Chemotherapy Side Effect Could Increase Healthy Cell Death

Dexamethasone or rapamycin may raise blood glucose to dangerous levels, leading to healthy cell death.

Results from a new study suggest that short-term fasting may prevent blood sugar spikes associated with cancer drugs. Fasting was also observed to protect healthy cells from being killed by the chemotherapy doxorubicin in mice models.

In the study, which was published by PLOS Biology, mice were treated with doxorubicin monotherapy or a combination of doxorubicin plus dexamethasone or rapamycin, which are traditionally administered during chemotherapy. These drugs are used to manage side effects, but also lead to increased blood glucose levels.

The authors discovered that mice treated with combination therapy experienced worse side effects, including greater damage to heart cells compared with mice treated with monotherapy, according to the study.

"This combination [doxorubicin with dexamethasone or rapamycin] could be very dangerous; it made the mice much more sensitive to chemotherapy and it could also make patients more sensitive to chemotherapy," said researcher Valter Longo, PhD. "What is concerning is that drugs such as dexamethasone could be toxic even though they are often given to patients to reduce minor side effects of chemotherapy treatment."

The investigators speculated that the increased susceptibility of healthy cells to chemotherapy was the direct result of blood sugar levels, since previous studies have shown yeast cells become highly susceptible to toxins when glucose levels are elevated.

To negate the dangerous uptick in blood glucose resulting from dexamethasone or rapamycin, certain mice underwent short-term fasting or a fasting-mimicking diet.

The authors found that mice that received the intervention while treated with combination therapy incurred less damage to heart cells compared with mice that ate a normal diet, according to the study. The authors noted similar benefits among mice that were treated with metformin to control blood sugar levels.

The authors speculate that the protective factor associated with fasting could be related to the PKA/EGR1 signaling pathway. The authors discovered that the glucose PKA/EGR1 pathway in mammalian cells is similar to the PKA Msn2/4 pathway in yeast glucose, according to the study. The PKA Msn2/4 pathway regulates cellular protection.

In previous studies involving yeast, the researchers found that glucose activated that PKA/Msn2/4 signaling pathway and resulted in lower expression of proteins involved in stress.

These findings suggest that patients treated with dexamethasone or rapamycin should be monitored for high glucose levels to prevent the death of healthy cells, which frequently leads to adverse events.

"These findings in mice, together with previous studies indicating that high glucose levels in combination with chemotherapy in patients is associated with an increased risk of developing complicated infections and with a significant increase in overall mortality, should discourage physicians from recommending combination of drugs that promote hyperglycemia and chemotherapy, particularly to reduce relatively minor side effects," Longo concluded.