Metformin treatment caused cancer stem cell death in pancreatic cancer cell lines

June 19, 2012

LAKE TAHOE, Nev. -- Results of some preclinical trials have shown that low doses of the antidiabetic drug metformin may effectively destroy cancer stem cells, a group of cells that are considered to be responsible for tumor initiation and, because they are resistant to standard chemotherapies, tumor relapse.

In addition, when metformin was combined with a standard chemotherapy used for pancreatic cancer, the combination treatment was able to efficiently eradicate both cancer stem cells and more differentiated cancer cells, which form the bulk of the tumor, according to data presented by Christopher Heeschen, M.D., Ph.D., at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held in Lake Tahoe, Nev., from June 18-21, 2012. Heeschen is professor for experimental medicine at the Spanish National Cancer Research Centre in Madrid, Spain.

Most clinical trials of pancreatic cancer conducted during the last 15 years have failed to show marked improvement in median survival, suggesting that the selected approaches were not sufficient for several reasons, according to Heeschen. In recent years, researchers have identified cancer stem cells which, as opposed to the cancer cells that make up the bulk of the tumor, are a small subset of cells that are resistant to conventional therapy.

"Therefore, efficiently targeting these cells will be crucial for achieving higher cure rates in patients with pancreatic cancer," he said. "Our newly emerging data now indicate that metformin, a widely used and well-tolerated drug for the treatment of diabetes, is capable of efficiently eliminating these cells."

Specifically, the researchers found that metformin-pretreated cancer stem cells were particularly sensitive to alterations to their metabolism through the activation of AMPK. In fact, metformin treatment resulted in the death of cancer stem cells. In contrast, treatment of more differentiated cancer cells with metformin only arrested the cells' growth.

"As the cancer stem cells represent the root of pancreatic cancer, their extinction by reprogramming their metabolism with metformin in combination with the stalling of the proliferation of more differentiated cells should result in tumor regression and long-term, progression-free survival," Heeschen said.

The researchers generated data to support this idea when they treated immunocompromised mice implanted with a diverse set of patient-derived tumors with a combination of metformin and gemcitabine, the standard chemotherapeutic treatment for pancreatic cancer. They found that the treatment resulted in reduced tumor burden and the prevention of relapse as compared with treatment with either drug alone.

"Intriguingly, in all tumors treated with metformin to date, relapse of disease was efficiently prevented and there were no noticeable adverse effects," Heeschen said.

He believes that testing metformin in pancreatic cancer is ready for clinical trials. The pancreatic research team is currently awaiting results of a study that tested metformin as a maintenance treatment in patients with advanced pancreatic cancer. Although the rationale for this study was based on retrospective data, Heeschen said given these new results he hopes that this treatment strategy would be highly efficacious.

"Pending the results of this study, an important aspect for the future will be to investigate if all patients respond to metformin or whether some patients, due to distinct genetic alterations, may not respond to this metabolic reprogramming," he said.
-end-
Follow the AACR on Twitter: @aacr #aacr
Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the AACR

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR's membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit www.AACR.org.

Abstract: Metformin targets human pancreatic cancer stem cells in preclinical mouse models. Enza Lonardo, Michele Cioffi, Yolanda Sanchez, Jorge Dorado, Christopher Heeschen. Spanish National Cancer Research Centre, Madrid, Madrid, Spain.

Pancreatic ductal adenocarcinomas contain a subset of exclusively tumorigenic cancer stem cells (CSCs), which are capable of repopulating the entire heterogeneous populations of cancer cells in the tumor and, even more importantly, are highly resistant to standard chemotherapy. Therefore, the identification of drugs that are capable of selectively targeting CSCs is urgently needed. Here, we demonstrate that low dose metformin, a widely used anti-diabetic drug with an exceptional safety profile, selectively targets freshly isolated human pancreatic CSCs. Specifically, metformin pretreated sphere-derived CSCs showed strong activation of AMPK and loss of expression of pluripotency-associated genes and CSC-associated surface markers. Consecutively, the ability of pretreated CSCs to clonally expand in vitro and in vivo was virtually abrogated, while non-CSCs remained mostly unaffected by metformin treatment. Importantly, induction of energetic crisis resulting in enhanced apoptosis was restricted to p53-deficient CSCs, while p53 wild-type CSCs were resistant to the effects of metformin. Intriguingly, the combination of metformin with gemcitabine, the standard chemotherapeutic agent for pancreatic cancer, efficiently erased both CSCs and non-CSCs. Finally, in primary tissue xenograft mouse models this combination treatment effectively reduced tumor burden and prevented relapse as compared to either drug alone. Therefore, these data provide a strong experimental basis for further evaluating the combination of metformin and chemotherapeutic drugs to eventually improve the poor prognosis of patients with pancreatic cancer.

American Association for Cancer Research

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.