Page 129 - Haematologica April 2020

Chronic Myeloid Leukemia
Leprosy drug clofazimine activates peroxisome proliferator-activated receptor-γ and synergizes with imatinib to inhibit chronic myeloid leukemia cells
Harish Kumar,1 Sourav Chattopadhyay,1,2 Nabanita Das,1 Sonal Shree,3 Dinesh Patel,4 Jogeswar Mohapatra,4 Anagha Gurjar,1,2 Sapana Kushwaha,1 Abhishek Kumar Singh,1 Shikha Dubey,3 Kiran Lata,3 Rajesh Kushwaha,5 Riyazuddin Mohammed,6 Krishnarup Ghosh Dastidar,4 Namrata Yadav,4 Achchhe Lal Vishwakarma,7 Jiaur Rahaman Gayen,6,2 Sanghamitra Bandyopadhyay,5
Abhijit Chatterjee,4 Mukul Rameshchandra Jain,4 Anil Kumar Tripathi,8
Arun Kumar Trivedi,1,2 Naibedya Chattopadhyay,9,2 Ravishankar Ramachandran2,3 and Sabyasachi Sanyal1,2
1Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow; 2AcSIR, CSIR- Central Drug Research Institute Campus, Lucknow; 3Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow; 4Zydus Research Center, Moraiya, Ahmedabad, Gujarat; 5Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow; 6Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow; 7Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow; 8Department of Clinical Hematology and Medical Oncology, King George's Medical University, Lucknow, Uttar Pradesh and 9Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, India
ABSTRACT
Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia (CML) and BCR-ABL1 inhibitor monotherapy fails to eliminate these cells, thereby necessitating alternate therapeutic strategies for patients CML. The peroxisome proliferator-activated receptor- γ (PPARγ) agonist pioglitazone downregulates signal transducer and activator of transcription 5 (STAT5) and in combination with imatinib induces com- plete molecular response in imatinib-refractory patients by eroding leukemia stem cells. Thiazolidinediones such as pioglitazone are, however, associated with severe side effects. To identify alternate therapeutic strategies for CML we screened Food and Drug Administration-approved drugs in K562 cells and identified the leprosy drug clofazimine as an inhibitor of viability of these cells. Here we show that clofazimine induced apoptosis of blood mononuclear cells derived from patients with CML, with a particularly robust effect in imatinib-resistant cells. Clofazimine also induced apoptosis of CD34+38- progenitors and quiescent CD34+ cells from CML patients but not of hematopoietic progenitor cells from healthy donors. Mechanistic evaluation revealed that clofazimine, via physical interaction with PPARγ, induced nuclear factor κB-p65 proteasomal degradation, which led to sequential myeloblastoma oncoprotein and peroxiredoxin 1 downregulation and concomitant induction of reactive oxygen species-mediated apoptosis. Clofazimine also suppressed STAT5 expression and consequently downreg- ulated stem cell maintenance factors hypoxia-inducible factor-1α and -2α and Cbp/P300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). Combining imatinib with clofazimine caused a far superior synergy than that with pioglitazone, with clofazimine reducing the half maximal inhibitory concentration (IC50) of imatinib by >4 logs and remarkably eroding quiescent CD34+ cells. In a K562 xenograft study clofaz- imine and imatinib co-treatment showed more robust efficacy than the indi- vidual treatments. We propose clinical evaluation of clofazimine in imatinib- refractory CML.
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):971-986
Correspondence:
SABYASACHI SANYAL
sanyal@cdri.res.in
Received: April 11, 2019 Accepted: July 12, 2019. Pre-published: August 1, 2019.
doi:10.3324/haematol.2018.194910
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/971
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