ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol

Mahoney, Emilia; Lucas, David M.; Gupta, Sneha; Wagner, Amy J.; Herman, Sarah E.M.; Smith, Lisa L.; Yeh, Yung‐Hui; Andritsos, Leslie A.; Jones, Jeffrey A.; Flynn, Joseph M.; Blum, Kristie A.; Zhang, Xiaoli; Lehman, Amy; Kong, Hui; Gürcan, Metin N.; Johnson, Amy J.; Byrd, John C.

doi:10.1182/blood-2011-12-400184

Cited by 92 publications

(82 citation statements)

References 48 publications

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“…418 A significant finding from our study is that autophagy inhibition 419 by HCQ or p62/SQSTM1 knockdown increased Ara-C cytotoxicity of 420 Ara-C-resistant leukemia cells. Our data are in line with recent 421 findings showing that interference with the autophagic response 422 increased the cytotoxicity of daunorubicin, flavopiridol triciribine, 423 and tyrosine kinase inhibitors towards leukemic cells [41][42][43][44]. 424 Our study is noteworthy, because we compared the cell death-425 inducing effects of HCQ between Ara-C-sensitive and Ara-C-426 resistant leukemia cells, which were functionally established from 427 the parental leukemia cells.…”

supporting

confidence: 75%

Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

Kim

Eom

Jeung

et al. 2015

Biomedicine & Pharmacotherapy

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supporting

confidence: 75%

Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

Kim

Eom

Jeung

et al. 2015

Biomedicine & Pharmacotherapy

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“…Autophagy is an evolutionarily conserved self‐digesting process in which cytoplasmic material is sequestered within cytosolic double‐membraned vesicles termed autophagosomes and delivered to the lysosome for degradation 31. A recent study showed that HSCs activation is suppressed by an autophagy inhibitor 32.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐30a ameliorates hepatic fibrosis by inhibiting Beclin1‐mediated autophagy

Chen

et al. 2017

J Cellular Molecular Medi

102

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We explored the role of microRNA‐30a (miR‐30a) and the mechanism involved in hepatic fibrosis. MiR‐30a overexpression was achieved by miR‐30a mimics transfection in hepatic stellate cells (HSCs) (HSC‐T6, LX‐2), and miR‐30a agomir (ago‐miR‐30a) treatment in mice. MiR‐30a levels were measured using TaqMan miRNA assay system, and the localization of miR‐30a was detected by fluorescence in situ hybridization (FISH). The interaction of miR‐30a and Beclin1 was confirmed by dual‐luciferase reporter assay. Autophagic flux was analysed using tandem mRFP‐GFP‐LC3 fluorescence microscopy, electron microscopy and Western blot of LC3‐II/I ratio. MiR‐30a was notably down‐regulated in activated HSCs and LX‐2‐exosomes induced by TGF‐β1; overexpression of miR‐30a down‐regulated extracellular matrix (ECM), such as α‐SMA, TIMP‐1, and Collagen I expression, and suppressed cell viability in HSCs. MiR‐30a was significantly down‐regulated in hepatic fibrosis mice and overexpression of miR‐30a prevented BDL‐induced fibrogenesis, concomitant with the down‐regulation of ECM. MiR‐30a inhibited HSCs autophagy and increased lipid accumulation in HSCs and in mice fibrotic hepatic tissues. MiR‐30a inhibited its downstream effector of Beclin1 by direct targeting its 3′‐UTR region. Moreover, Knock‐down of Beclin1 by small interfering RNA (siRNA) inhibited HSC autophagy and activation in LX‐2 cells. In conclusion, miR‐30a is down‐regulated in hepatic fibrosis models and its overexpression prevents liver fibrogenesis by directly suppressing Beclin1‐mediated autophagy; therefore, miR‐30a may be a new potential therapeutic target for controlling hepatic fibrosis.

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“…Evaluation of the activity of alvocidib in combination with additional agents is planned as part of the further clinical development of alvocidib. Future studies should focus on identification of biomarkers of clinical response 29 and risk for TLS 30 . Enhanced supportive care strategies may yield further improvement in patient adherence and response rates.…”

Section: Discussionmentioning

confidence: 99%

Final results of EFC6663: A multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia

et al. 2015

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Purpose Chronic lymphocytic leukemia (CLL) patients refractory to fludarabine based therapies have poor outcomes with currently available therapies. Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients and Methods Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. Results One hundred and sixty five patients were enrolled at 34 centers, and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Conclusion Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Clinical responses were observed in patients with high risk clinical and genomic features. With careful monitoring, alvocidib has a manageable safety profile. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures.

show abstract

ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol

Cited by 92 publications

References 48 publications

Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

MicroRNA‐30a ameliorates hepatic fibrosis by inhibiting Beclin1‐mediated autophagy

Final results of EFC6663: A multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia

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