Study of Growth Differentiation Factor 15(GDF15) and Some Biochemical Parameters in Multiple Myeloma Patients Subjected to Chemotherapy with Added Paroxetine in-Vitro

  • Zahraa A. H. Al-Timeeme Department of Chemistry, College of Science, Al-Nahrain University, Baghdad-Iraq
  • Wisam Kadhum H. Alhashemi Department of Chemistry, College of Science, Al-Nahrain University, Baghdad, Iraq
  • Alaadin Sahham Naji Baghdad Medical College, Baghdad, Iraq
  • Ahmed Fadhil Neama Biotechnology Center, Al-Nahrain University, Baghdad, Iraq
Keywords: Multiple myeloma (MM), Albumin, Serum Calcium, C-reactive protein CRP, Growth differentiation factor GDF-15, Bortezomib, Cyclophosphamide, Paroxetine


Introduction: Multiple myeloma (MM) is a cancer that shapes from excessive amounts of a monoclonal immunoglobulin (Ig) which accumulate in the bone marrow, where they assemble healthy blood cells.

Materials and Methods: there are two lines was dealt with it: For in vivo the study involved 80 multiple myeloma Patients grouped according sessions of chemotherapy (new diagnosis without treatment, and patients subjected to six sessions of chemotherapy treatment) for each group the following biochemical parameters were measured Growth differentiation factor 15 (GDF-15), albumin, calcium, C-reactive protein(CRP) in serum. In vitro was measured Growth differentiation factor 15 on RPMI 8226 cell line of multiple myeloma with mixture of chemotherapy (Mix1) and with combination of standard chemotherapy and antideportation paroxetine (Mix2).

Results: In serum Growth differentiation factor 15 was showed significantly increased (p<0.05) for 1st cycle and 6th Cycle in comparison with new diagnosis group, for other cycles there are no significant difference. For Serum albumin, calcium and, C-reactive protein were appeared no significant between-groups differences when compared with their new diagnosis patients’ group. In vitro Growth differentiation factor 15 was appeared significant different when compared results of cell line with Mix1 in comparison to Mix2.


[1] Konrad, C. N.; William, D. L.; "Multiple myeloma: diagnosis and treatment"; Am. Fam. Physician, 78, 853-859, 2008.
[2] Hargreaves, R. M.; Lea, J. R.; Griffiths, H.; Faux, J. A.; Holt, J. M.; Reid, C.; Bunch, C.; Lee, M.; Chapel, H. M.; "Immunological factors and risk of infection in plateau phase myeloma"; Am. J. Clin. Pathol., 48, 260-266, 1995.
[3] Nissim, O.; Ory, R.; Karen, N.; Dimitri, S.; Daniel, B.; "Classification of Solitary Plasmacytoma, is it more Intricate than Presently Suggested? A Commentary"; J.Cancer, 9, 3894, 2018.
[4] Roberto, J. P. M.; María-Belén, V.; Bruno, P.; Carlos, F.; Ramón, G.; Maria-Victoria, M.; Norma, C. G.; Quentin, L.; Juan, F. B.; Jose, H.; “Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry"; Haematologica, 98, 79-86, 2013.
[5] Michaela, R. R.; Lucy, L.; Clifford, J. R.; Irene, M.G.; "Dynamic interplay between bone and multiple myeloma: emerging roles of the osteoblast"; Bone, 75,161-169, 2015.
[6] Al-Farsi, K.; "Multiple myeloma: an update"; Oman Med. J., 28, 3, 2013.
[7] Nikolaus, B.; "Epidemiology of multiple myeloma"; Springer, 25-35; 2011.
[8] Rajkumar, S. V.; "Multiple myeloma: 2016 update on diagnosis, risk‐stratification, and management"; Am. J. Hematol., 91, 719-734, 2016.
[9] Dickran, K.; "Multiple myeloma epidemiology and survival: A unique malignancy"; SEMIN ONCOL, Elsevier,. 43, 676-681, 2016.
[10] Robert, A. K.; Morie, A. G.; Thomas, E. T.; John, A. L.; Martha, Q. L.; Angela, D.; Rafael, F.; "Review of 1027 patients with newly diagnosed multiple myeloma"; Mayo Clin. Proc., Elsevier, 78, 21-33, 2003.
[11] Regis, B.; Daniel, C.; Christian, M.; Philippe, M.; Jacques, S.; Pierre, B.; Christian, A.; "Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease"; J. Clin. Oncol., 7, 1909-1914, 1989.
[12] Oranger, A.; Carbone, C.; Izzo, M.; Grano, M.; "Cellular mechanisms of multiple myeloma bone disease"; Clin. Dev. Immunol., 2013, 2013.
[13] Chen, D.; Frezza, M.; Schmitt, S.; Kanwar, J.; Dou, Q. P.; "Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives"; Curr. Cancer Drug Targets, 11, 239-253, 2011.
[14] Masaki, R.; "Mechanism of action of bortezomib in multiple myeloma therapy"; Inte. J. Myeloma, 6, 1-6, 2016.
[15] Davies, F. E.; Wu, P.; Jenner, M.; Srikanth, M.; Saso, R.; Morgan, G. J.; "The combination of cyclophosphamide, velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to velcade alone (V) and velcade plus dexamethasone (VD) "; Haematologica, 92, 1149-1150, 2007.
[16] Ramirez, D. A.; Collins, K. P.; Aradi, A. E.; Conger, K. A.; Gustafson, D. L; "Kinetics of Cyclophosphamide Metabolism in Humans, Dogs, Cats, and Mice and Relationship to Cytotoxic Activity and Pharmacokinetics"; Drug Metab. Dispos. 47, 257-268, 2019.
[17] Marianna, P.; Davide, P.; Chiara, G.; Carlotta, T.; Laura, R. M.; Carla, R.; Toshi, A. F.; Norio, W.; Andrea, C.; Corrado, B.; "Paroxetine versus other anti‐depressive agents for depression"; Cochrane Database Syst. Rev., 2014.
[18] Caraci, F.; Crupi, R.; Drago, F.; Spina, E.; "Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract"; Curr. Drug Metab., 12, 570-577, 2011.
[19] Ughachukwu, P.; Unekwe, P.; "Efflux Pump. Mediated Resistance in Chemotherapy"; Ann. Med. Health Sci. Res., 2, 191-198, 2012.
[20] Derya, A.; Tugba, C.; Dogan, K.; Husamettin, V.; Derya, C.; Yavuz, K.; Bulent, O.; Fikret, A.; "Growth-differentiation factor-15 and tissue doppler ımaging in detection of asymptomatic anthracycline cardiomyopathy in childhood cancer survivors"; Clin. Biochem., 46, 1239-1243, 2013.
[21] Lung-An, H.; Semon, W.; Jyh-Ming, J. J.; Fu-Tien, J.; Ming-Sheng, T.; Jeng-Feng, J.; Hsuan-Li, H.; Yu-Lin, K.; "Growth differentiation factor 15 may predict mortality of peripheral and coronary artery diseases and correlate with their risk factors"; Mediat. Inflamm., 2017, 2017.
[22] Ting, W.; Jian, L.; Caitlin, M.; Katherine, L.; Xiandun, Z.; Benjamin, J. W.; Hakon, H.; Liming, P.; "GDF15 is a heart‐derived hormone that regulates body growth"; EMBO mol. Med., 9, 1150-1164, 2017.
[23] Jill, C.; Elodie, L.; Nicolas, E.; Benjamin, H.; Avet-Loiseau, H.; Murielle, R.; Anne, H.; Mélanie, A.; Pierre, C.; Bernard, K.; "Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma"; Cancer Res., 72, 1395-1406, 2012.
[24] Efstathios, K.; Giampaolo, M.; Ioannis, P.; Paolo, M.; Evangelos, T.; Marco, B.; Athanasios, A.; Francesca, R.; Erasmia, P.; Filia, P.; "Growth Differentiation Factor-15 (GDF-15) Is a new biomarker with independent prognostic significance for survival and renal outcomes in different cohorts of patients with light chain (AL) Amyloidosis"; ASH., DC, 128, 2016.
[25] Efstathios, K.; Giampaolo, M.; Ioannis, P.; Paolo, M.; Evangelos, T.; Marco, B.; Athanasios, A.; Francesca, R.; Erasmia, P.; Filia, P.; "Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis"; blood, 131, 1568-1575, 2018.
[26] Shiu Lun Au, Y.; Shan, L.; Mary, C. S.;"The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study"; Diabetologia, 1-9, 2019.
[27] Adela, R.; Banerjee, S. K.; "GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective"; J. Diabetes Res., 2015, 2015.
[28] Toshihiko, T.; Yiting, L.; Qiuju, W.; Marta, C.; Leif, B. P.; Geoff, M.; Ricky, W. J.; Nilanjan, G.;"Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells"; Blood, 123, 725-733, 2014.
[29] Caraceni, P.; Tufoni, M.; Bonavita, M. E.; "Clinical use of albumin"; Blood, 11, 18, 2013.
[30] Kim, J. E.; Yoo, C.; Lee, D. H.; Kim, S.-W.; Lee, J.-S.; Suh, S.; "Serum albumin level is a significant prognostic factor reflecting disease severity in symptomatic multiple myeloma"; Ann. Hemat., 89, 391-397, 2010.
[31] Rami, S. K.; Corrales‐Yepez, M.; Kharfan‐Dabaja, M. A.; Al Ali, N. H.; Eric, P.; Dana, E. R.; Pinilla‐Ibarz, J.; Ling, Z.; Epling‐Burnette, P. K.;
[32] Jeffrey. E. L.; "Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes"; Am. J. Hematol., 87, 1006-1009, 2012.
[33] Astrid, S.; Helmut, S.; Roland-KO, S.; “Interrelations between essential metal ions and human diseases”; Springer, 13; 2013.
[34] Nepal, A.K.; Shakya, P. R.; Gelal, B.; Das, B. L.; Shrestha, B. P.; Lamsal, M.; Baral, N.; Majhi, S.; "Biochemical profile of Multiple Myeloma in the patients visiting bpkihs as diagnosed by agarose gel electrophoresis"; Health Renaiss., 8, 122-125, 2010.
[35] Ashrafi, F.; Iraj, B.; Nematollahi, P.; Darakhshandeh, A.; "Pseudohypercalcemia in multiple myeloma: A case report"; Int. J. Hematol. Oncol. Stem Cell Res., 11, 246, 2017.
[36] Chandrashekara, S.; "C-reactive protein: An inflammatory marker with specific role in physiology, pathology, and diagnosis"; Int. J. RCI., 2, 2014.
[37] Jing, Y.; Zhiqiang, L.; Huan, L.; Jin, H.; Jianling, Y.; Pei, L.; Qiang, W.; Juan, D.; Wencai, M.; Zheng, Y.;"C-reactive protein promotes bone destruction in human myeloma through the CD32–p38 MAPK–Twist axis"; Sci. Signal., 10, 6282, 2017.
[38] Bataille, R.; Boccadoro, M.; Klein, B.; Durie, B.; Pileri, A.; "C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system"; Am. J. Hematol., 80, 733-737, 1992.
[39] Chakraborty, R.; Muchtar, E.; Kumar, S. K.; Buadi, F. K.; Dingli, D.; Dispenzieri, A.; Hayman, S.R.; Hogan, W.J.; Kapoor, P.; Lacy, M. Q.; "Elevated pre-transplant C-reactive protein identifies a high-risk subgroup in multiple myeloma patients undergoing delayed autologous stem cell transplantation"; Bone Marrow Transplant., 53, 155-161, 2018.
[40] Tammen, H.; Hess, R.; "Collection and handling of blood specimens for peptidomics"; Springer, 161-168, 2013.
[41] Cary, N.; "Statistical Analysis System, User's Guide. Statistical. Version 9.SAS. Inst"; Inc. USA, 2012.
[42] Toshihiko, T.; Yiting, L.; Qiuju, W.; Marta, C.; Leif, B. P.; Geoff, M.; Ricky, W. J.; Nilanjan, G.; Ivan, B.; Carol, A. H.; "Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells"; Am. J. Hematol., Blood, 123, 725-733, 2014.
[43] Akirov, A.; Masri-Iraqi, H.; Atamna, A.; Shimon, I.; "Low albumin levels are associated with mortality risk in hospitalized patients"; Am. J. Med., 130, 1465. e11-1465. e19, 2017.
[44] Ma, T. Z.; Piao, Z.; Jin, S. Y.; Kwak, Y. G.; "Differential expression of serum proteins in multiple myeloma"; Exp. Ther. Med., 17, 649-656, 2019.
[45] Jia-Hong, C.; Shun-Neng, H.; Tzu-Chuan, H.; Yi-Ying, W.; Chin, L.; Ping-Ying, C.; Yeu-Chin, C.; Ching-Liang, H.; "Prognostic significance of initial serum albumin and 24-hour daily protein excretion before treatment in multiple myeloma"; PloS one, 10, 2015.
[46] Busher, J. T.; "Serum albumin and globulin"; Clinical methods: The history, physical, and laboratory examinations, 3, 1990.
[47] Stein, A.; Voigt, W.; Jordan, K.; "Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management"; Ther. Adv. Med. Oncol., 2, 51-63, 2010.
[48] Pravina, P.; Sayaji, D.; Avinash, M.; "Calcium and its role in human body"; Int. J. Res. Pharm. Biomed. Sci, 4, 659-668, 2013.
[49] Oyajobi, B. O.; "Multiple myeloma/hypercalcemia," Arthritis Res. Ther., 9, S4, 2007.
[50] Mateu, J. M.; González, G. L.; Vila, M.; Rivera, M. U.; Marqués, G. G.; Tugores, A.; "Multiple myeloma, severe hypercalcaemia, acute renal failure and multiple organ failure due to calcinosis"; Nefrología, 31, 233-234, 2011.
[51] Merigan, T. C.; Hayes, R. E.; "Treatment of Hypercalcemia in Multiple Myeloma: Report of Two Patients"; Arch. Intern. Med., 107, 389-394, 1961.
[52] David, B.; Tracy, L. N.; Hans-Georg, K.; Benedict, K.; Xiaowei, W.; Jan, R. T.; Craig, J. M.; Johannes, Z.; Jurij, K.; Lawrence, A. K.; "Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites"; Nat. Commun., 8, 14188, 2017.
[53] Antonio, P.; Avet-Loiseau, H.; Stefania, O.; Henk, M. L.; Hartmut, G.; Laura, R.; Paul, R.; Simona, R.; Juan-José, L.; Thierry, F.; "Revised international staging system for multiple myeloma: a report from International Myeloma Working Group"; J. Clin. Oncol., 33, 2863, 2015.
[54] Sproston, N. R.; Ashworth, J. J.; "Role of C-reactive protein at sites of inflammation and infection"; Front. Immunol., 9, 754, 2018.
How to Cite
A. H. Al-Timeeme, Z., Kadhum H. Alhashemi, W., Sahham Naji, A., & Fadhil Neama, A. (2020). Study of Growth Differentiation Factor 15(GDF15) and Some Biochemical Parameters in Multiple Myeloma Patients Subjected to Chemotherapy with Added Paroxetine in-Vitro. Al-Nahrain Journal of Science, 23(2), 18-25. Retrieved from