Majority of the drugs available in the market for cancer bind to proteins, nucleic acids, receptors, etc. present in cancer cells and help destroy the cells. On many occasions, cancer cells generate resistance against these drugs during the treatment period. So, there is a continuous need to develop new strategies to target cancer.
A new approach introduced by Prof. Pinaki Talukdar and coworkers at IISER Pune uses synthetic molecules that do not bind to any protein, nucleic acid or receptor of cancer cells but destroy cancer cells nevertheless. The group collaborated with Dr Mayurika Lahiri's and Dr Arnab Mukherjee’s groups at IISER Pune bringing together expertise in chemical synthesis with cell biological and computational approaches. The team developed synthetic molecules that were found to form channel type structures in the lipid membrane of cells, disturb the balance of chloride, potassium and sodium ions and kills the cells by a process known as apoptosis.
“In Nature, the disturbance of ionic balance of other biologically relevant ions such as sodium, potassium, and calcium are also linked to apoptosis. Therefore, we envisaged that simultaneous transport of chloride and either of these cations by synthetic molecules can kill the cancer cells more efficiently,” said Prof. Pinaki Talukdar describing the hypothesis that they began this work with.
The team developed small-sized synthetic fluorescent molecules that can aggregate in the lipid bilayer membranes to form supramolecular ion channels. The team observed that the molecules prefer the lipid membranes of cells and showed that channels formed by these molecules can transport chloride, potassium as well as sodium ions across cellular membranes. The team then found that transport of these ions promoted the generation of excess reactive oxygen species (ROS) inside the cancer cells and induced apoptosis, a cell suicide pathway, thus eliminating the cancer cells.
“We have developed here what might be one of the first synthetic versions of the naturally occurring sodium-potassium-chloride co-transporters (NKCCs). This holds great promise for the development of synthetic channels for biomedical applications in cancer treatment,” said Prof. Talukdar commenting on their success.
This work was supported by research grants from SERB, Govt. of India and Department of Biotechnology (DBT), Govt. of India.
The paper “Apoptosis-inducing activity of a fluorescent barrel-rosette M+/Cl− channel” is authored by Javid Ahmad Malla, Rintu M. Umesh, Amal Vijay, Arnab Mukherjee, Mayurika Lahiri, and Pinaki Talukdar and published in the journal Chemical Science (2020) 11: 2420-2428.- By Shanti Kalipatnapu, with inputs from Prof. Pinaki Talukdar