Abstract
Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (> 90%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and simultaneous induction of a pro-apoptotic state of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.
Highlights
Bax Bcl-2-associated X protein Bcl-xL B-cell lymphoma-extra-large bFGF Basic fibroblast growth factor BRAF V-Raf murine sarcoma viral oncogene homolog B1 CD31 Cluster of differentiation 31 CHL Cholesterol DMEM Dulbecco’s Modified Eagle’s Medium dimethylxanthenone-4-acetic acid (DMXAA) 5,6-Dimethylxanthenone-4-acetic acid DPPC 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine ECM Extracellular matrix PEG-2000-DSPE (N-(Carbonyl-methoxypolyethylene-glycol-2000)-1,2-distearoyl-sn-glycero-3 phosphoethanolamine, sodium salt) EPR Enhanced permeability and retention FasL Fas ligand G-CSF Granulocyte-colony stimulating factor GM-CSF Granulocyte-macrophage-colony stimulating factor HE Hematoxylin and Eosin hypoxia-inducible factor 1α (HIF-1α) Hypoxia-inducible factor 1α HPLC High-Performance Liquid Chromatography HRP Horseradish peroxidase iNOS Inducible nitric oxide synthase IFN-γ Interferon γ IGF-II Insulin-like growth factor 2 IL-12p40 Interleukin 12 p40 IL-12p70 Interleukin p70 IL-13 Interleukin IL-1α Interleukin 1α IL-1β Interleukin 1β IL-6 Interleukin 6 IL-9 Interleukin 9 i.v
After vascular disrupting agents (VDA) treatment, a remaining viable tumor rim, characterized by intratumor overexpression of hypoxia-inducible factor 1α (HIF-1α) and enhanced oxidative stress mediated by tumorassociated macrophages (TAMs), is responsible for selecting aggressive tumor cell phenotypes ready to escape oxygen and nutrient deprivation and accelerating the undesired outcome of the d isease[4,5,6]
These results suggest that the reduction of intratumor production of HIF-1α and of pAP-1 c-Jun by combined liposomal therapy with long circulating liposomes (LCL)-SIM + LCL-DOX significantly weakened the invasive and metastatic ability of B16.F10 melanoma cells, via strong inhibition of MMPs activity
Summary
Bax Bcl-2-associated X protein Bcl-xL B-cell lymphoma-extra-large bFGF Basic fibroblast growth factor BRAF V-Raf murine sarcoma viral oncogene homolog B1 CD31 Cluster of differentiation 31 CHL Cholesterol DMEM Dulbecco’s Modified Eagle’s Medium DMXAA 5,6-Dimethylxanthenone-4-acetic acid DPPC 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine ECM Extracellular matrix PEG-2000-DSPE (N-(Carbonyl-methoxypolyethylene-glycol-2000)-1,2-distearoyl-sn-glycero-3 phosphoethanolamine, sodium salt) EPR Enhanced permeability and retention FasL Fas ligand G-CSF Granulocyte-colony stimulating factor GM-CSF Granulocyte-macrophage-colony stimulating factor HE Hematoxylin and Eosin HIF-1α Hypoxia-inducible factor 1α HPLC High-Performance Liquid Chromatography HRP Horseradish peroxidase iNOS Inducible nitric oxide synthase IFN-γ Interferon γ IGF-II Insulin-like growth factor 2 IL-12p40 Interleukin 12 p40 IL-12p70 Interleukin p70 IL-13 Interleukin IL-1α Interleukin 1α IL-1β Interleukin 1β IL-6 Interleukin 6 IL-9 Interleukin 9 i.v. The involvement of intratumor macrophages in tumor cell resistance to apoptosis and chemotherapy might be exploited for future TAMs-targeted therapies that can counteract negative outcomes of the anti-angiogenic t reatments[8]. In another recent study, when we administered SIM in combination with a VDA, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), the aggressiveness of melanoma cells was suppressed due to the synergistic action on cancer cell proliferation as well as inhibition of protumor function of TAMs in vitro[9]. Our results showed that this novel targeted therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities
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