CUDC-101 overcomes arsenic trioxide resistance via caspase-dependent promyelocytic leukemia-retinoic acid receptor alpha degradation in acute promyelocytic leukemia

Autor: Qin Fang, Danna Wei, Jishi Wang, Tingting Lu, Zhaoyuan Zhang, Weili Wang, Dan Ma, Tianzhuo Zhang, Kunlin Yu
Rok vydání: 2020
Předmět:
0301 basic medicine
Acute promyelocytic leukemia
Cancer Research
Antineoplastic Agents
Apoptosis
Mice
SCID
Hydroxamic Acids
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Arsenic Trioxide
Leukemia
Promyelocytic
Acute
Mice
Inbred NOD
immune system diseases
In vivo
Biomarkers
Tumor
Tumor Cells
Cultured
medicine
Animals
Humans
Cytotoxic T cell
Pharmacology (medical)
Arsenic trioxide
neoplasms
Caspase
Cell Proliferation
Pharmacology
biology
Retinoic Acid Receptor alpha
Prognosis
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation
Neoplastic
Leukemia
030104 developmental biology
Oncology
chemistry
Drug Resistance
Neoplasm
Retinoic acid receptor alpha
Caspases
030220 oncology & carcinogenesis
Quinazolines
biology.protein
Cancer research
Female
Zdroj: Anti-Cancer Drugs. 31:158-168
ISSN: 0959-4973
DOI: 10.1097/cad.0000000000000847
Popis: Although arsenic trioxide (ATO) treatment has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, many high-risk APL patients who fail to achieve a complete molecular remission or relapse become resistant to ATO. Herein, we report that 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) exhibits specific anticancer effects on APL and ATO-resistant APL in vitro and in vivo, while showing negligible cytotoxic effect on the noncancerous cells including normal CD34 cells and bone marrow mesenchymal stem cells from APL patients. Further mechanistic studies show that CUDC-101 triggers caspase-dependent degradation of the promyelocytic leukemia-retinoic acid receptor alpha fusion protein. As a result, APL and ATO-resistant APL cells undergo apoptosis upon CUDC-101 treatment and this apoptosis-inducing effect is even stronger than that of ATO. Finally, using a xenograft mouse model, we demonstrated that CUDC-101 significantly represses leukemia development in vivo. In conclusion, these results suggested that CUDC-101 can serve as a potential candidate drug for APL, particularly for ATO-resistant APL.
Databáze: OpenAIRE
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