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A drug that kills cancer cells when shone by light

Researchers at IISc have designed a trio of compounds that can be triggered by light to become toxic to cancer cells. These compounds target the cells’ mitochondria ─ their “energy factories”─ setting off a chain reaction that turns on cell death pathways and kills the cancer cells.  

The newly-designed compounds could potentially lead to novel mitochondria-targeting cancer drugs that are safe, controlled and efficient.

Using light to treat cancer, called photodynamic therapy (PDT), is emerging as a “safer” alternative to harsh treatments such as chemotherapy or radiation. In PDT, a drug called a photosensitizer is injected into cancer cells in a non-reactive or dormant form. When exposed to light of a specific wavelength, the drug gets activated and triggers the release of a reactive oxygen molecule that kills cancer cells.  

Prof. Akhil R. Chakravarty’s group designed the new compounds which are a novel blend of organic and metallic components ─ alkylpyridinium salts and ferrocene (a form of iron), respectively. Biological studies were carried out with the help of the Prof. Anjali Karande’s research group.  

Positively-charged elements in the compounds' structure help them travel across the negatively-charged mitochondrial membrane and accumulate inside. When exposed to light, the stable ferrocene switches to an unstable ferrocenium molecule, triggering the release of reactive oxygen species (ROS). ROS are destructive molecules that start off a chain reaction of events eventually killing the cancer cells ─ a process called apoptosis or programmed cell death.

Organic (carbon-containing) drugs derived from porphyrin, a cyclic molecule, are currently used in PDT to treat certain lung and esophageal cancers. The new ferrocene-complexes, however, could substitute for these expensive porphyrin-based drugs, said Prof. Chakravarty. Porphyrin-based drugs are also known to have harmful side effects on the skin, liver and kidney. By contrast, the new compounds are “expected to be bio-friendly” as they contain no toxic heavy metal components, he said. Ferrocene is also known to be safe in biological cells.

Another advantage is their target site: the mitochondria. Common drugs try to kill cancer cells by targeting and breaking down their DNA. However, cancer cells have DNA repair mechanisms that can reverse the damage, reducing the drugs’ efficiency. Targeting mitochondria instead would significantly boost the drugs’ efficiency, as mitochondria also play a key role in activating cell death pathways.

One of the three compounds, abbreviated as FPBP, showed nearly a 12-fold increase in toxicity to cancer cells when exposed to light, and had the highest level of accumulation in mitochondria.

“The present results can be compared with two other anticancer drugs, viz. tamoxifen and its ferrocenyl conjugate, known as ferrocifen. Our compound shows better selectivity and can only be activated by light. This will reduce the unwanted dark toxicity which affects healthy cells by presently known chemotherapeutic drugs,” said Prof. Chakravarty.

Further studies using animal models would help researchers fully understand these compounds’ efficiency inside living cells, he said.

About the authors:

Akhil R. Chakravarty is a professor in the Department of Inorganic and Physical Chemistry. Babu Balaji is a graduate student in his lab. Anjali Karande is a professor in the Department of Biochemistry. Babita Balakrishnan is a post-doctoral scholar in her lab. Sravanakumar Perumalla is a graduate student in the Department of Inorganic and Physical Chemistry.

The paper first appeared online on 5 February, 2015 in the European Journal of Inorganic Chemistry published ChemPubSoc Europe.

http://onlinelibrary.wiley.com/doi/10.1002/ejic.201403118/abstract

Contact information:

Prof. Akhil R. Chakravarty: arc@ipc.iisc.ernet.inTel: 91-80-2293 2533; Fax: +91-80-23600683; Web: http://ipc.iisc.ernet.in/arc.html

Prof. Anjali Karande: anjali@biochem.iisc.ernet.inTel: +91-80-22932306; Web: http://biochem.iisc.ernet.in/anjalikarande.php