Cutting off the energy supply
Every living thing needs energy in some form in order to survive.
In their latest paper published in the prestigious Nature Cell Biology, Worldwide Cancer Research grantholder Professor Marcos Malumbres and his team at the Spanish National Cancer Research Centre (CNIO), propose blocking a tumour’s energy supply as a way of enhancing the effects of a group of cancer drugs called taxanes.
Taxanes include the well-known drug taxol, which was first made from the bark of a yew tree. It is now commonly used to treat breast, ovarian, lung, bladder, prostate, melanoma (skin), oesophageal (food pipe) and other cancers. These findings could potentially benefit a vast number of patients with a wide range of cancers.
CNIO released the following press release, and below we discuss the research findings.
One of the hallmarks of cancer cells is their ability to divide in an uncontrolled and almost unlimited way. This demands a high amount of energy.
Cancer cells therefore become addicted to glucose (sugar). They use it as their main source of energy to grow and divide rapidly. The idea then is simple: Stop the glucose supply and kill the cancer cells.
But despite the ‘sugar-addiction’ phenomenon being observed over 90 years ago, there is still no cancer treatment that can take advantage of this special energy requirement.
Targeting a sweet tooth
Professor Marcos Malumbres and his team have shown that blocking glycolysis, the chemical process used by cells to extract energy from glucose, is especially damaging to cell division. Cell division is the process where the cell splits to form two identical new cells.
He also discovered that acting on this sugar addiction could be especially effective in combination with chemotherapy drugs, such as taxol.
The researchers found that two key proteins - AMPK and PFKFB3 - become active during cell division. These proteins make cells rely on glycolysis to make energy instead of energy production by mitochondria, the cell’s power plant.
“These proteins detect damage to the mitochondria in response to cell division and make the energy depend mainly on glucose,” explains Elena Doménech, who performed the majority of the research in the study.
In other words, when cells divide, they need extra glucose as fuel.
The researchers also analysed the glucose requirements of cancer cells treated with taxol. Surprisingly, in this situation the cells had an even higher demand for glucose.
Starved to death
Stopping glycolysis should enhance the anti-cancer effect of drugs like taxol. The logic is this: Taxol forces cancer cells to need more glucose. If they can be prevented from getting it, they should die of starvation.
The research team went on to confirm this hypothesis and found that drugs like taxol do indeed work better when the cells’ ability to use glycolysis is blocked.
"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 like taxol," explains Professor Malumbres.
Other taxanes, such as docetaxel, are standard treatments for cancers like lung, prostate, and breast cancer. Different cell division-blocking cancer drugs are the alkaloids originally made from Vinca, or periwinkle (Catharanthus roseus), such as vinblastine, vincristine and vinorelbine. These are widely used to treat leukaemia, lymphoma and melanoma.
The next step, according to the CNIO team, will be to identify groups of patients who would benefit more from chemotherapy if the tumour’s energy supply was blocked.
Its still early days, but this is a great example of how research studying the behaviour of cancer cells in the lab can open up new paths to better cancer treatment. If this new understanding can be turned into new treatments - and we wish the CNIO team the best of luck - these findings could benefit a huge number of cancer patients in future.
This work was funded by Worldwide Cancer Research, the Scientific Foundation of the Spanish Association against Cancer (AECC), the Ministry of Economy and Competition, the Community of Madrid, and the European Union.
Photo credit and caption: CNIO. Genetic material is shown in blue and mitochondria in red. During this process, the mitochondria are damaged (yellow) making the cells particularly dependent on glucose as a source of energy.
Find out more about Professor Malumbres' new tactics to beat breast cancer.