Scientists propose attacking bioenergetic metabolism to improve anti-cancer therapies

August 31, 2015
Cells dividing. Genetic material is shown in blue and mitochondria in red. During this process, the mitochondria are damaged (yellow signs) making the cells particularly dependent on glucose as a source of energy. Credit: CNIO

Cancer cells become addicted to glucose, which they use as their regular source of energy to grow and develop. Although this was observed over nine decades ago by the German physiologist, Otto Warburg; there is still not therapeutic strategy today that can effectively take advantage of this special energy requirement. The initial approach appears to be simple: the lack of glucose could specifically induce the death of cancer cells.

A new study by the Spanish National Cancer Research Centre Cell and Cancer Unit, headed by the Cell Division and Cancer group of the Spanish National Cancer Research Centre, headed Marcos Malumbres, has now proven that blocking glycolysis - the molecular mechanism that makes it possible to extract energy from - is especially damaging to the division of cancer cells and that specifically acting on this energy-based peculiarity could be effective in treating cancer in combination with chemotherapeutic agents such as .

The research project, published in the prestigious journal, Nature Cell Biology, brought together, in addition to a number of CNIO collaborators, the teams headed by Patricia Boya and Eduardo Rial from the Centre for Biological Research (CIB) in Madrid; Raúl Méndez from the IRB Barcelona; Guillermo Velasco, from the Complutense Univeristy of Madrid; Miguel López, from the University of Santiago de Compostela; and Asish Saha, from Boston University.

Changes In Cellular Metabolism

One of the typical aspects of cancer cells is their capacity to divide in an uncontrolled and almost unlimited manner. "There are many therapeutic agents today, such as taxol, that precisely prevent the division of cancer cells by interrupting the mitosis (an especially delicate part of the process in which the genetic material is passed from the mother cell to the daughter cells)", says María Salazar Roa, CNIO researcher and co-director of the study.

One of the issues the researchers are raising is how cancer cells obtain the energy they need to maintain their high rate of division. Using molecular biology and biochemistry techniques, the authors describe, in line with Warburg's theory, how the AMPK and PFKFB3 proteins become significantly active during mitosis, leading cell metabolism towards glycolysis.

"These proteins detect damage to the mitochondria (the cell's energy sources) in response to cell division and make the energy depend mainly on glucose", clarifies Elena Doménech, whose signature appears first on the paper that she has been preparing as her doctoral thesis.

Greater Addiction To Glucose In The Presence Of Taxol

The researchers also analysed the glucose requirements of cancer cells treated with taxol and, therefore, when mitosis is interrupted. "We can see that antimitotic treatments, such as taxol, increase the need cancer cells have for glucose even more than when there is no treatment", says Salazar.

Based on the fact that cancer cells need more glucose when they are being treated with taxol, the inhibition of glycolysis should enhance the anti-cancer effect of antimitotic drugs. In a way, it would be like forcing them to need more glucose and, at the same time, preventing its use. Then, the would die of starvation as they would be unable to obtain the energy they need to cover their vital functions.

Cancer Cell Death By Starvation

The authors used cellular models taken from breast cancer and mice, finding that, indeed, mitotic drugs, such as taxol, are more efficient when the cells' ability to metabolize glucose is eliminated using PFKFB3 inhibitors.

"The therapeutic value of inhibiting PFKFB3 has often been discussed; however, no appropriate cell-based scenario had been proposed for its clinical use. Our results suggest that PFKFB3 inhibitors can be extremely efficient in combination with antimitotic drugs", explains Malumbres.

Taxol, a compound derived from the bark of the yew tree, is one of the greatest revolutionary elements in the history of chemotherapy over the last 25 years. Today, other taxanes, such as paclitaxel and docetaxel, are part of the standard treatment provided in the case of certain cancers, such as lung, breast and ovarian cancer. Other antimitotic drugs are the alkaloids derived from Vinca (Catharanthus roseus), such as vinblastine, vincristine and vinorelbine, widely used to treat leukaemia, lymphoma and melanoma. The future direction, according to the team from CNIO, will be to identify groups of patients with these and other tumours in which to enhance the effects of antimitotic agents by blocking the tumour's source.

Explore further: Inducing metabolic catastrophe in cancer cells

More information: AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest, DOI: 10.1038/ncb3231

Related Stories

Inducing metabolic catastrophe in cancer cells

August 31, 2015
A study published in The Journal of Cell Biology describes a way to force cancer cells to destroy a key metabolic enzyme they need to survive.

Scientists develop potential new class of cancer drugs in lab

June 26, 2015
In research published in Cancer Cell, Thomas Burris, Ph.D., chair of pharmacology and physiology at Saint Louis University, has, for the first time, found a way to stop cancer cell growth by targeting the Warburg Effect, ...

Fasting and less-toxic cancer drug may work as well as chemotherapy

March 30, 2015
Fasting in combination with chemotherapy has already been shown to kill cancer cells, but a pair of new studies in mice suggests that a less-toxic class of drugs combined with fasting may kill breast, colorectal and lung ...

Discovery of a mechanism that makes tumor cells sugar addicted

April 4, 2014
For almost a hundred years ago is known that cancer cells feel a special appetite for a type of sugar called glucose. The tumor uses this molecule is like the gasoline which depends a sports car to burn faster and grows and ...

CNIO researchers propose a new therapeutic target that prevents cell division

October 8, 2013
Cell division is an essential process for the development of an organism. This process, however, can cause tumour growth when it stops working properly. Tumour cells accumulate alterations in their genetic material, and this ...

Non-invasive imaging instead of repeated biopsy in active monitoring of prostate cancer

April 6, 2014
Your body's cells have two major interconnected energy sources: the lipid metabolism and the glucose metabolism. Most cancers feed themselves by metabolizing glucose, and thus can be seen in Positron Emission Topography (PET) ...

Recommended for you

Researchers unravel novel mechanism by which tumors grow resistant to radiotherapy

November 23, 2017
A Ludwig Cancer Research study has uncovered a key mechanism by which tumors develop resistance to radiation therapy and shown how such resistance might be overcome with drugs that are currently under development. The discovery ...

African Americans face highest risk for multiple myeloma yet underrepresented in research

November 23, 2017
Though African-American men are three times more likely to be diagnosed with multiple myeloma, a type of blood cancer, most scientific research on the disease has been based on people of European descent, according to a study ...

Encouraging oxygen's assault on iron may offer new way to kill lung cancer cells

November 22, 2017
Blocking the action of a key protein frees oxygen to damage iron-dependent proteins in lung and breast cancer cells, slowing their growth and making them easier to kill. This is the implication of a study led by researchers ...

One-size treatment for blood cancer probably doesn't fit all, researchers say

November 22, 2017
Though African-American men are three times more likely to be diagnosed with a blood cancer called multiple myeloma, most scientific research on the disease has been based on people of European descent, according to a study ...

One in four U.S. seniors with cancer has had it before

November 22, 2017
(HealthDay)—For a quarter of American seniors, a cancer diagnosis signals the return of an old foe, new research shows.

Combination immunotherapy targets cancer resistance

November 22, 2017
Cancer immunotherapy drugs have had notable but limited success because in many cases, tumors develop resistance to treatment. But researchers at Yale and Stanford have identified an experimental antibody that overcomes this ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.