Lymphoid Organ Proteomes Identify Therapeutic Efficacy Biomarkers Following the Intracavitary Administration of Curcumin in a Highly Invasive Rat Model of Peritoneal Mesothelioma.

This study aimed to identify the proteomic changes produced by curcumin treatment following stimulation of the host immune system in a rat model of malignant mesothelioma. We analyzed the proteomes of secondary lymphoid organs from four normal rats, four untreated tumor-bearing rats, and four tumor-bearing rats receiving repeated intraperitoneal administrations of curcumin. Cross-comparing proteome analyses of histological sections of the spleen from the three groups first identified a list of eighty-three biomarkers of interest, thirteen of which corresponded to proteins already reported in the literature and involved in the anticancer therapeutic effects of curcumin. In a second step, comparing these data with proteomic analyses of histological sections of mesenteric lymph nodes revealed eight common biomarkers showing a similar pattern of changes in both lymphoid organs. Additional findings included a partial reduction of the increase in spleen-circulating biomarkers, a decrease in C-reactive protein and complement C3 in the spleen and lymph nodes, and an increase in lymph node purine nucleoside phosphorylase previously associated with liver immunodeficiency. Our results suggest some protein abundance changes could be related to the systemic, distant non-target antitumor effects produced by this phytochemical.

Curcumin Treatment Identifies Therapeutic Targets within Biomarkers of Liver Colonization by Highly Invasive Mesothelioma Cells-Potential Links with Sarcomas.

Investigations of liver metastatic colonization suggest that the microenvironment is preordained to be intrinsically hospitable to the invasive cancer cells. To identify molecular determinants of that organotropism and potential therapeutic targets, we conducted proteomic analyses of the liver in an aggressive model of sarcomatoid peritoneal mesothelioma (M5-T1). The quantitative changes between SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra) proteotype patterns of the liver from normal rats (G1), adjacent non-tumorous liver from untreated tumor-bearing rats (G2), and liver from curcumin-treated rats without hepatic metastases (G3) were compared. The results identified 12 biomarkers of raised immune response against M5-T1 cells in G3 and 179 liver biomarker changes in (G2 vs. G1) and (G3 vs. G2) but not in (G3 vs. G1). Cross-comparing these 179 candidates with proteins showing abundance changes related to increasing invasiveness in four different rat mesothelioma tumor models identified seven biomarkers specific to the M5-T1 tumor. Finally, analysis of correlations between these seven biomarkers, purine nucleoside phosphorylase being the main biomarker of immune response, and the 179 previously identified proteins revealed a network orchestrating liver colonization and treatment efficacy. These results highlight the links between potential targets, raising interesting prospects for optimizing therapies against highly invasive cancer cells exhibiting a sarcomatoid phenotype and sarcoma cells.

Evaluation of intracavitary administration of curcumin for the treatment of sarcomatoid mesothelioma.

A rat model of sarcomatoid mesothelioma, mimicking some of the worst clinical conditions encountered, was established to evaluate the therapeutic potential of intracavitary curcumin administration. The M5-T1 cell line, selected from a collection established from F344 rats induced with asbestos, produces tumors within three weeks, with extended metastasis in normal tissues, after intraperitoneal inoculation in syngeneic rats. The optimal concentration/time conditions for killing M5-T1 cells with curcumin were first determined in vitro. Secondly, the potential of intraperitoneal curcumin administration to kill tumor cells in vivo was evaluated in tumor-bearing rats, in comparison with a reference epigenetic drug, SAHA. Both agents administered at days 21 and 26 after tumor challenge produced necrosis within the solid tumors at day 28. However, tumor tissue necrosis induced with curcumin was much more extensive than with SAHA, and was characterized by infiltration with mononuclear phagocytic cells. In contrast, tumor tissue treated with SAHA contained foci of resistant cells and was infiltrated by many isolated CD8+ cells. The treatment of tumor-bearing rats with 1.5 mg/kg curcumin on days 7, 9, 11 and 14 after tumor challenge dramatically reduced the mean total tumor mass at day 16. Clusters of CD8+ T lymphocytes were observed at the periphery of small residual tumor masses in the peritoneal cavity, which presented a significant reduction in mitotic index, IL6 and vimentin expression compared with tumors in untreated rats. These data open up interesting new prospects for the therapy of sarcomatoid mesothelioma with curcumin and its derivatives.