Page 143 - Haematologica April 2020

Clofazimine inhibits chronic myeloid leukemia
NFκB activation has been reported in CML61 and LSC.62 Furthermore, p65 inhibition was shown to inhibit CML cells including those harboring the multidrug-resistant T315I BCR-ABL1 mutation.63,64 Our results show that clo- fazimine decreased p65 protein by increasing the ubiqui- tin ligase activity of PPARγ. While thiazolidinediones increase PPARγ ubiquitin ligase activity at a suprapharma- cological concentration of ≥100 μM,41 clofazimine was effective at a concentration of 5 μM. Clofazimine also dis- played superior cytotoxic effects than thiazolidinediones. Furthermore, combining clofazimine with imatinib reduced the IC50 of imatinib by >4 logs whereas pioglita- zone reduced it by 7- to 10-fold only. Combining imatinib with clofazimine in a K562 xenograft study caused greater reductions in tumor volume and weight than either drug alone, effects which were accompanied by substantially reduced proliferation and increased degenerative morpho- logical changes in the group given combination therapy.
Pioglitazone is associated with cardiac and hepatic safe- ty issues along with a significant risk of bladder cancer in users.3 That rosiglitazone does not increase the risk of bladder cancer3 indicates that this side effect is not associ- ated with all PPARγ agonists. Being a phenazine deriva- tive, clofazimine belongs to a different class of molecule. Given its superior efficacy over thiazolidinediones and
that long-term assumption of clofazimine is not associated with major adverse effects; we propose clinical evaluation of clofazimine in combination with tyrosine kinase inhibitors in CML.
Acknowledgments
We dedicate this paper to the memory of Ranjan Kumar Bhagat. We thank Rune Toftgard, Odd Stokke Gabrielsen, Miguel Campanero, Chieko Kai, Giorgio Pochetti, David Mangelsdorf and Kimitoshi Kohno for kind gifts of plasmids. We thank Sharad Sharma and Madhav Nilkanth Mugale for help with histological analyses, and Dipak Datta and Jayanta Sarkar for useful discussions. SS acknowledges a mission-mode in-house project for cancer from CSIR, NC acknowledges funding from CSIR network project ASTHI (BSC 0201) and a grant-in-aid from the Department of Health Research-Indian Council of Medical Research (5/10/FR/5/2012-RHN/156), Government of India and AKT acknowledges funding from the CSIR network project INDEPTH. The authors acknowledge the sophisticated analytical instrument facility at CSIR-CDRI for FACS studies. HK, SoS, SC and RK were supported by fellowships from the University Grants Commission. AKS, SK, AG, SD, KL and RM were supported by fellowships from CSIR. ND acknowl- edges the DBT-RA Program in Biotechnology and Life Sciences for a Fellowship. CDRI communication number: 9805.
References
1. Prost S, Relouzat F, Spentchian M, et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature. 2015;525(7569):380-383.
2. Glodkowska-Mrowka E, Manda-Handzlik A, Stelmaszczyk-Emmel A, et al. PPARγ lig- ands increase antileukemic activity of sec- ond- and third-generation tyrosine kinase inhibitors in chronic myeloid leukemia cells. Blood Cancer J. 2016;6:e377.
3. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352(i)1541.
4. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471.
5. Gopal M, Padayatchi N, Metcalfe JZ, O'Donnell MR. Systematic review of clofaz- imine for the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2013;17(8):1001-1007.
6. Cholo MC, Steel HC, Fourie PB, Germishuizen WA, Anderson R. Clofazimine: current status and future prospects. J Antimicrob Chemother. 2012;67 (2):290-298.
7. Ren YR, Pan F, Parvez S, et al. Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lympho- cytes. PLoS One. 2008;3(12):e4009.
8. Leanza L, Henry B, Sassi N, et al. Inhibitors of mitochondrial Kv1.3 channels induce BAX/Bak-independent death of cancer cells. EMBO Mol Med. 2012;4(7):577-593.
9. Leanza L, Trentin L, Becker KA, et al. Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic
lymphocytic leukemia. Leukemia. 2013;27
(8):1782-1785.
10. Smith GA, Tsui HW, Newell EW, et al.
Functional up-regulation of HERG K+ chan- nels in neoplastic hematopoietic cells. J Biol Chem. 2002;277(21):18528-18534.
11. Schaad-Lanyi Z, Dieterle W, Dubois JP, Theobald W, Vischer W. Pharmacokinetics of clofazimine in healthy volunteers. Int J Lepr Other Mycobact Dis. 1987;55(1):9-15.
12. Yawalkar SJ, Vischer W. Lamprene (clofaz- imine) in leprosy. Basic information. Lepr Rev. 1979;50(2):135-144.
13. O'Connor R, O'Sullivan JF, O'Kennedy R. The pharmacology, metabolism, and chem- istry of clofazimine. Drug Metab Rev. 1995;27(4):591-614.
14. Marcato P, Dean CA, Giacomantonio CA, Lee PW. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle. 2011;10(9):1378-1384.
15. Melemed AS, Ryder JW, Vik TA. Activation of the mitogen-activated protein kinase pathway is involved in and sufficient for megakaryocytic differentiation of CMK cells. Blood. 1997;90(9):3462-3470.
16. Fichelson S, Freyssinier JM, Picard F, et al. Megakaryocyte growth and development factor-induced proliferation and differentia- tion are regulated by the mitogen-activated protein kinase pathway in primitive cord blood hematopoietic progenitors. Blood. 1999;94(5):1601-1613.
17. Sardina JL, Lopez-Ruano G, Sanchez-Abarca LI, et al. p22phox-dependent NADPH oxi- dase activity is required for megakaryocytic differentiation. Cell Death Differ. 2010;17(12):1842-1854.
18. Nurhayati RW, Ojima Y, Nomura N, Taya M. Promoted megakaryocytic differentia- tion of K562 cells through oxidative stress
caused by near ultraviolet irradiation. Cell
Mol Biol Lett. 2014;19(4):590-600.
19. Chen S, Su Y, Wang J. ROS-mediated platelet generation: a microenvironment- dependent manner for megakaryocyte pro- liferation, differentiation, and maturation.
Cell Death Dis. 2013;4:e722.
20. Shibayama-Imazu T, Sonoda I, Sakairi S, et
al. Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells. Apoptosis. 2006;11(9):1535-1543.
21. Dabrosin C, Ollinger K. Protection by alpha- tocopherol but not ascorbic acid from hydrogen peroxide induced cell death in normal human breast epithelial cells in cul- ture. Free Radic Res. 1998;29(3):227-234.
22. Makpol S, Zainuddin A, Rahim NA, Yusof YA, Ngah WZ. Alpha-tocopherol modulates hydrogen peroxide-induced DNA damage and telomere shortening of human skin fibroblasts derived from differently aged individuals. Planta Med. 2010;76(9):869-875.
23. da Silveira Vargas F, Soares DG, Ribeiro AP, Hebling J, De Souza Costa CA. Protective effect of alpha-tocopherol isomer from vita- min E against the H2O2 induced toxicity on dental pulp cells. Biomed Res Int. 2014;2014:895049.
24. Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479-496.
25. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009;8 (7):579-591.
26. Panieri E, Santoro MM. ROS homeostasis and metabolism: a dangerous liason in can- cer cells. Cell Death Dis. 2016;7(6):e2253.
27. Shi X, Zhang Y, Zheng J, Pan J. Reactive oxy- gen species in cancer stem cells. Antioxid
haematologica | 2020; 105(4)
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