Abstract
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor, often associated with exposure to asbestos and characterized by poor prognosis and limited treatment options. The biologically active form of vitamin D, calcitriol, exerts anticancer effects in many cell types, both alone and in combination with chemotherapy drugs, through binding to vitamin D receptor (VDR); however, the role of calcitriol in MPM is still unknown. This study aimed to determine the potential antitumor role of calcitriol in MPM. The results showed that calcitriol reduces cell viability and proliferation in human MPM cells lines, which express both cytoplasmic and nuclear VDR; furthermore, calcitriol potentiated the inhibitory activity of the chemotherapy drug PEM. These effects were paralleled by cell cycle arrest and inhibition in expression of c-Myc and cyclins involved in cell cycle progression. Exposure of MPM cells to calcitriol also produced an alteration in mitochondrial function and inhibition in the expression of respiratory chain complex subunits. Finally, the inhibitory effects of calcitriol were also observed on viability of human primary MPM cells. Collectively, these results indicate a novel anticancer role for calcitriol in MPM, suggesting potential for vitamin D derivatives, alone or in combination with chemotherapy, in the treatment of this malignancy.
Highlights
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a dismal prognosis, that occurs because of malignant transformation of pleural mesothelial cells
This study shows that calcitriol, the active form of vitamin D, reduces cell viability and growth of MPM cells; calcitriol potentiates the cytotoxic effect of the chemotherapy drug PEM
The biological activity of calcitriol is mainly regulated by vitamin D receptor (VDR), which modulates the expression of many target genes [5, 28]
Summary
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a dismal prognosis, that occurs because of malignant transformation of pleural mesothelial cells. The principal cause of MPM development is exposure to asbestos, different minerals, such as erionite and radiation therapy in patients treated for other cancers, have been implicated [1]. Exposure to asbestos generates a chronic inflammatory state, with activation of macrophages, production of reactive oxygen species and mediators of inflammation, such as cyclooxygenases, cytokines and growth factors, all promoting tumor formation [2]. Some MPM have an epithelial morphology, the most frequent and less malignant variant, others sarcomatoid, with the worst prognosis, while a mixed biphasic population comprising both histologic subtypes exists [2, 3]. The first-line treatment for inoperable patients with MPM consists in a combination of cisplatin and the antifolate pemetrexed (PEM), which, increase overall survival only of 9–12 months, novel therapeutic strategies are urgently needed [4].
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