Dr. Weeks’ Comment: Fasting has a long history of benefit. As part of religious disciplines, it is widely used around the world. Now science tells us that fasting potentiates chemotherapy: “fasting can actually make cancerous cells more susceptible to chemotherapy”
Let’s consider these wise words: “Stop eating while still hungry and do not continue until you are satisfied.” St. John Cassian
“….One of the most surprising findings of this study is the ability of mice of three different genetic backgrounds that have been starved for 48-60 h to show no visible signs of toxicity in response to doses of chemotherapy highly toxic to control animals and gain back the 20-40% of weight that was lost during starvation even in the presence of doses of etoposide that caused a 20-30% weight loss and killed 40% of the control mice…”
Starving the Beast
Feb 9th 2012, 22:02 by T.C
DENIAL, famously, is good for the soul. It is also good for the body. Scientists have known for decades that animals fed near-starvation diet in laboratories see dramatic boosts in their lifespans. A lack of nutrients seems to spur the activity of cellular repair mechanisms, which help to slow the gradual accumulation of cellular damage that is one cause of aging.
Some humans, too, try to cheat aging by starving themselves. No one yet knows if such forbearance has the desired effect on members of Homo sapiens. In the meantime, though, boosting a body’s repair mechanisms may have other uses. One could be in cancer treatment, where fasting seems both to protect healthy tissue and to make tumours easier to treat.
In 2008 a group led by Lizzia Raffaghello, a biologist at the University of Southern California (USC), published a paper suggesting that a short, sharp course of fasting””not eating at all for a few days, as opposed to months of eating much less than normal””could make ordinary, non-cancerous cells more resistant to the side-effects of chemotherapy, at least in yeast and mice. If the same results were found in humans, it could mean less suffering for cancer patients; or it could free doctors to use higher doses of chemotherapy in an attempt to tackle cancers more aggressively.
But fasting may bring other benefits, too. On February 8th Valter Longo, one of Dr Raffaghellos’ colleagues at USC (and a contributing author to her paper from 2008) published a paper of his own showing that””again in yeast and in mice””fasting can actually make cancerous cells more susceptible to chemotherapy than they otherwise might be. Cancerous mice treated with a combination of chemotherapy and fasting had better survival chances and smaller tumours, for several different types of cancer, than those treated with either fasting or chemotherapy alone. In some cases, the combination treatment eradicated even metastasised cancers completely.
The researchers suggest that the explanation for this double bill of fewer side effects and more vulnerable tumours is that cancer cells do not do what the rest of the body would like them to. In thin times, normal cells switch their attention away from reproduction and towards preservation, beefing up their repair mechanisms, and hunker down to wait for better days.
Not so cancer cells which, after all, are distinguished by their reckless proliferation. So while ordinary cells become resistant to chemotherapy drugs following a fast, cancer cells do not. In fact, in Dr Vango’s study, tumour cells seemed to boost their activity levels during times of famine. That, in turn, boosted the quantity of free radicals, highly oxidising and damaging chemicals produced as a side-effect of metabolism, inside them. Thus stressed, the tumour cells found it much harder to cope with the added battering from chemotherapy drugs.
The usual caveats apply, as they do to all studies of lab animals; mice and yeast cells are not human. But if fasting shows similar effects in humans with cancer””and early-stage clinical trials are already under way””then the attractions are obvious. Fasting is cheap, safe and, in theory, should work against a wide variety of cancer types. Not quite a magic bullet, then, but not far off.
Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy.
Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
….The data above indicate that STS protects normal cells and mice but not a variety of cancer cells treated with ROS or certain chemotherapy drugs that are also implicated in the generation of ROS. In yeast, worms, and mice, starvation or the genetic manipulation of starvation response pathways causes a major increase in life span and protection against multiple stresses including heat shock and oxidative damage. In mammals, starvation causes a reduction in IGF1 signaling, which is associated with increased stress resistance (5). For example, CR protects mice against liver cell death caused by acetaminophen (9) and against carcinogen-induced cancer (11). Furthermore, CR protects against the development of spontaneous tumors in mice (12, 31).
Here, we show that yeast Ras and Sch9, orthologs of components of two of the major oncogenic pathways activated by IGF1, regulate starvation-dependent resistance to oxidants or alkylating agents. As anticipated based on the constitutive activation of
pathways that included homologs of yeast Ras and Sch9 in cancer cells, starvation (STS) was highly effective in protecting mammalian cells and mice but not cancer cells against the toxicity of chemotherapy drugs including oxidants and alkylating agents. Although we have not investigated the role of IGF1 in the mediation of DSR in mammalian cells and mice, others have shown a 40% decrease in IGF1 in CD-1 mice that were starved for 36 h (32), raising the possibility that decreasing IGF1 signaling may mediate in part the protective effect of starvation. One of the most surprising findings of this study is the ability of mice of three different genetic backgrounds that have been starved for 48-60 h to show no visible signs of toxicity in response to doses of chemotherapy highly toxic to control animals and gain back the 20-40% of weight that was lost during starvation even in the presence of doses of etoposide that caused a 20-30% weight loss and killed 40% of the control mice. This high resistance to a drug that damages the DNA of dividing cells, particularly blood cells, would be consistent with the entry of most or all of the normally dividing cells into a high-protection/ cell-cycle-arrested mode in response to the 48- to 60-h starvation (Fig. 5D). Because etoposide is rapidly excreted (up to 90% within 48 h in humans), such a ”˜”˜protective mode” may only need to last for a few days. Our recent results in S. cerevisiae indicate that the lack of SCH9, and to a lesser extent starvation, protected against DNA damage in cells lacking the RecQ helicase SGS1, which forms a DNA repair complex with topoisomerase III, by reducing errors during DNA repair (18). It will be important to establish whether STS or reduction of IGF1/Akt/S6K signaling can protect mammalian cells against the topoisomerase II inhibitor etoposide by similar mechanisms.
Chemotherapy treatment often relies on the combination of several DNA-damaging agents such as etoposide, CP, and doxorubicin. Although these agents are supposedly much more toxic to cancer cells than to normal cells, our in vitro studies show that CP, for example, can be as or more toxic to primary glial cells than it is to glioma cancer cells. This implies that the combination of multiple chemotherapy drugs causes massive damage not only to blood cells but also other tissues, especially at high doses. Notably, the DSR of mammalian cells to the alkylating agent CP by our starvation-response methods was 10-fold, whereas starved yeast lacking SCH9 reached a 1,000-fold higher resistance to menadione and hydrogen peroxide compared with RAS2 val19-expressing yeast cells (Fig. 1). Furthermore, the 1,000- fold differential toxicity in yeast was obtained after only 30 min with hydrogen peroxide compared with the several days required for the differential toxicity of MMS or CP. Although toxic molecules such as hydrogen peroxide are not suitable for human cancer treatments, these results suggest that the identification of novel chemotherapy drugs and possibly agents that generate a high level of ROS in combination with DSR has the potential to result in an even more rapid and effective toxicity to cancer cells.
The ability to reach a 1,000-fold or much more modest differential toxicity between cancer cells and normal human cells would lead to improved therapies for many cancers. Naturally, we do not know whether such an elevated DSR can be achieved in cancer patients, but considering the results obtained with a single treatment with etoposide in mice bearing metastasis of the aggressive NXS2 neuroblastoma line that we injected, we are optimistic about the potential efficacy of multiple cycles of STS/etoposide treatment against different types of cancers.
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.
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