Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro
- PMID: 32437909
- PMCID: PMC7335335
- DOI: 10.1016/j.exphem.2020.05.001
Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro
Abstract
Our previous study revealed that expression of G protein-coupled receptor 68 (GPR68) was upregulated in MDSL cells, a cell line representing myelodysplastic syndromes (MDS), in response to lenalidomide (LEN), and mediated a calcium/calpain proapoptotic pathway. Isx, a GPR68 agonist, enhanced the sensitivity to LEN in MDSL cells. The fact that Isx is not a U.S. Food and Drug Administration-approved drug prompts us to look for alternative candidates that could enhance the sensitivity of LEN in MDS as well as other hematologic malignancies, such as acute myeloid leukemia (AML). In the study described here, we found that regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of calcineurin (CaN), was upregulated in MDSL cells in response to LEN, possibly through degradation of IKZF1. Consistently, cyclosporin (Cys), a pharmacological inhibitor of CaN, inhibited the activity of CaN and induced apoptosis in MDSL cells, indicating that CaN provided a prosurvival signal in MDSL cells. In addition, Cys enhanced the cytotoxic effect of LEN in MDS/AML cell lines as well as primary bone marrow cells from MDS patients and AML patient-derived xenograft models. Intriguingly, pretreatment with LEN reversed the suppressive effect of Cys on T-cell activation. Our study suggests a novel mechanism of action of LEN in mediating cytotoxicity in MDS/AML via upregulation of RCAN1, thus inhibiting the CaN prosurvival pathway. Our study also suggests that Cys enhances the sensitivity to LEN in MDS/AML cells without compromising T-cell activation.
Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Conflict of interest disclosure The authors declare no competing financial interests.
Figures
![Figure 1.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7335335/bin/nihms-1592409-f0001.gif)
![Figure 2.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7335335/bin/nihms-1592409-f0002.gif)
![Figure 3.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7335335/bin/nihms-1592409-f0003.gif)
Similar articles
-
Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.Cancers (Basel). 2021 Oct 11;13(20):5084. doi: 10.3390/cancers13205084. Cancers (Basel). 2021. PMID: 34680233 Free PMC article. Review.
-
A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes.Nat Med. 2016 Jul;22(7):727-34. doi: 10.1038/nm.4127. Epub 2016 Jun 13. Nat Med. 2016. PMID: 27294874 Free PMC article.
-
Cyclosporine Broadens the Therapeutic Potential of Lenalidomide in Myeloid Malignancies.J Cell Immunol. 2020;2(5):237-244. doi: 10.33696/immunology.2.049. J Cell Immunol. 2020. PMID: 32984863 Free PMC article.
-
Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia.Blood. 2013 Jan 3;121(1):159-69. doi: 10.1182/blood-2012-05-428573. Epub 2012 Oct 25. Blood. 2013. PMID: 23100311 Free PMC article.
-
Immunomodulating drugs in myelodysplastic syndromes.Hematology Am Soc Hematol Educ Program. 2011;2011:556-60. doi: 10.1182/asheducation-2011.1.556. Hematology Am Soc Hematol Educ Program. 2011. PMID: 22160089 Review.
Cited by
-
Reshaping the tumor microenvironment: The versatility of immunomodulatory drugs in B-cell neoplasms.Front Immunol. 2022 Oct 12;13:1017990. doi: 10.3389/fimmu.2022.1017990. eCollection 2022. Front Immunol. 2022. PMID: 36311747 Free PMC article. Review.
-
RCAN1-mediated calcineurin inhibition as a target for cancer therapy.Mol Med. 2022 Jun 18;28(1):69. doi: 10.1186/s10020-022-00492-7. Mol Med. 2022. PMID: 35717152 Free PMC article. Review.
-
Put in a "Ca2+ll" to Acute Myeloid Leukemia.Cells. 2022 Feb 4;11(3):543. doi: 10.3390/cells11030543. Cells. 2022. PMID: 35159351 Free PMC article. Review.
-
Ikaros Proteins in Tumor: Current Perspectives and New Developments.Front Mol Biosci. 2021 Dec 7;8:788440. doi: 10.3389/fmolb.2021.788440. eCollection 2021. Front Mol Biosci. 2021. PMID: 34950704 Free PMC article. Review.
-
Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.Cancers (Basel). 2021 Oct 11;13(20):5084. doi: 10.3390/cancers13205084. Cancers (Basel). 2021. PMID: 34680233 Free PMC article. Review.
References
-
- Pan B and Lentzsch S, The application and biology of immunomodulatory drugs (IMiDs) in cancer. Pharmacol Ther, 2012. 136(1): p. 56–68. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous