In their bid to tackle cancer, scientists have been
trying out newer and innovative strategies. In a preliminary study, Indian scientists have
explored the possibility of reaching out to cancer cells and triggering their natural programmed
death.
This approach uses the combined effect of targeting and inducing a ‘stress’ inside the cell
structures called Endoplasmic Reticulum of tumour cells, along with administering a small
amount of a drug. Laboratory tests on cervical cancer cell lines have found that the
combination treatment increases death of cancer cells due to apoptosis or natural cell
disintegration.
Endoplasmic Reticulum is a network of folded membrane spreading across the cell. It is the
protein and lipid factory of the cell, responsible for manufacturing, packaging and dispersing of
various functional proteins for the body.
The production process sometimes yields unwanted proteins, which are immediately scavenged
away by another resident protein called Hsp 90. When Hsp 90 stops functioning many waste
proteins build up inside the cell, creating stress, which eventually kills the cell.
The present study focuses on inhibiting Hsp 90 in cancer cells, thereby initiating their death.
“The key aspect of our research is to navigate inside cancer cells, reach the protein synthesis
organelle and trigger stress into it for therapy. For this, we have engineered a nanoparticle
which can do that as well as show us how it reaches its target, in this case, endoplasmic
reticulum, inside the cancer cells,” explained Dr Sudipta Basu, the lead researcher of the study
at the Indian Institute of Technology, Gandhinagar, while speaking to India Science Wire.
To target the endoplasmic reticulum, the team synthesised a lipid modified molecule and
attached a chemical entity called sulfoxide to its structure such that it would be recognised 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 hypothesised
that the nano packages target tumour cells explicitly with minimal effect on healthy cells.
When tracked by a confocal microscope, it was confirmed that nano packages reached and
permeated into 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 tumour 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.
“In direct drug treatment, cancer cells get acclimatized to the drug and develop resistance
toward it, while combined strategy may offer a better scope of treatment down the line.
Although our research is in 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 (India Science Wire)
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