Abstract
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.
Highlights
Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome
From the four malignant mesothelioma cell lines in our biocollection, which were isolated from F344 rats induced with asbestos, the M5-T1 cell line was selected for this study because of its high invasive capacity in vitro (Figure 1A)
In this study we determined the curcumin concentration/ time combination that led to the killing of all tumor cells in vitro without the generation of resistant cells, and these results were compared with those observed after treatment with 10 μM suberoylanilide hydroxamic acid (SAHA) or 10 μM cisplatin
Summary
Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome. Despite some advances in chemotherapy with the association of cisplatin and pemetrexed [2], in over a decade there has been no significant progress in systemic treatment for MM [3], and this depressing www.impactjournals.com/oncotarget situation is mainly due to the to a lack of understanding of the complex biology of this cancer [4]. The situation is even more complicated by the fact that MM is often detected late in the development of the disease, with patients presenting with advanced cancers associated with breathlessness and pain [5]. Nearly two-thirds of patients fail to show a response to current procedures. To improve outcomes for patients with such aggressive cancers, clinicians are faced with two challenges. The second is to stimulate recognition of tumor cells by induction of a specific immune response directed towards eradicating residual tumor cells and avoiding early relapses
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