Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Lethal combination: Drug cocktail turns off the juice to cancer cells

12.12.2018

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the treatment of diabetes is too low to inhibit cancer growth.


Scanning electron microscopy image of a cancer cell.

Image: University of Basel, Swiss Nanoscience Institute/Biozentrum

The previous study of Prof. Hall’s group at the University of Basel’s Biozentrum revealed that the antihypertensive drug syrosingopine enhances metformin’s anti-cancer efficacy.

In the follow-up study, jointly performed at the Biozentrum and Basilea Pharmaceutica International Ltd, the scientists shed light on this phenomenon: The combination of the two drugs blocks a critical step in energy production thus leading to an energy shortage, which finally drives cancer cells to “suicide”.

Drug cocktail cripples sophisticated machinery

Cancer cells have high energy demands due to their increased metabolic needs and rapid growth. A limiting factor in meeting this demand is the molecule NAD+, which is key for the conversion of nutrients into energy.

“In order to keep the energy-generating machinery running, NAD+ must be continuously generated from NADH,” explains Don Benjamin, first author of the study. “Interestingly, both metformin and syrosingopine prevent the regeneration of NAD+, but in two different ways.”

Taking a closer look at the mode of action

Many tumor cells shift their metabolism toward glycolysis, which means that they generate energy mainly via the breakdown of glucose to lactate. Since the accumulation of lactate leads to a blockade of the glycolytic pathway, cancer cells eliminate lactate by exporting it from the cell via specific transporters.

“We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export,” says Benjamin. “High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+.”

Lethal combination

Because the anti-diabetes drug metformin blocks the second of the two cellular pathways for NAD+ regeneration, combined metformin-syrosingopine treatment results in complete loss of the cell’s NAD+ recycling capacity.

The depletion of NAD+ in turn leads to cell death, as the cancer cells are no longer able to produce sufficient energy. Thus, pharmacological inhibition of lactate transporters by syrosingopine or other similarly acting drugs can increase the anti-cancer efficacy of metformin and may prove a promising approach to fighting cancer.

The former Basel-based company Ciba originally developed syrosingopine for the treatment of hypertension in 1958. The identification of syrosingopine as a dual inhibitor of the two main lactate transporters is an important discovery, as currently there is no pharmacological inhibitor available for one of these two transporters (MCT4). The potential application of syrosingopine in cancer therapy could trigger a second career for this old drug.

Wissenschaftliche Ansprechpartner:

Prof. Dr. Michael N. Hall, University of Basel, Biozentrum, tel. +41 61 207 21 50, email: m.hall@unibas.ch

Dr. Don Gary Benjamin, University of Basel, Biozentrum, tel. +41 61 207 21 70, email: don.benjamin@unibas.ch

Originalpublikation:

Don Benjamin, Dimitry Robay, Sravanth K. Hindupur, Jens Pohlmann, Marco Colombi, Mahmoud Y. El-Shemerly, Sauveur-Michel Maira, Christoph Moroni, Heidi A. Lane, and Michael N. Hall
Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells
Cell Reports (2018), doi: 10.1016/j.celrep.2018.11.043

Dr. Katrin Bühler | Universität Basel
Further information:
http://www.unibas.ch

More articles from Life Sciences:

nachricht Quality control in immune communication: Chaperones detect immature signaling molecules in the immune system
20.09.2019 | Technische Universität München

nachricht Moderately Common Plants Show Highest Relative Losses
20.09.2019 | Universität Rostock

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: 'Nanochains' could increase battery capacity, cut charging time

How long the battery of your phone or computer lasts depends on how many lithium ions can be stored in the battery's negative electrode material. If the battery runs out of these ions, it can't generate an electrical current to run a device and ultimately fails.

Materials with a higher lithium ion storage capacity are either too heavy or the wrong shape to replace graphite, the electrode material currently used in...

Im Focus: Stevens team closes in on 'holy grail' of room temperature quantum computing chips

Photons interact on chip-based system with unprecedented efficiency

To process information, photons must interact. However, these tiny packets of light want nothing to do with each other, each passing by without altering the...

Im Focus: Happy hour for time-resolved crystallography

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Hamburg and the European Molecular Biology Laboratory (EMBL) outstation in the city have developed a new method to watch biomolecules at work. This method dramatically simplifies starting enzymatic reactions by mixing a cocktail of small amounts of liquids with protein crystals. Determination of the protein structures at different times after mixing can be assembled into a time-lapse sequence that shows the molecular foundations of biology.

The functions of biomolecules are determined by their motions and structural changes. Yet it is a formidable challenge to understand these dynamic motions.

Im Focus: Modular OLED light strips

At the International Symposium on Automotive Lighting 2019 (ISAL) in Darmstadt from September 23 to 25, 2019, the Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, a provider of research and development services in the field of organic electronics, will present OLED light strips of any length with additional functionalities for the first time at booth no. 37.

Almost everyone is familiar with light strips for interior design. LED strips are available by the metre in DIY stores around the corner and are just as often...

Im Focus: Tomorrow´s coolants of choice

Scientists assess the potential of magnetic-cooling materials

Later during this century, around 2060, a paradigm shift in global energy consumption is expected: we will spend more energy for cooling than for heating....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

Society 5.0: putting humans at the heart of digitalisation

10.09.2019 | Event News

Interspeech 2019 conference: Alexa and Siri in Graz

04.09.2019 | Event News

 
Latest News

Quality control in immune communication: Chaperones detect immature signaling molecules in the immune system

20.09.2019 | Life Sciences

Moderately Common Plants Show Highest Relative Losses

20.09.2019 | Life Sciences

The Fluid Fingerprint of Hurricanes

20.09.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>