Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.

Cancer Prev Res (Phila). 2014 Feb 11. [Epub ahead of print]
Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.

1Medicine/Population Science, Rutgers Cancer Insititue of New Jersey.

Abstract

Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3-5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMPK-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of Cox-1/Cox-2 and modulation of the NFκB or STAT3 pathway. Additionally, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer.

PMID:24520038   [PubMed – as supplied by publisher]

Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.

Cancer Lett. 2014 Jan 27. pii: S0304-3835(14)00041-X. doi: 10.1016/j.canlet.2014.01.015. [Epub ahead of print]
Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.
Choi YW1, Lim IK2.

Author information

1Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
2Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea. Electronic address: iklim@ajou.ac.kr.

Abstract

To investigate sensitization of metformin-cytotoxicity, cancer cells were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK). Metformin-cytotoxicity was mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas DCA cotreatment enhanced metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting PDK and increasing mitochondrial respiration. DCA cotreatment elicited cell death rather than cell survival despite high glucose and high GSH condition. In conclusion, DCA sensitized metformin-cytotoxicity by reprogramming glucose metabolism in part from aerobic glycolysis to mitochondrial oxidation, evidenced by measurements of glucose consumption, lactate release, and the ratio of oxygen consumption rate/extracellular acidification rate.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.

Integr Cancer Ther. 2009 Dec;8(4):416-22. doi: 10.1177/1534735409352082.
Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.
Berkson BM, Rubin DM, Berkson AJ.

Author information

The Integrative Medical Center of New Mexico, Las Cruces, NM, USA.

Erratum in

Integr Cancer Ther. 2010 Jun;9(2):247.

Abstract

The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

PMID: 20042414 [PubMed – indexed for MEDLINE]

CD47 Update

CD47
CD47 is a kind of protein that is found on the surface of many cells in the body. It tells circulating immune cells called macrophages not to eat these cells. The body uses the CD47 protein to protect cells that should be protected and to help dispose of cells that are aged or diseased. For instance, red blood cells start off with a lot of CD47 on their cell surface when young but slowly lose CD47 as they age. At some point, the amount of CD47 on the surface of an aging red blood cells is not enough to stave off the macrophages, and those older cells are devoured and destroyed, making way for new red blood cells. In this way, the supply of fresh blood cells is constantly replenished.
Unfortunately, some cells that should be destroyed are not. Researchers at Stanford have discovered that nearly every kind of cancer cell has a large amount of CD47 on the cell surface. This protein signal protects the cancer against attack by the body’s immune system. Stanford investigators have discovered if that they block the CD47 “don’t-eat-me” signal through the use of anti-CD47 antibodies, macrophages will consume and destroy cancer cells. Deadly human cancers have been diminished or eliminated in animal models through the use of anti-CD47 antibody.
Clinical Trials in humans
After the successful outcomes of the experiments testing the use of anti-CD47 antibodies against human cancers transplanted into mice, plans were immediately begun to start clinical trials in humans. Unfortunately, the process of preparing for human clinical trials is long. The initial experiments were done in animals and the animal versions of anti-CD47 antibody cannot be used in humans. So researchers first have to create a “humanized” antibody to CD47, then the production of antibody must be scaled up in a sterile facility of the kind that is used to create other pharmaceutical products. Finally, clinical trials must be designed so that the data they generate will produce a valid scientific result, and the trials must be approved by regulatory officials.
All of this takes time.
For the last year, many people have been working to make clinical trials possible. We are now hopeful that the first human clinical trials of anti-CD47 antibody will take place at Stanford in mid-2014, if all goes well. Clinical trials may also be done in the United Kingdom.

(1/14/14) Update on the anti-CD47 cancer therapy clinical trials

Researchers and staff at Stanford are continuing to work hard preparing the groundwork for the clinical trials of our anti-CD47 antibody as a cancer therapy. We are anticipating the start of clinical trials sometime in the first half of this year, though unforeseen delays may yet slow that progress. As we get closer to the start of the clinical trials, we will be posting information about eligibility for the trials and how to apply.

There has been a huge amount of interest in these trials from patients and their families and friends. However, we feel compelled to emphasize that, as is typical of FDA phase I clinical trials, the first tests of this therapy will be very small safety trials involving only a very few patients. Unfortunately, this means only a tiny fraction of those interested will be admitted to the first phase I clinical trials. Accordingly, we are urging patients to continue exploring existing treatments and other clinical trials.