Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors

Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib thera...

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Autores principales:	Hyeok-Jae Jang, Young-Min Woo, Kazuhito Naka, Jong-Ho Park, Ho-Jae Han, Hee-Jin Kim, Sun-Hee Kim, Jae-Sook Ahn, Taehyung Kim, Shinya Kimura, Sarah Zarabi, Jeffrey H. Lipton, Mark D. Minden, Chul-Won Jung, Hyeoung-Joon Kim, Jong-Won Kim, Dennis Dong Hwan Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CML drug resistance statin tyrosine kinase inhibitor combination therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/8322a5e3f83e40388263140905c6e5f5
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spelling	oai:doaj.org-article:8322a5e3f83e40388263140905c6e5f52021-11-11T15:34:23ZStatins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors10.3390/cancers132155432072-6694https://doaj.org/article/8322a5e3f83e40388263140905c6e5f52021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5543https://doaj.org/toc/2072-6694Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (<i>p</i> = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and <i>ABL1</i> mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS<sup>+</sup> cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34<sup>+</sup> cells. The growth-inhibitory effects of the statin/imatinib combination against CD34<sup>+</sup>/CML primary cells were higher than those against CD34<sup>+</sup>/Norm cells (<i>p</i> = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34<sup>+</sup> cells, but not against normal CD34<sup>+</sup> cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy.Hyeok-Jae JangYoung-Min WooKazuhito NakaJong-Ho ParkHo-Jae HanHee-Jin KimSun-Hee KimJae-Sook AhnTaehyung KimShinya KimuraSarah ZarabiJeffrey H. LiptonMark D. MindenChul-Won JungHyeoung-Joon KimJong-Won KimDennis Dong Hwan KimMDPI AGarticleCMLdrug resistancestatintyrosine kinase inhibitorcombination therapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5543, p 5543 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CML drug resistance statin tyrosine kinase inhibitor combination therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	CML drug resistance statin tyrosine kinase inhibitor combination therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hyeok-Jae Jang Young-Min Woo Kazuhito Naka Jong-Ho Park Ho-Jae Han Hee-Jin Kim Sun-Hee Kim Jae-Sook Ahn Taehyung Kim Shinya Kimura Sarah Zarabi Jeffrey H. Lipton Mark D. Minden Chul-Won Jung Hyeoung-Joon Kim Jong-Won Kim Dennis Dong Hwan Kim Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors
description	Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (<i>p</i> = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and <i>ABL1</i> mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS<sup>+</sup> cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34<sup>+</sup> cells. The growth-inhibitory effects of the statin/imatinib combination against CD34<sup>+</sup>/CML primary cells were higher than those against CD34<sup>+</sup>/Norm cells (<i>p</i> = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34<sup>+</sup> cells, but not against normal CD34<sup>+</sup> cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy.
format	article
author	Hyeok-Jae Jang Young-Min Woo Kazuhito Naka Jong-Ho Park Ho-Jae Han Hee-Jin Kim Sun-Hee Kim Jae-Sook Ahn Taehyung Kim Shinya Kimura Sarah Zarabi Jeffrey H. Lipton Mark D. Minden Chul-Won Jung Hyeoung-Joon Kim Jong-Won Kim Dennis Dong Hwan Kim
author_facet	Hyeok-Jae Jang Young-Min Woo Kazuhito Naka Jong-Ho Park Ho-Jae Han Hee-Jin Kim Sun-Hee Kim Jae-Sook Ahn Taehyung Kim Shinya Kimura Sarah Zarabi Jeffrey H. Lipton Mark D. Minden Chul-Won Jung Hyeoung-Joon Kim Jong-Won Kim Dennis Dong Hwan Kim
author_sort	Hyeok-Jae Jang
title	Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors
title_short	Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors
title_full	Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors
title_fullStr	Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors
title_full_unstemmed	Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors
title_sort	statins enhance the molecular response in chronic myeloid leukemia when combined with tyrosine kinase inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/8322a5e3f83e40388263140905c6e5f5
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Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors

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