Circadian Rhythms Could Improve Chemotherapy for Triple-Negative Breast Cancer

Every cell in the human body runs according to its own internal clock, including cancer cells.

Research from the Charité in Berlin, Germany, Europe’s largest university hospital, suggests that aligning chemotherapy with these roughly 24-hour circadian cycles could markedly enhance treatment.

Circadian rhythms in triple-negative breast cancer

In experiments involving triple-negative breast cancer cells, an especially aggressive cancer that is difficult to treat, scientists found that the performance of one chemotherapy medicine varied by as much as 30 percent according to when it was given to particular cell lines.

"Overall, our findings indicate that personalized treatment plans based on individual circadian rhythms could substantially improve the efficacy of cancer treatment," concludes computational biologist Adrián Enrique Granada from the Charité Comprehensive Cancer Center (CCCC).

A cell’s internal timekeeping system consists of clock-regulated genes and protein feedback loops, which keep the cell coordinated with the rest of the body.

Key ‘clock’ genes encode cellular proteins that are produced in a daily rhythm. These proteins influence the cell’s metabolism, proliferation, immune response, DNA repair and even death.

The timing of every cellular clock differs according to the tissue where the cell resides. Liver-cell circadian clocks, for example, are strongly shaped by meals, whereas the daily rhythm of brain cells is closely linked to light.

Cancer cells have internal clocks of their own as well, and their growth and division may occur at different times of day depending on the cancer type.

For example, research published in 2022 showed that breast cancer cells taken from human patients divide and spread more rapidly at night.

A further study released earlier this year found that the 24-hour circadian cycle can affect both the strength of tumour defences and a medicine’s capacity to penetrate them.

Using the chronotherapeutic index to time chemotherapy

Investigating the way cellular clocks affect disease progression is a developing area of research. "Yet, uncovering the optimal treatment timings remains challenging," explain cell biologist Carolin Ector, from CCCC, and her colleagues from institutes in Germany and Luxembourg.

The researchers developed a new approach for modelling and tracking living cells, including their circadian rhythms, growth and responses to drugs.

They have named the technique the "chronotherapeutic index", which in effect identifies the most suitable time of day for delivering a medicine.

This screening method can be used with many cell types, including non-malignant skin cancer cells and malignant bone cancer cells. However, the team demonstrated its potential with triple-negative breast cancer cells.

Across the various cancer cell lines, their screening approach ultimately detected 80 clearly distinct cancer-cell responses based on when the chemotherapy drugs 5-fluorouracil, cisplatin and doxorubicin were administered.

For one specific breast cancer cell lineage, chemotherapy produced the greatest overall benefit 10 to 12 hours and 18 to 20 hours into the approximately 24-hour cellular cycle. Treating the cells earlier delivered the least benefit.

When used on that same cell line, the chemotherapy drug 5-FU displayed a "clear preference for administration" from 8 to 10 hours into a cycle. Torin and paclitaxel, meanwhile, had greater variation in the timings of their maximum and minimum benefits.

Different cell lines, different treatment windows

In contrast, two other breast cancer cell lines achieved their greatest treatment benefits throughout the day. Put simply, the timing of chemotherapy administration mattered less for these cells.

The work was carried out only in cells, although the researchers hope that their new index will help shape future cancer treatments.

"We're also planning to study the molecular mechanisms behind the circadian influences on medication sensitivity to further optimize treatment times and identify new therapeutic targets," says Granada.

The study was published in Nature Communications.