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Breaking Cancer’s back: Targeting the DNA

Cancer is no stranger in today’s world. Each year, about 14 million people receive this dreaded diagnosis and 8 million die from the disease. According to reports, 1300 people succumb to cancer every day in India. Moreover, statistics have indicated a steady increase in the number of cancer patients in the past 5 years. In order to bring down this rapidly increasing number, newer therapeutic approaches against cancer are of the utmost need.

 A step in this direction has been taken by scientists at the Indian Institute of Science, Bangalore. Researchers here have designed a novel compound that serves to target DNA in cancer cells. The DNA present in all our cells has a double helical structure. All basic processes like making more copies of DNA or synthesizing proteins from DNA require the separation of the two DNA strands. At times, toxic agents like environmental chemicals or certain drugs can interfere with this separation process and introduce crosslinks between the two strands. These crosslinks connected by very strong covalent bonds are known as Interstrand Cross Links (ICLs).

“ICLs are extremely toxic and just one single unrepaired ICL can kill the cell, especially rapidly dividing cells because they irreversibly block DNA strand separation through chemical reactions”, says Prof. Ganesh Nagaraju, one of the scientists involved in this research. The body, however, has repair mechanisms that can correct this DNA damage to a certain extent. The cells in which the DNA cannot get repaired are killed. 

DNA crosslinking agents have been used clinically for killing cancer cells for over six decades. Several such anti-cancer agents are in use, like 'cisplatin', a Platinum derivative. However, these agents cannot be used in higher doses since they have the ability to damage normal cells too. According to Prof. Nagaraju, a problem that has developed recently is that cancer cells are developing resistance against anti-cancer agents like cisplatin. Psoralen is another ICL agent that is used clinically for cancer therapy and requires activation by UV-radiation inorder to achieve ICLs in cancer cells. However, patients can develop skin cancer due to prolonged exposure to UV-radiation.

Taking into account with the limitations of existing ICL inducing agents, Prof. Chakravarty’s and Prof. Nagaraju’s groups together have designed a new compound: trans-dichloro oxovanadium(IV) complex of pyrenyl terpyridine (VDC-visible light inducible DNA crosslinker) which can be activated by visible light. As complex as the name sounds, what VDC does is simple. It forms crosslinks in the DNA when cancer cells are exposed to UV-A or visible light.

“VDC is a novel compound that has overcome the barrier of activation using UV light that Psoralen faces”, says Prof. Nagaraju. VDC gets activated upon exposure to visible light, making it safer for human use. Additionally, monitoring VDC uptake can be very convenient owing to its natural fluorescence.

The study has been conducted on human cancer cell lines like cervical cancer, breast cancer and bone cancer cells and has been published in the journal Carcinogenesis. Prof. Nagaraju asserts, “Though the study is in its infancy, we have plans to extrapolate the research to animal models and eventually to humans.”            

About the authors:

Ganesh Nagaraju is an Assistant Professor at the Department of Biochemistry, Indian Institute of Science. Akhil R. Chakravarty is an Assistant Professor at the Department of Inorganic and Physical Chemistry, Indian Institute of Science.

Kumar Somyajit, Sneha Saxena,Sharath Babu are research scholars in Nagaraju's lab. Bhabatosh Banik is a research scholar in Chakravarty's lab. Collaborator Manoor Prakash Hande is with the Department of Physiology, NUS Yong Loo Lin School of Medicine, Singapore.

Contact:nganesh@biochem.iisc.ernet.in. Telephone: 91-80-22933055

arc@ipc.iisc.ernet.in. Telephone: 91-80-22932533

About the publication:

“Trans-dichlorooxovandium (IV) complex as a novel photoinducible DNA interstrand crosslinker for cancer therapy” is published in the journal Carcinogenesis.The abstract of the paper can be accessed at http://www.ncbi.nlm.nih.gov/pubmed/26678223