The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

Abstract

14 Background: The effects of diet in cancer, in general, and breast cancer in particular, 15 are not well understood. Insulin inhibition in ketogenic, high fat diets, modulate 16 downstream signaling molecules and are postulated to have therapeutic benefits.17 Obesity and diabetes have been associated with higher incidence of breast cancer.18 Addition of anti-cancer drugs together with diet is also not well studied.19 Methods: Two diets, one ketogenic, the other standard mouse chow, were tested in a 20 spontaneous breast cancer model in mice. The diets were implemented either with or 21 without added rapamycin, an mTOR inhibitor and potential anti-cancer drug.22 Results: Blood glucose and insulin concentrations in mice ingesting the ketogenic diet 23 (KD) were significantly lower, whereas beta hydroxybutyrate (BHB) levels were 24 significantly higher, respectively, than in mice on the standard diet (SD). Growth of 25 primary breast tumors and lung metastases were inhibited, and lifespans were longer in 26 the KD mice compared to mice on the SD (p<0.005). Rapamycin improved survival in 27 both mouse diet groups, but when combined with the KD was more effective than when 28 combined with the SD.29 Conclusions: The study provides proof of principle that a ketogenic diet a) results in 30 serum insulin reduction and ketosis in a spontaneous breast cancer mouse model; b) 31 can serve as a therapeutic anti-cancer agent; and c) can enhance the effects of 32 rapamycin, an anti-cancer drug, permitting dose reduction for comparable effect.33 Further, the ketogenic diet in this model produces superior cancer control than standard 34 mouse chow whether with or without added rapamycin. 36 Introduction 37Insulin inhibition by a ketogenic diet has been shown to slow cancer growth and 38 prolong survival in animal models and has shown safety and feasibility in small pilot 39 studies in humans [1], [2] [3] [4] . We previously demonstrated in a pilot study of ten 40 people with diverse, metastatic PET positive cancers that higher levels of ketosis 41 correlated with stability vs. disease progression [5]. The full potential of ketosis in 42 cancer therapy, however, may reside in its potential to synergize with anti-cancer drugs 43 and other modalities of treatment. Increased overall efficacy may permit lower drug 44 doses, thereby reducing their toxicities and side effects. Accordingly, it may be possible 45 that the overall improvement in therapy will result in extended survival with a better 46 quality of life. 47 An understanding of ketogenic diets (KD) in cancer is limited at this point but it 48 seems unlikely that KDs by themselves can control all the features of the oncogenic 49 state. There is much interest, therefore, in the possibility of synergy with other drugs or 50 other therapies. Hsieh, et al., for example, demonstrated that a squamous cell 51 carcinoma that over expressed GLUT1 receptors showed attenuated growth when 52 animals were on a KD [6]. There was, however, little regression of tumors. The addition 53 of th...

Avenues of research in dietary interventions to target tumor metabolism in osteosarcoma

“…For instance, KD synergized with radiation therapy [142] and chemotherapy [143,144], leading to significantly smaller gliomas and prolonged survival in mice in comparison to stand-alone treatments and controls. Similar effects were observed in neuroblastoma [145] and breast cancer [146] mouse models treated with KD and chemotherapy, as well as in a lung cancer mouse model treated with KD, chemotherapy and radiation therapy [147].…”

Management of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia

“…Mice on a ketogenic diet also had reduced lung metastasis. 47 The ketogenic diet also improved responses to PI3Kis in various preclinical models of cancer, including PIK3CA -mutated breast cancer. 26 …”

Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions

“…The anticancer effects of KD were also investigated. For example, in a mouse model, KD alone has been shown to inhibit the growth of a variety of tumors [ 279 , 280 ]. In mice with pancreatic cancer, combining radiotherapy with KD may improve radiation sensitivity and extend survival time compared to radiotherapy alone [ 281 ].…”

“…In mice with pancreatic cancer, combining radiotherapy with KD may improve radiation sensitivity and extend survival time compared to radiotherapy alone [ 281 ]. Additionally, it may enhance the anticancer properties of rapamycin and other chemotherapeutic agents [ 279 , 282 ]. In humans, KD has been shown to enhance the effects of chemotherapy, promote the incidence of complete or partial responses, and increase patient survival rate without inducing side effects [ 283 - 285 ].…”