Leprosy drug clofazimine activates peroxisome proliferator-activated receptor-γ and synergizes with imatinib to inhibit chronic myeloid leukemia cells.
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| 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 complete 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 kB-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 downregulated 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 clofazimine and imatinib co-treatment showed more robust efficacy than the individual treatments. We propose clinical evaluation of clofazimine in imatinib-refractory CML.
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| Authors | Harish Kumar, Sourav Chattopadhyay, Nabanita Das, Sonal Shree, Dinesh Patel, Jogeswar Mohapatra, Anagha Gurjar, Sapana Kushwaha, Abhishek Kumar Singh, Shikha Dubey, Kiran Lata, Rajesh Kushwaha, Riyazuddin Mohammed, Krishnarup Ghosh Dastidar, Namrata Yadav, Achchhe Lal Vishwakarma, Jiaur Rahaman Gayen, Sanghamitra Bandyopadhyay, Abhijit Chatterjee, Mukul Rameshchandra Jain, Anil Kumar Tripathi, Arun Kumar Trivedi, Naibedya Chattopadhyay, Ravishankar Ramachandran, Sabyasachi Sanyal |
| Journal | Haematologica (Haematologica) Vol. 105 Issue 4 Pg. 971-986 (04 2020) ISSN: 1592-8721 [Electronic] Italy |
| PMID | 31371410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright© 2020 Ferrata Storti Foundation. |
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