combining an NFKappa-beta inhibitor with metformin seems a "dynamic duo" vs. cancer

[Lani]

Scientists use diabetes drug in double hit to starve cancer cells
[Cancer Research UK]

CANCER RESEARCH UK scientists have discovered how blocking a key controller of energy production in cancer cells and treating them with a diabetes drug, metformin, effectively starves cancer cells. The research1 is published today (Sunday) in Nature Cell Biology.

One of the key characteristics of cancer cells is their ability to divide and grow quickly. To do this they need to switch to a method of producing energy rapidly, which breaks down glucose in a process called glycolysis. By doing this they generate the energy and raw materials needed to create new cells.

The researchers found that this switching is controlled by a protein complex called NF-kB, which controls the balance between different types of energy generation. When glucose supplies run short, NF-kB moves energy generation to an alternative process that doesn't rely on glucose. But blocking NF-kB in cancer cells leaves them unable to make this switch and so they ultimately die.

By targeting this protein complex, the researchers showed they could kill bowel cancer cells in the lab. To mimic the effect of glucose starvation, the researchers first treated the cancer cells with a molecule that blocks NF-kB, though by itself it has no effect on survival. But when combined with the diabetes drug metformin, which blocks alternative methods of energy production, they effectively besiege the cancer cells so that they starve and die.

Professor Guido Franzoso, lead researcher based at Imperial College London, said: "This is the first time that NF-kB has been shown to control how cells generate energy. We already knew that NF-kB plays a role in cancer. It is part of a family of regulators that control the immune and inflammation responses and have been shown to promote the disease.

"Inhibitors of NF-kB are currently used in the clinic to treat cancer patients but have had limited success, due to their side effects. We hope that we can now start exploring the possibility of combining them with metformin as a double hit to increase their effectiveness against cancer."

Dr Julie Sharp, senior science information manager at Cancer Research UK, said: "Cancer cells need a rapid supply of energy to grow and divide and understanding how they generate energy is an exciting area of research. By blocking energy production, effectively starving the cells, researchers have revealed a new way to selectively attack cancer cells leaving normal cells unharmed."

EARLY VIEW: ABSTRACT: NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration
[Nature Cell Biology]

Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-κB inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-κB-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. 4). Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer

NfKappa beta inhibitors presently seem to have a lot of side effects, but compounds known to decrease NfKappa beta activation, like NAC and trental
are approved and similar compounds may be the subject of trials in the future.

Always great to find ways (usually combinations it seems) to block tumors escape from treatment.

[Ellie F]

Thanks Lani, seems like the info on metformin just keeps getting better and better. Wouldn't it be great if a drug already in use was able to cure/control bc with minimal side effects!
Ellie

[fullofbeans]

Thanks Lani,

Right I may be wrong but if the cancer cell cannot switch to alternative source away from glucose (because of metformin) then how about having a ketogenic diet and metformin???

A ketogenic diet mimic the effect of fasting ( what they call starvation) but making your body rely on fat for energy and even the brain can switch to ketones/fat

[fullofbeans]

Also
curcumin, a well-known inhibitor of NF-kB activity

http://www.transonc.com/abstract.php?msid=101

Curcumin promotes apoptosis, increases chemosensitivity and inhibits nuclear factor-kappa beta in esophageal adenocarcinoma.

Wibisono Hartojo, Amy L Silvers, Dafydd G Thomas, Christopher W Seder, Lin Lin, Hyma R Rao, Zhuwen Wang, Joel K Greenson, Thomas J Giordano, Mark B Orringer, Alnawaz Rehemtulla, Mahaveer S Bhojani, David G Beer and Andrew C. Chang

Year 2010, Volume 3, Issue 2
Abstract
The transcription factor, Nuclear Factor-kB (NF-kB), plays a central role as a key mediator of cell survival and proliferation, and its activation may confer increased tumor chemoresistance. Curcumin, an orally-available naturally-occurring compound, has been shown to inhibit NF-kB and has a potential role in cancer chemoprevention. We investigated the effects of curcumin on NF-kB activity, on cell viability, and as a chemosensitizing agent with 5-fluorouracil (5FU) or cisplatin (CDDP) in esophageal adenocarcinoma (EAC). Oligonucleotide microarray analysis of 46 cases, consisting of Barrett’s metaplasia, low-grade dysplasia, high-grade dysplasia and EAC, showed increased expression of NF-kB and IkB kinase subunits and decreased effector caspase expression in EAC compared to Barrett’s metaplasia. Stromal expression of both IkB and phospho-IkB was detected in several EAC samples by tissue microarray (TMA) analysis. Curcumin alone inhibited NF-kB activity and induced apoptosis in both Flo-1 and OE33 EAC cell lines as determined by Western blotting, NF-kB reporter assays, and Caspase-Glo 3/7 assays. It also increased 5FU- and CDDP-induced apoptosis in both cell lines. These data suggest that activation of NF-kB and inhibition of apoptosis may play a role in the progression from Barrett’s metaplasia to esophageal adenocarcinoma. In addition, curcumin, a well-known inhibitor of NF-kB activity, was shown to increase apoptosis and enhance both 5FU and CDDP-mediated chemosensitivity, suggesting that it may have potential application in the therapy of patients with esophageal adenocarcinoma.

[fullofbeans]

Natural NF-kB inhibitors: allicin, curcumin, EGCG, genistein, gingko biloba, melatonin, quercetin, resveratrol, silymarin, sulphoraphane, vitamins A, C, E...

I have not down the background work on above and inhibitor effect but since these are usually good against cancer well maybe keep on doing it.. with without metformin

[radiant]

very cool to hear the natural NF-k8 inhibitors. THANK-YOU fullofbeans.

[zoco]

Hi anyone tried this?
It actually can work only if ONLY ALL 3 THING ARE COMBINED:
KETOGENICDIET + METF + NFKB inhibitors. If NFKB missing cnc switches to fat burning, if Metf missing, liver makes glucose from lactic acid. So all 3 must go together.
I guess 4 weeks course could make some interesting results, 8 would be best:
0.week- allow normal sugar diet to get cnc cells adapted to glucose
1.week- 1st half of weekNFKB inhibitors, 2nd half of week: start Keto.d.
2-3-4week: add metformin.
The more weeks, perhaps the better.
Ketogenic diet-use urine test strips to see if body is in ketosis - violet colour typically in respective test square. Only this is real ketosis. Otherwise you are ketting some sugar from diet in maybe you are not aware of (eg. Milk, ...). Coconut oil or MCT oil is base for Ketogenic diet. Allow more calories intake that out so you dont loose weight.
Worth a try..

interesting, related:
Unexpected Antitumorigenic Effect of Fenbendazole when Combined with Supplementary Vitamins-http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687140/

the mechanism in this study is same, but Fenbendazole antiworm drug makes similar effect like Keto.d.&Metf - it block glucose update of cells - its like artificial ketosis.
And in this study they accidentally discovered the same mechanism - block the NFKB switch by vitamins (A,C,E,...) and glucose and cnc cell cannot switch to alternative sources of energy..

[europa]

I was on the Ketogenic diet and I am on a Metformin trial and I do take Turmeric every day. The Ketogenic diet is very difficult to follow if you have a child as cooking becomes a nightmare. But I have modified my diet and it is a low glycemic low calorie zone diet. I test my blood a couple of times a day to see where my glucose levels are. When I was diagnosed my levels were around 107!!!!!!! Now I'm at 81. I also have the Ketone blood strips but since I am no longer doing the Ketogenic diet, I don't use them.
The Keto diet is high in fat (the ratio for fat to protein is 4:1). The fat can come from olive oil, coconut oil, heavy cream or butter. I lasted about 2 weeks and I can no longer consume heavy cream or coconut oil...it makes me gag. Yuck.
If anyone is interested in the Ketogenic diet, I would recommend speaking to Miriam Kalamian. She does Skype consultations and her husband is a chef. The monitor all of the recipes you want using the Ketocalculator. If you are disciplined, it's worth a shot. Just remember that the Keto diet can cause kidney stones and gallbladder issues because of the amount of fat you consumer. oh, and you can get very constipated...very.

[zoco]

If kone does ketogenic diet right, there are no stone dangers.
Basenof proper ketogenicmdiet is MCT oil or coconut oil.
Olive oil only innmoderation,,ormflaxseedmoil. No other vegetable oils. Animal fats low.
Eating bad fats -omega6, polyunsaturated are very bad.
Lot of saturated not good too. MCT fats are best for body.
I think Atkinson diet done properly with above fat rules can be considered as ketogenic.
Cheers