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How cells’ ‘lava lamp’ effect could make cancer drugs more powerful – Biodiversity Nepal
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How cells’ ‘lava lamp’ effect could make cancer drugs more powerful

Discovery that synthetic compounds form concentrated droplets inside cells could shake up drug development — including the hunt for coronavirus treatments.

Fluorescently tagged molecules of the cancer drug cisplatin clump up inside droplets in cells.Credit: Isaac Klein/Whitehead Institute

There’s a long-standing assumption in the pharmaceutical industry that when drug molecules enter a cell, they spread through it evenly — but, says biologist Rick Young, “that could not be further from the truth”.

In a study published in Science, Young and his colleagues at the Whitehead Institute in Cambridge, Massachusetts, show that cancer-drug compounds become concentrated in precise spots in cells — because of a phenomenon called phase separation by which all cells partition their contents.

The results challenge basic assumptions about the action, dynamics and distribution of small-molecule therapeutics. They are already leading to new strategies for drug design in the fight against the new coronavirus — and could help to explain why so many therapies that work in a laboratory dish ultimately fail to treat people.

“This paper has the chance to reshape our understanding of drug metabolism and drug targeting to cells,” says Jonathon Ditlev, a cellular biophysicist at the Hospital for Sick Children in Toronto, Canada.

Biological material has a simple way of establishing order inside cells. Like blobs in a lava lamp or oil shaken in water, proteins, RNA and other cellular components can self-organize into liquid-like droplets known as condensates, which help to compartmentalize the cell’s insides.

Researchers have previously shown that this effect occurs in natural molecules, but the latest work reveals that synthetic compounds can be selectively sequestered in droplets in a similar way. The phenomenon could be exploited to make certain drugs hit their targets more effectively while limiting unintended toxicity that causes harmful side effects.

“If we can begin to understand how these condensates discriminate between small molecules, we can begin to develop ways of taking advantage of existing condensates so we can better treat disease,” says Ditlev.

Clusters of cisplatin

In the study, Young and his team tracked the dynamics of five small-molecule cancer drugs inside condensates, in test-tube experiments and in human cancer cells in culture. They started with cisplatin, the cornerstone drug of many chemotherapy regimens. By mixing cisplatin with proteins known to form condensates in the cell nucleus, the researchers showed that it selectively clusters inside droplets formed by a gene-activating protein called MED1.

Wherever MED1 was found, cisplatin molecules assembled: concentrations of the drug inside the condensates were 600 times greater than those outside. MED1 mainly acts on cancer-promoting genes, so cisplatin ends up targeting the same DNA with its toxic platinum atoms, the researchers showed — essentially hitting cancer cells where it hurts most.

The effect also seems to influence drug resistance. The team showed that the breast-cancer drug tamoxifen also nestles into MED1 condensates. But cancer cells that are resistant to tamoxifen produce much higher levels of MED1, and the team found that this causes the condensates to balloon in size, diluting the drug and weakening its effect.

“Every cancer drug we’ve examined finds itself concentrated in these phase-separated condensates,” says Young. “I don’t know of a case where you can ignore this.”

The team is now trying to find out why drug molecules enter condensates. “If we can understand more about the molecular ‘grammar’, then we might be able to modify small molecules so that we can get them concentrated in the right spot,” says study co-author Isaac Klein, an oncologist at the Whitehead Institute.

Coronavirus condensates

Klein and co-author Ann Boija, a molecular biologist at the Whitehead Institute, have spent the past two months applying lessons from this work to the fight against SARS-CoV-2, the coronavirus that causes COVID-19.

In unpublished experiments, they have found that three key viral proteins involved in SARS-CoV-2’s replication machinery clump together in condensates that can absorb and concentrate drug compounds.

“This is the result we need to start screening small molecules for their ability to both inhibit viral RNA replication and to partition selectively into condensates where that replication occurs,” Young says. The only antiviral drug proven to have any effect against COVID-19 in a rigorous trial — a molecule called remdesivir — provided only a modest benefit, and Young suspects that poor partitioning could be the reason.

Phase separation “is going to be part of drug discovery from now on”, says Mark Murcko, chief scientific officer at Dewpoint Therapeutics in Boston — a company that Young co-founded in 2018 with Tony Hyman, a cell biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. Dewpoint aims to develop drugs that exploit condensate biology by disrupting condensates implicated in disease, or by accumulating in specific condensates in the cell.

But not everyone is convinced. Robert Tjian, a biochemist at the University of California, Berkeley, thinks that scientists have rushed to link condensates to multiple biological processes, even though other mechanisms could account for how both natural and synthetic molecules accumulate inside cells. And he worries that the excitement generated by papers such as Young’s could set off a search for drugs designed to enter phase-separated droplets that might only exist in the lab. “It’s a bit of a house of cards,” he says.

Written By Elie Dolgin for Nature

doi: 10.1038/d41586-020-01838-z

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