論文 - 詳細
| RRC ID | 66853 |
|---|---|
| 著者 | Yi X, Sarkar A, Kismali G, Aslan B, Ayres M, Iles LR, Keating MJ, Wierda WG, Long JP, Bertilaccio MTS, Gandhi V. |
| タイトル | AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Survival of CLL cells due to the presence of Bcl-2 and Mcl-1 has been established. Direct inhibition of Bcl-2 by venetoclax and indirect targeting of Mcl-1 with transcription inhibitors have been successful approaches for CLL. AMG-176 is a selective and direct antagonist of Mcl-1, which has shown efficacy in several hematologic malignancies; however, its effect on CLL is elusive. We evaluated biological and molecular effects of AMG-176 in primary CLL cells. EXPERIMENTAL DESIGN:Using samples from patients (n = 74) with CLL, we tested effects of AMG-176 on CLL and normal hematopoietic cell death and compared importance of CLL prognostic factors on this biological activity. We evaluated CLL cell apoptosis in the presence of stromal cells and identified cell death pathway including stabilization of Mcl-1 protein. Finally, we tested a couplet of AMG-176 and venetoclax in CLL lymphocytes. RESULTS:AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nmol/L, there was 30% and 45% cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death. IGHV unmutated status, high β2M and Mcl-1 protein levels resulted in slightly lower cell death. Mcl-1, but not Bcl-2 protein levels, in CLL cells increased with AMG-176. Low concentrations of venetoclax (1-30 nmol/L) were additive or synergistic with AMG-176. CONCLUSIONS:AMG-176 is active in inducing CLL cell death while sparing normal blood cells. Combination with low-dose venetoclax was additive or synergistic. |
| 巻・号 | 26(14) |
| ページ | 3856-3867 |
| 公開日 | 2020-7-15 |
| DOI | 10.1158/1078-0432.CCR-19-1397 |
| PII | 1078-0432.CCR-19-1397 |
| PMID | 31937611 |
| PMC | PMC7358119 |
| MeSH | Adult Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Antineoplastic Combined Chemotherapy Protocols / pharmacology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Apoptosis / drug effects Bridged Bicyclo Compounds, Heterocyclic / pharmacology Bridged Bicyclo Compounds, Heterocyclic / therapeutic use Cell Line, Tumor Drug Screening Assays, Antitumor Drug Synergism Female Humans Leukemia, Lymphocytic, Chronic, B-Cell / blood Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / pathology Leukocytes, Mononuclear Male Middle Aged Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors* Naphthalenes / pharmacology* Naphthalenes / therapeutic use Primary Cell Culture Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 / metabolism Spiro Compounds / pharmacology* Spiro Compounds / therapeutic use Sulfonamides / pharmacology Sulfonamides / therapeutic use |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | StromaNKtert(RCB2350) |