Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.

The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER21 BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER21 BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high-risk subjects, in combination with chemo and/or targeted therapy and/or as post-therapy consolidation or maintenance therapy for the prevention of BC recurrence.There is increasing preclinical evidence that the biguanide Metformin (Met), commonly used for the therapy of Type 2 diabetes, might have activity against several types of neoplastic diseases 1-25 including breast cancer (BC). Another biguanide, phenformin (Phe), which was dismissed from the arsenal of antidiabetes drug because of some side effects, has shown preclinical activity in a model of BC. 26 We and others have recently shown that two populations of human white adipose tissue (WAT) CD45-CD341 progenitors have cooperative roles in BC angiogenesis, local and metastatic progression. [27][28][29][30][31][32][33][34][35] In orthotopic murine models we found that (i) purified human WAT CD341CD131 mesenchymal adipose stromal cell progenitors (ASCs) were not able to migrate but promoted local tumor growth in the mammary fat pad and (ii) purified human WAT CD341CD311 endothelial progenitor cells (EPCs) were able to migrate toward lymph nodes and blood and promoted BC cell EMT, migration, invasion and metastatic growth. 34In another recent study we have found that Met inhibited the formation of capillary-like networks by human umbilical vein endothelial cells (HUVEC), and decreased microvessel density (MVD) in tumor-free mice. 36 Here we report that Met and Phe (with even more efficacy) targeted in vitro and in vivo both BC cells and WAT EPCs, resulting in profound effects on BC angiogenesis, local and metastatic growth that are likely due to additive effects on both tumor and microenvironment cells. These effects were observed both in triple negative and in HER21 models o...

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Obesity is associated with an increased frequency, morbidity, and mortality of several types of neoplastic diseases, including postmenopausal breast cancer. We found that human adipose tissue contains two populations of progenitors with cooperative roles in breast cancer. CD45

A cell population with progenitor-like phenotype (CD45-CD34) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer-derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer..