Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells

Our plain-English summary of Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells, by I. Gesmundo, F. Silvagno, D. Banfi, et al (Frontiers in Endocrinology, 2020).

The study

• Authors: I. Gesmundo, F. Silvagno, D. Banfi, V. Monica, A. Fanciulli, G. Gamba, N. Congiusta, R. Libener, C. Riganti, E. Ghigo, R. Granata
• Journal: Frontiers in Endocrinology
• Published: 2020;11:559586
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Copyright © 2020 Gesmundo, Silvagno, Banfi, Monica, Fanciulli, Gamba, Congiusta, Libener, Riganti, Ghigo and Granata.

In plain English

This laboratory study tested calcitriol, the active form of vitamin D, on human malignant pleural mesothelioma cells. The authors used two mesothelioma cell lines (MSTO-211H and REN), one non-cancerous mesothelial cell line (MeT-5A), and tumor cells from nine patients in Italy. Only cells were studied; asbestos exposure was not. The mesothelioma lines had more vitamin D receptor than non-cancerous cells. In serum-deprived conditions, 100 nM calcitriol for 24 hours cut viability and proliferation by 24.7% and 31.1% in MSTO-211H cells and 24% and 21.3% in REN cells; with 2.5% serum, viability fell less (12.8% and 14.9%). Non-cancerous cells were unchanged. With 50 nM of the chemotherapy drug pemetrexed, calcitriol acted synergistically in both cancer cell lines (combination index 0.944 and 0.426). Calcitriol moved more cancer cells into the resting phase of the cell cycle and fewer into the dividing phase, without affecting apoptosis (programmed cell death), and reduced measures of mitochondrial function. At 100 nM it lowered viability in all three types of patient tumor cells. The authors concluded that vitamin D derivatives with chemotherapy could have potential in treating this cancer.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on human mesothelioma cell lines, a non-malignant mesothelial cell line, and primary tumor cells from patients
• Who was studied: Human biphasic MPM cell line MSTO-211H, human epithelioid MPM cell line REN, and human non-malignant mesothelial cell line MeT-5A, plus primary MPM cells from diagnostic thoracoscopies of patients (3 epithelioid, 3 biphasic, 3 sarcomatoid), with ethics approval from hospitals in Alessandria and Orbassano (Turin), Italy
• Exposure: Calcitriol (1 to 100 nM), alone or combined with the chemotherapy drug pemetrexed (PEM); asbestos exposure was not studied
• Main results:
  • Vitamin D receptor (VDR) levels were significantly higher in the MPM cell lines, particularly REN, than in MeT-5A mesothelial cells, where it was barely detectable
  • In serum-deprived medium, 100 nM calcitriol for 24 hours gave maximum inhibition of viability and proliferation, compared with untreated control cells, of 24.7% and 31.1% in MSTO-211H cells and 24% and 21.3% in REN cells
  • With 2.5% serum, the reduction in viability from 100 nM calcitriol at 24 hours was smaller: 12.8% in MSTO-211H cells and 14.9% in REN cells
  • Viability and proliferation of non-malignant MeT-5A mesothelial cells did not change with calcitriol at any concentration tested
  • After 10 days of treatment, calcitriol reduced the ability of MSTO-211H and REN cells to form colonies
  • In MSTO-211H cells, 100 nM calcitriol with 50 nM pemetrexed gave a combination index of 0.944 for viability, which the authors interpreted as a synergistic effect
  • In REN cells, calcitriol with 50 nM pemetrexed gave a combination index of 0.426, interpreted by the authors as synergistic
  • Calcitriol did not increase the effect of pemetrexed in MeT-5A mesothelial cells
  • In both MPM cell lines, 100 nM calcitriol for 24 hours increased the share of cells in the resting G0/G1 phase of the cell cycle and decreased the share in the active G2/M phase
  • Calcitriol did not affect apoptosis (programmed cell death) in any of the cell lines tested
  • Calcitriol reduced expression of the mitochondrial respiratory chain subunit COX2 in MSTO-211H cells (at 50 nM) and REN cells (at 100 nM); no changes were seen in MeT-5A cells
  • In patients' primary MPM cells, calcitriol lowered viability at 10 to 100 nM in biphasic cells, at 50 and 100 nM in epithelioid cells, and at 100 nM in sarcomatoid cells
• The authors' conclusion: The authors concluded that calcitriol inhibited the viability and growth of MPM cells, alone or with pemetrexed, and suggested that vitamin D derivatives combined with chemotherapy could have potential in treating MPM
• Limitations the authors state:
  • The authors noted that the reductions in COX2 and COX4 expression were small

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Chemotherapy.

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