Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy

TLDR

Cancer therapies have traditionally aimed at directly killing tumor cells. This study proposes a differential stress resistance strategy that protects normal tissues while sparing cancer cells during chemotherapy. The DSR approach relies on transient starvation to activate protective pathways in healthy cells, leaving cancer cells vulnerable. Starvation-induced DSR conferred up to 1,000‑fold protection to normal cells and mice, but not to various cancer cell lines or tumor xenografts, indicating that transient nutrient deprivation can selectively shield healthy tissues during high‑dose chemotherapy.

Abstract

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2 val19 . Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.