The combination of the FMD and DXR/CP had an additive effect on tumor suppression, causing a three-fold reduction in tumor volume compared to that observed in ad lib-fed counterparts ( Figures 1C-1E). Similar effects of the FMD were also observed in a murine melanoma (B16) model, in which mice were treated with DXR ( Figure 1E). Four days of FMD feeding were as effective as two days of STS in retarding tumor growth and reducing circulating IGF-1 in the absence of chemotherapy ( Figures 1A and 1B), and in sensitizing cancer cells to doxorubicin (DXR) and cyclophosphamide (CP) ( Figures 1C, 1D, S2C, and S2D)( Lee et al., 2012 Lee et al., 2010 Raffaghello et al., 2008). Here we tested the efficacy of cycles of the FMD ( Brandhorst et al., 2015) in inducing DSS in a syngeneic murine breast cancer (4T1) model ( Figure S1).
We have previously shown that STS is safe and effective in inducing DSS via IGF-1 signaling ( Lee et al., 2012 Raffaghello et al., 2008 Safdie et al., 2009). Here, we tested the effect of FMD in combination with chemotherapy on the immune system, and on the immunogenicity of cancer cells.Ī Fasting-mimicking diet (FMD) alone or in combination with chemotherapy is as effective as short-term starvation (STS) in reducing tumor progression This FMD reduces circulating IGF-1 and glucose, two major factors involved in DSR and DSS, to levels similar to those observed during STS ( Brandhorst et al., 2015). Because water only STS is challenging for mice and cancer patients, we have developed a fasting-mimicking diet (FMD) that is low in calories, protein, and sugar ( Brandhorst et al., 2015). Recently, we also reported that STS promotes hematopoietic stem cell (HSC) self-renewal and reverses chemotherapy-induced immunosuppression ( Cheng et al., 2014).
We have previously shown that a short-term starvation (STS) can selectively sensitize cancer cells to chemotherapeutics (differential stress-sensitization DSS), while simultaneously protecting normal cells from its side effects (differential stress-resistance DSR) ( Lee et al., 2012 Raffaghello et al., 2008) via the insulin-like growth factor 1 (IGF-1) pathway ( Lee et al., 2010). Conversely, some chemotherapeutics, such as anthracyclines, are known to stimulate the recognition of cancer cells by the immune system ( Arinaga et al., 1986 Casares et al., 2005 Orsini et al., 1977), which may potentiate the effect of some immune-based therapies. Such therapeutic inefficacy and tumor resistance can also be caused by regulatory T cells (Tregs), which can suppress the lymphocytic activity through a mechanism mediated by heme oxygenase-1 (HO-1) ( Choi et al., 2005 El Andaloussi and Lesniak, 2007). The immunosuppressive effect of some standard interventions, including radiotherapy and chemotherapy ( Weinblatt et al., 1985 Weiner and Cohen, 2002), can compromise their therapeutic efficacy ( Balow et al., 1975 Rasmussen and Arvin, 1982). Moreover, some traditional cytotoxic chemotherapeutics rely on the cooperation of the patient's immune system to eliminate cancer cells ( Alizadeh et al., 2014 Arinaga et al., 1986 Bracci et al., 2014). The importance of a healthy immune system is underlined by the fact that immunosuppressed/immunocompromised subjects are at a higher risk for cancer ( Zitvogel et al., 2006).
Cancer immunotherapy exploits this property of the immune system to recognize and eliminate cancer cells ( Vesely et al., 2011 Zitvogel et al., 2008) by triggering the activation of inherent antitumor T cells ( Pardoll, 2012 Wolchok et al., 2013) or through the reintroduction of engineered T cells into patients ( Burns et al., 2010 Maude et al., 2014). Immune cells act as sentinels that recognize peptides originating from mutated genes and eliminate malignant and possibly pre-malignant cells ( Rock and Shen, 2005).
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