In Vitro Effect of Pomalidomide on Bone Marrow Mononuclear Cells From Multiple Myeloma Patients

Tajik, Shaghayegh; Jalali Nadoushan, Mohammadreza; Shams, Jalaledin; Yaraee, Roya

doi:10.32598/Immunoregulation.1.1.21

In Vitro Effect of Pomalidomide on Bone Marrow Mononuclear Cells From Multiple Myeloma Patients

Document Type : Original Article

Authors

¹ Department of Immunology, Faculty of Medical, Shahed University, Tehran, Iran.

² Department of Pathology, Mostafa Komeini Hospital, Shahed University, Tehran, Iran.

³ Department of Oncology and Hematology, Mostafa Komeini Hospital, Shahed University, Tehran, Iran.

10.32598/Immunoregulation.1.1.21

Abstract

Background: Many features of anticancer drugs, including cytotoxicity and/or cytokine induction, are studied using cell lines or human blood leukocytes. However, in a disease such as multiple myeloma, most cancerous cells are resided within bone marrow mononuclear cells. In the present study, we investigated the effect of pomalidomide on apoptosis and IL-2 production of bone marrow mononuclear cells in patients with multiple myeloma and controls.
Materials and Methods: The Bone Marrow Mononuclear Cells from 10 multiple myeloma patients and 10 controls were cultured using pomalidomide for 48-hour. Apoptosis induction rate, viability, cytotoxicity, and IL-2 production were evaluated.
Results: The results showed that apoptosis and cytotoxicity significantly increased in bone marrow mononuclear cells of multiple myeloma patients cultured in the presence of pomalidomide (PConclusion: The results of the current study confirmed the toxic effect of pomalidomide on bone marrow mononuclear cells of patients, with no toxic effect on controls. On the other hand, pomalidomide has the potential to increase IL2 production within bone marrow mononuclear cells and consequently make changes in the immune response, which requires further studies for more clarifications.

Keywords

References

Hideshima T, Raje N, Richardson PG, Anderson KC. A review of lenalidomide in combination with dexamethasone for the treatment of multiple myeloma. Ther Clin Risk Manag. 2008; 4(1):129-36. [DOI:10.2147/TCRM.S1445] [PMID] [PMCID]
Tohnya TM, Figg WD. Immunomodulation of multiple myeloma. Cancer Biol Ther. 2004; 3(11):1060-1. [DOI:10.4161/cbt.3.11.1303]
Terpos E, Kanellias N, Christoulas D, Kastritis E, Dimopoulos MA. Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma. Onco Targets Ther. 2013; 6:531. [DOI:10.2147/OTT.S34498] [PMID] [PMCID]
Longo D, Kasper D, Braunwald E, Fauci A. Harrison’s principles of internal medicine. New York: McGraw-Hill Medical; 2008.
Walker BR, Colledge NR, Ralston SH, Penman I. Davidson’s principles and practice of medicine: Elsevier Health Sciences; 2013.
Anderson KC, Carrasco RD. Pathogenesis of myeloma. Annu Rev Pathol. 2011; 6:249-74. [DOI:10.1146/annurev-pathol-011110-130249] [PMID]
Sedlarikova L, Kubiczkova L, Sevcikova S, Hajek R. Mechanism of immunomodulatory drugs in multiple myeloma. Leukemia Research. 2012; 36(10):1218-24. [DOI:10.1016/j.leukres.2012.05.010] [PMID]
Colledge N, Walker BR, Ralston SH. Davidson’s Principles and Practice of Medicine–20th Edition; 2007.
Anderson KC, Alsina M, Irannsinger W, Biermann JS, Chanan-Khan A, Cohen AD, et al. Multiple myeloma. Journal of the National Comprehensive Cancer Network. 2009; 7(9):908-42. [DOI:10.6004/jnccn.2009.0061] [PMID]
Mahindra A, Hideshima T, Anderson KC. Multiple myeloma: biology of the disease. Blood Rev. 2010; 24:S5-S11. [DOI:10.1016/S0268-960X(10)70003-5]
Sadjadi A, Semnani S, Nouraie SM, Khademi H, Bahadori M. Cancer registry in Iran: A brief overview. Arch Iran Med. 2008; 11(5):577. [PMID]
Munshi NC, editor. Recent advances in the management of multiple myeloma. Semin Hematol. Elsevier; 2004.
Winther H, Jørgensen JT. Drug-diagnostic co-development in cancer. Pharmaceut Med. 2010;24(6):363-75. [DOI:10.1007/BF03256837]
Baskar R, Lee KA, Yeo R, Yeoh K-W. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193. [DOI:10.7150/ijms.3635] [PMID] [PMCID]
Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010; 24(1):22-32. [DOI:10.1038/leu.2009.236] [PMID] [PMCID]
Chanan-Khan AA, Swaika A, Paulus A, Kumar SK, Mikhael JR, Rajkumar SV, et al. Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma. Blood Cancer J. 2013; 3:e143. [DOI:10.1038/bcj.2013.38] [PMID] [PMCID]
Cavo M. A third-generation IMiD for MM. Blood. 2011; 118(11):2931-2. [DOI:10.1182/blood-2011-07-364315] [PMID]
Richardson PG, Mark TM, Lacy MQ. Pomalidomide: new immunomodulatory agent with potent antiproliferative effects. Crit Rev Oncol Hematol. 2013;88:S36-S44. [DOI:10.1016/j.critrevonc.2013.02.001] [PMID]
Corral LG, Haslett PA, Muller GW, Chen R, Wong L-M, Ocampo CJ, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J Immuno. 1999; 163(1):380-6. [PMID]
Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001; 98(1):210-6. [DOI:10.1182/blood.V98.1.210] [PMID]
Teo SK. Properties of thalidomide and its analogues: implications for anticancer therapy. The AAPS J. 2005;7(1):E14-E9. [DOI:10.1208/aapsj070103] [PMID] [PMCID]
Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Fundam Appl Toxicol. 2011; 122(1):1-6.
Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol. 2007; 39(7):1489-99. [DOI:10.1016/j.biocel.2007.01.022] [PMID]
Görgün G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood. 2010; 116(17):3227-37. [DOI:10.1182/blood-2010-04-279893] [PMID] [PMCID]
Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi A, Kang J, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012; 26(11):2326-35. [DOI:10.1038/leu.2012.119] [PMID]
Schey S, Ramasamy K. Pomalidomide therapy for myeloma. Expert Opin Investig Drugs. 2011; 20(5):691-700. [DOI:10.1517/13543784.2011.567265] [PMID]
Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009; 27(30):5008-14. [DOI:10.1200/JCO.2009.23.6802] [PMID]
Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011; 118(11):2970-5. [DOI:10.1182/blood-2011-04-348896] [PMID] [PMCID]
Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011; 118(18):4771-9. [DOI:10.1182/blood-2011-05-356063] [PMID] [PMCID]
Das DS, Ray A, Song Y, Richardson P, Trikha M, Chauhan D, et al. Synergistic anti‐myeloma activity of the proteasome inhibitor marizomib and the IMiD® immunomodulatory drug pomalidomide. Br J Haematol. 2015; 171(5):798-812. [DOI:10.1111/bjh.13780] [PMID] [PMCID]
Baskić D, Popović S, Ristić P, Arsenijević NN. Analysis of cycloheximide-induced apoptosis in human leukocytes: fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide. Cell Biol Int. 2006; 30(11):924-32. [DOI:10.1016/j.cellbi.2006.06.016] [PMID]
Moutouh-de Parseval LA, Verhelle D, Glezer E, Jensen-Pergakes K, Ferguson GD, Corral LG, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. Journal of Clinical Investigation. 2008; 118(1):248. [DOI:10.1172/JCI32322] [PMID] [PMCID]
Tefferi A, Verstovsek S, Barosi G, Passamonti F, Roboz GJ, Gisslinger H, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009; 27(27):4563-9. [DOI:10.1200/JCO.2008.21.7356] [PMID] [PMCID]
Lacy MQ, Tefferi A. Pomalidomide therapy for multiple myeloma and myelofibrosis: an update. Leuk Lymphoma. 2011; 52(4):560-6. [DOI:10.3109/10428194.2011.552139] [PMID]
Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunology, Immunotherapy. 2009; 58(7):1033-45. [DOI:10.1007/s00262-008-0620-4] [PMID]
Lauta VM. A review of the cytokine network in multiple myeloma. Cancer. 2003; 97(10):2440-52. [DOI:10.1002/cncr.11072] [PMID]
Sehgal K, Das R, Zhang L, Verma R, Deng Y, Kocoglu M, et al. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood; 2015.