Why does chemotherapy succeed in some patients, yet fail in other patients? Even within a patient, why does chemotherapy kill some cancer cells, yet spare others? What if scientists could peer directly into cells to see what effects a drug was having? A recent article published in the journal Science shows how this can be done.

The research team from the Weizmann Institute, in Rehovot, Israel, tagged over 1000 different proteins in a human lung cancer cell line with fluorescent tags and created time lapse videos that allowed them to watch movies of individual cells over a 72 hour period. Cells were grown for 24 hours and then treated with a chemotherapy drug, camptothecin (an inhibitor of the protein topoisomerase I, an enzyme involved in the untangling of DNA during replication and transcription). Over the next 48 hours, cells were observed and photographed every 20 seconds, allowing the scientists to get a detailed view each protein—how much of it and where it concentrated—in each cell.

The scientists observed a dramatic decrease in cell division and cell movement after the addition of the drug. Proteins with related functions tended to behave similarly; for example, a group of proteins that are all involved in cell structure and movement all decreased in abundance after the drug treatment. The timing of this decrease is directly correlated with the reduction in cell movement that was observed.

The protein that is the direct target of the drug, TOP1, had the fastest response to the drug. Proteins involved in functions directly related to the DNA also reacted quickly.

In general, a given protein had the same basic response in all cells examined, with a moderate amount of variation. However, the researchers found 24 proteins that had dramatically different responses in different cells after the drug was added. They referred to this phenomenon as a "bimodal" response: after adding the drug, the amount of protein would go up in some cells, but go down or stay the same in other cells. Two of these proteins had responses that were correlated with the fate of the cell; in cells that survived, the amount of protein increased, but in cells that died, the amount of protein decreased. The authors suggest that these proteins may be involved in the response of the cell to the drug, allowing the cell to survive and escape the drug when these proteins are increased.

The authors also examined the behavior of a small number of proteins in the presence of other drugs, and compared the responses to those seen in the presence of camptothecin. Irinotecan, a clinically relevant drug closely related to camptothecin with the same molecular target, elicited very similar protein responses. However, the drug etoposide, and other unrelated drugs, evoked significantly different responses.

The divergent responses of seemingly identical cells to the same drug remains a mystery, but the high-throughput approach described in this article begins to provide insight into the ways in which cells respond to drugs.
— Sheryl Krevsky Elkin

Supporting movies

Reference:
Cohen et al. (2008) Dynamic Proteomics of Individual Cancer Cells in Response to a Drug.
Science 322: 1511-1516. Abstract.