22 February 2018
Shields for resistant cancer cells
Published online 13 November 2016
Epigenetic reprogramming can sensitize cancer cells that are resistant to chemotherapies.
Scientists unveil the mechanism by which cancer cells can develop resistance against irinotecan — a chemotherapeutic agent frequently used against solid tumours such as colorectal and breast cancer.
Irinotecan induces irreversible DNA breaks. These breaks are normally sensed by an army of gatekeepers at cell cycle ‘checkpoints’ eventually inducing apoptosis — the programmed death — of cancer cells. However, during the course of treatment, cancer cells can (through previously undefined mechanisms) learn to outsmart irinotecan.
Now, scientists from multiple research centers in the United Kingdom and Zewail City of Science and Technology in Egypt have revealed in a new study published in Nucleic Acids Research1 how specific epigenetic modifications empower cancer cells against irinotecan.
The study not only shows how irinotecan-resistant cells are able to bypass cell cycle ‘checkpoints’ and in turn avoid the programmed cell death, but also how these cells quickly self-repaired, compared to irinotecan-sensitive cells.
Interestingly, changes in the acetylation of the histones wrapped around the DNA have been implicated in this mechanism. By manipulating these changes, the cells’ ability to resist death can be hindered.
"The histone mark proteins are like the directors in a movie that can eliminate, slow down or speed up certain scenes or dialogues, altering the movie for better — cancer cell death — or worse — cancer cell survival," explains principal investigator, Sherif El-Khamisy, the director of the Center for Genomics at Zewail City.
“We were able to reprogram the outcome by inhibiting the activity of the enzyme that controls the ‘scene’ ensuring that the movie always has a happy ending — i.e. reversing the resistance of cancer cells,” adds El-Khamisy.
- Meisenberg C. et al. Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan. Nucleic Acids Res. http://dx.doi.org/10.1093/nar/gkw1026 (2016).