New combination strategy may kill cancer cells better: study

To target the endoplasmic reticulum, the team synthesized a lipid-modified molecule and attached a chemical entity called sulfoxide to its structure such that it would be recognized by the external receptor structure of endoplasmic reticulum. A fluorescent chemical acted as a tracking system tag which traced the path and ascertained the destination of the nanoparticle.

Then, an Hsp 90 inhibiting drug called 17AAG was encapsulated in the lipid nanoparticle to form a nano-package which would quickly disperse in water, which is the chief constituent of cells. The size of the nano packages was so designed to easily enter through pores of cancerous cells and at the same time, be blocked by small healthy cells. By doing so, the team hypothesized that the nano packages target tumor cells explicitly with minimal effect on healthy cells.

When tracked by a confocal microscope, it was confirmed that nano packages reached and permeated into the endoplasmic reticulum and dispersed in the cells. A cell enzyme called Esterase broke opened the nano package to release 17AAG, which inhibited the housekeeping protein Hsp 90, leading to the build-up of unwanted proteins in the tumor cells.

Cell and molecular biology techniques revealed that 17AAG activated stress in the ER, which led to a fair amount of cell death due to the nano packages.

However, cancer cells are known to respond in a ‘smart’ way to the endoplasmic reticulum stress by resorting to autophagy. Autophagy is a survival mechanism of the cancer cells where they eat up their unnecessary proteins to stay alive. To overcome this, chloroquine was introduced, which is an antimalarial drug found to have autophagy inhibitor and anticancer potential. The combination treatment resulted in a significant death of cancer cells.

“Indirect drug treatment, cancer cells get acclimatized to the drug and develop resistance toward it, while the combined strategy may offer a better scope of treatment down the line. Although our research is in the early stages, our work proves that this strategy has the potential as a safer route for cancer treatment,” said Dr. Basu. The team now proposes further studies.

Besides Sudipta Basu, the research team included Chandramouli Ghosh and Aditi Nandi from Indian Institute of Science Education and Research (IISER), Pune. The results were published in journal ACS Applied Biomaterials

By Susheela Srinivas