and he agreed that it showed inhibition of cellular proliferation in the cancer cell line.  However, he was still doubtful and reluctant to accept this data and he said he wanted to repeat this experiment 3 more times. He did repeat it 3 more times and the exact same results were obtained; it definitely inhibited the cancer cell proliferation. What was the mechanism?

Therefore, we decided the next experiment we would repeat the same experiment but this time after so many days we could change the media and test the drug sensitivity. We found after co-incubating the cancer cells with normal mitochondria not only inhibited proliferation, but also increased tremendously drug sensitivity. In essence, it makes drugs more responsive and made the cancer cells more responsive to chemotherapy agents increasing their sensitivity indicating that in a patient possibly this would mean you could give a lot less drug, get the same effect, and maybe even a better effect, and cut down on a lot of the toxicity from chemotherapy.

This finding was extremely exciting and after repeating the experiment many more times, we decided to publish our first paper in the Breast Cancer Research and Treatment Journal on “Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity” in 2012.

We have had a tremendous response to that paper, and more research has been done since that time and we will be presenting further results of this research in future posts. Thank you for reading and please if you would like to contribute to support our research, visit the Donate page on our Blog website. This is getting very exciting and it is ground breaking new research for cellular biotherapy especially in cancer. As a short note, we feel like mitochondrial organelle transplantation may also play a significant role in neurodegenerative diseases and we will mention that in later posts.

Thank you,

Robert L. Elliott, M.D., Ph.D., D.Sc.

Warburg and cancer as a metabolic disease due to mitochondrial dysfunction

I have decided to post information on the exciting research that has consumed us the past seven years.  This research was stimulated by the wonderful work of Otto Warburg. He is one of my research heroes. He stated that cancer was caused by a defect in cellular respiration due to mitochondrial dysfunction. In the 1920’s he showed cells produced their energy by fermenting glucose in the cytoplasm producing large amounts of lactic acid. Normal cells produced energy in the mitochondria by oxidative phosphorylation. This involves the inner membrane (electron transport chain) of the mitochondrion. Cancer cells crave large amounts of glucose and this craving is the rationale of using the PET scan to diagnose and stage disease in cancer patients. Cancer cells use glycolytic metabolism even in the presence of adequate oxygen. This is known as aerobic glycolysis and the “Warburg Effect”. Warburg made his own equipment to perform these experiments and won the Nobel Prize in 1931. He later won another but Hitler would not let him go to receive the award. Although Warburg was of Jewish decent, Hitler left Warburg alone knowing he worked on cancer and Hitler had a tremendous fear of cancer.

What about the origin of mitochondria? Well, most know it as the powerhouse of the cell. The cellular organelle involved in cellular respiration and energy production. Few laymen know its evolution of origin. It is postulated and there is strong genetic evidence that mitochondria are evolutionary bacteria that were engulfed by eukaryotic cells 3-4 billion years ago. This created a symbiotic relationship and thus we and many forms of life developed.

We have worked on cancer iron metabolism and cancer immunology for many years, but Warburg’s and recent work of Thomas Seyfried, Ph.D., inspired me to look at mitochondria in our breast cancer patients. We had studied the ultrastructure of breast cancer specimens in in many patients by electron microscopy. Therefore, I decided to review these electron micrographs. I found that mitochondrial appearance in these micrographs could be divided into 3 groups:

1. mitochondrial plentiful and normal
2. mitochondria sparse and abnormal
3. mitochondria essentially absent

After defining these 3 groups, the patient’s charts were reviewed. The patients in group one (mitochondria plentiful and normal) were found to have low grade tumors and good overall survival. The patients in group two (mitochondria sparse and abnormal) had more aggressive tumors, poor outcome and survival. The patients in group three (mitochondria absent), had very aggressive tumors with much poorer outcome and survival. This observation impressed me that Warburg was correct about cancer cell metabolism being caused by defective mitochondrial leading to aerobic glycolysis.

One night as I thought and prayed about this problem and how to approach it; I soon realized if mitochondria are evolutionary bacteria, then they may act like bacteria. I thought why can’t we isolate normal mitochondria from normal cells and see if they can enter cancer cells and reverse the “Warburg Effect”? This led to our work on mitochondria organelle transplantation in breast cancer cells. These results will be presented in the next posting.

We welcome comments and questions!

Thank you,

Robert L. Elliott, M.D., Ph.D., Dsc

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Any type of cancer immunotherapy works better when there is less tumor burden.  In other words, a cancer vaccine is most effective when there are minimal cancer cells in the body, such as after a cancer tumor is removed or after chemotherapy. There is rationale of using immunotherapy after standard of care therapy and when there is no evidence of disease. Using immunotherapy in this setting is advantageous because sometimes it is possible to have micrometastatic disease that is undetectable by modern imaging, but these cancer cells can cause a recurrence years later.

We have been using our cancer vaccine for over 20 years in our practice.  We have used this cancer vaccine for solid epithelial tumors such as breast, prostate, colon, and lung.  The prostate cancer vaccine ProscaVax (OncBioMune Pharmaceuticals) is currently enrolling patients to begin a Phase II trial. As we have previously published, there has been minimal side effects with the cancer vaccine, and there has been improvement in the survival of our cancer patients.

We will now show you the results of our breast cancer vaccine in a group of patients that were vaccinated from 1994 to 2006. There were 37 women with breast cancer in this study. A patent on the vaccine was granted in 1994. The results of this study were published in a peer review journal in 2013 (the full reference is listed below). The image below is taken from this article and shows there is an improvement in survival when our breast cancer patients had the cancer vaccine to boost their immune system.  The cancer patients with a weakened or depressed immune system are shown in red and had a decrease in their survival.  The cancer patients who got the cancer vaccine are shown in blue and they had a better survival as compared to the red line.

(Elliott & Head, 2013)

The vaccine improved the disease specific survival of the patients that had depressed lymphocyte immunity to their own tumor.

We believe that probably all patients with any kind of cancer should have an autologous vaccine in the adjuvant setting after completion of standard of care therapy.

Adjuvant cancer immunotherapy may possibly prevent recurrence and improve survival in certain patients with cancer.

Robert L. Elliott, M.D., Ph.D. and Catherine C. Baucom, M.D., Ph.D.

 

(Elliott RL and Head JF. 2013. Adjuvant breast cancer vaccine improves specific survival of breast cancer patients with depressed lymphocyte immunity. Surgical Oncology. 22:172-177.)

Here is the link to purchase the journal article:

http://www.sciencedirect.com/science/article/pii/S0960740413000601