Abstract
Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose–PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.
Highlights
Despite advances in cancer therapy, the standard of care predominantly includes chemotherapy, radiotherapy, or their combination
Because glucose sensitizes yeast cells to stress and considering that several widely used drugs that increase glucose levels are administered in combination with chemotherapy, we tested the role of glucose reduction on the sensitivity of normal cells and mice to the chemotherapy drug doxorubicin (DXR)
We show that fasting or glucose restriction (GR) reduce protein kinase A (PKA) activation and increase AMP-activated protein kinase (AMPK) activity
Summary
Despite advances in cancer therapy, the standard of care predominantly includes chemotherapy, radiotherapy, or their combination. These treatments are associated with a multitude of side effects ranging from discomfort to the development of secondary tumors and severe toxicity to multiple systems [1,2,3,4]. To increase the efficacy of cancer treatment or to help with the management of the adverse effects of the therapy, other drugs such as dexamethasone (Dexa), aprepitant, and lorazepam are often used in combination with chemo- and radiotherapy [7, 8]. The corticosteroid Dexa is mainly used as a palliative drug but can be effective in the treatment of multiple myeloma, leukemia, and lymphoma [9,10,11,12]. Treatment with Dexa can raise blood glucose levels [13, 14], and several studies have proposed that it can promote toxicity in the brain [15, 16]
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