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Novel HDAC inhibitor MAKV-8 and imatinib synergistically kill chronic myeloid leukemia cells via inhibition of BCR-ABL/MYC-signaling: effect on imatinib resistance and stem cells.
Lernoux, Manon; Schnekenburger, Michael; Losson, Hélène; Vermeulen, Koen; Hahn, Hyunggu; Gérard, Déborah; Lee, Jin-Young; Mazumder, Aloran; Ahamed, Muneer; Christov, Christo; Kim, Dong-Wook; Dicato, Mario; Bormans, Guy; Han, Byung Woo; Diederich, Marc.
Afiliação
  • Lernoux M; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg.
  • Schnekenburger M; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg.
  • Losson H; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg.
  • Vermeulen K; Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • Hahn H; Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
  • Gérard D; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg.
  • Lee JY; Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
  • Mazumder A; Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
  • Ahamed M; Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • Christov C; Faculté de Médecine, Université de Lorraine, Nancy, France.
  • Kim DW; Seoul St. Mary's Hospital, Leukemia Research Institute, the Catholic University of Korea, Seoul, Korea.
  • Dicato M; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg.
  • Bormans G; Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • Han BW; Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea. bwhan@snu.ac.kr.
  • Diederich M; Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea. marcdiederich@snu.ac.kr.
Clin Epigenetics ; 12(1): 69, 2020 05 19.
Article em En | MEDLINE | ID: mdl-32430012
ABSTRACT

BACKGROUND:

Chronic myeloid leukemia (CML) pathogenesis is mainly driven by the oncogenic breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) fusion protein. Since BCR-ABL displays abnormal constitutive tyrosine kinase activity, therapies using tyrosine kinase inhibitors (TKis) such as imatinib represent a major breakthrough for the outcome of CML patients. Nevertheless, the development of TKi resistance and the persistence of leukemia stem cells (LSCs) remain barriers to cure the disease, justifying the development of novel therapeutic approaches. Since the activity of histone deacetylase (HDAC) is deregulated in numerous cancers including CML, pan-HDAC inhibitors may represent promising therapeutic regimens for the treatment of CML cells in combination with TKi.

RESULTS:

We assessed the anti-leukemic activity of a novel hydroxamate-based pan-HDAC inhibitor MAKV-8, which complied with the Lipinski's "rule of five," in various CML cells alone or in combination with imatinib. We validated the in vitro HDAC-inhibitory potential of MAKV-8 and demonstrated efficient binding to the ligand-binding pocket of HDAC isoenzymes. In cellulo, MAKV-8 significantly induced target protein acetylation, displayed cytostatic and cytotoxic properties, and triggered concomitant ER stress/protective autophagy leading to canonical caspase-dependent apoptosis. Considering the specific upregulation of selected HDACs in LSCs from CML patients, we investigated the differential toxicity of a co-treatment with MAKV-8 and imatinib in CML versus healthy cells. We also showed that beclin-1 knockdown prevented MAKV-8-imatinib combination-induced apoptosis. Moreover, MAKV-8 and imatinib co-treatment synergistically reduced BCR-ABL-related signaling pathways involved in CML cell growth and survival. Since our results showed that LSCs from CML patients overexpressed c-MYC, importantly MAKV-8-imatinib co-treatment reduced c-MYC levels and the LSC population. In vivo, tumor growth of xenografted K-562 cells in zebrafish was completely abrogated upon combined treatment with MAKV-8 and imatinib.

CONCLUSIONS:

Collectively, the present findings show that combinations HDAC inhibitor-imatinib are likely to overcome drug resistance in CML pathology.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Protocolos de Quimioterapia Combinada Antineoplásica / Inibidores de Histona Desacetilases / Mesilato de Imatinib Limite: Adult / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Protocolos de Quimioterapia Combinada Antineoplásica / Inibidores de Histona Desacetilases / Mesilato de Imatinib Limite: Adult / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article