Starvation-dependent differential stress resistance protects normal but not cancer cells against 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 . Lowglucose 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/prooxidant 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.reactive oxygen species ͉ short-term starvation ͉ maintenance mode O ur studies in S. cerevisiae and those of others in worms, flies, and mice have uncovered a strong association between lifespan extension and resistance to oxidative stress (1-6). This resistance is observed in long-lived yeast cells lacking RAS2 and SCH9, the orthologs of components of the human Ras and Akt/S6K pathways (2, 5, 7), and in long-lived worms and mice with reduced activity of homologs of the IGF1 receptor (IGF1R), implicated in many human cancers (8). Notably, the IGF1R functions upstream of Ras and Akt in mammalian cells (3-6). Stress resistance is also observed in model systems in which calorie intake is reduced by at least 30% (9). This reduced calorie intake, also known as calorie restriction (CR) or dietary restriction (DR), has been studied for many years and is known to extend life span in organisms ranging from yeast to mice (10). CR also protects against spontaneous cancers and against carcinogen-induced cancers (10-12), raising the possibility that CR and reduced IGF1 may increase stress resistance by similar mechanisms.Our discovery of the role of Ras2 and Sch9 in the negative regulation of antioxidant and other protective systems together with the association between mutations that activate IGF1R, Ras, or Akt and many human cancers prompted our hypothesis that normal but not cancer cells would respond to starvation or down-regulation of Ras/Akt signaling by entering a stressresistance mode. In fact, one of the major ''hallmarks of cancer cells'' is the self-sufficiency for growth signals (13). In the majority of cancers, this ability to grow or remain in a growth mode even in the absence of growth factors is provided by the hyperactivation of one or several components of the IGF1R, Ras, Akt, and mTor pathways.Here, we tested the hypothesis that short-term starvation (STS) or low glucose/low serum can protect mammalian c...

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…As discussed in more detail later, in mice, fasting for 48-60 h increases protection from oxidative stress and protects three different strains of mice to etoposide, a drug known to promote oxidative stress, with remarkable improvement in survival compared with its normally fed counterparts (Raffaghello et al, 2008). In addition, 72-h of fasting protects the outbred CD-1 (Longo and Finch 2003a, b;Holehan and Merry, 1985) Required time 2-3 days (Raffaghello et al, 2008;Lee et al, 2010;Mitchell et al, 2009) Weeks-months (Longo and Finch 2003a, b;Fontana et al, 2010) Abbreviations: DR, dietary restriction; FFA, free fatty acid; GH, growth hormone; IGF-I, insulin-like growth factor 1; TG, triglycerides.…”

“…In addition, 72-h of fasting protects the outbred CD-1 (Longo and Finch 2003a, b;Holehan and Merry, 1985) Required time 2-3 days (Raffaghello et al, 2008;Lee et al, 2010;Mitchell et al, 2009) Weeks-months (Longo and Finch 2003a, b;Fontana et al, 2010) Abbreviations: DR, dietary restriction; FFA, free fatty acid; GH, growth hormone; IGF-I, insulin-like growth factor 1; TG, triglycerides. Reduction in glucose and increased utilization of protein and lipid occur following both fasting and DR, but more pronounced in the former (Al-Regaiey et al, 2007;Felgines et al, 1999;Filaire et al, 2004;Lee et al, 2010;Menahan and Sobocinski 1983;Spindler et al, 1990;Wang et al, 2006).…”

“…DR in rats, maintains body weight at 50% of control, reduced both litter number and size (Holehan and Merry 1985). It should be noted that one of the major differences between fasting and DR is the time required to reach the desired stress-resistant state, which makes fasting a much more applicable dietary intervention Lee et al, 2010;Longo and Finch 2003a;Mitchell et al, 2009;Raffaghello et al, 2008).…”

“…Fasting has been demonstrated to selectively protect normal cells and mice, but not cancerous cells against oxidants and common chemotherapeutic agents (Longo et al, 1997;Raffaghello et al, 2008). In cancer patients, preliminary data suggest that fasting is not only safe and feasible, but may also be effective in reducing common side-effects associated with chemotherapy (Safdie et al, 2009).…”

Sugar-free approaches to cancer cell killing

“…In this sense, an in vivo study showed that the treatment with 2-DG concomitantly with doxorubicin led to inhibition of apoptosis induced by this DNA-damaging drug in intestinal cells (Thakkar and Potten, 1993). Moreover, Regulation of tumor cell death by the glycolytic metabolism N El Mjiyad et al a differential effect of the influence of low glucose on chemotherapy resistance between normal and tumor cells has been observed (Raffaghello et al, 2008). Low glucose protected only primary glial cells, but not glioblastoma cancer cell lines, from cyclophosphamide.…”