1,721,664 research outputs found
Identification of Targets of the HIF‑1 Inhibitor IDF-11774 Using Alkyne-Conjugated Photoaffinity Probes
No full textWe developed a hypoxia-inducible
factor-1 (HIF-1) inhibitor, IDF-11774,
as a clinical candidate for cancer therapy. To understand the mechanism
of action of IDF-11774, we attempted to isolate target proteins of
IDF-11774 using bioconjugated probes. Multifunctional chemical probes
containing sites for click conjugation and photoaffinity labeling
were designed and synthesized. After fluorescence and photoaffinity
labeling of proteins, two-dimensional electrophoresis (2DE) was performed
to isolate specific molecular targets of IDF-11774. Heat shock protein
(HSP) 70 was identified as a target protein of IDF-11774. We revealed
that IDF-11774 inhibited HSP70 chaperone activity by binding to its
allosteric pocket, rather than the ATP-binding site in its nucleotide-binding
domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate
(OCR) and ATP production, thereby increasing intracellular oxygen
tension. This result suggests that the inhibition of HSP70 chaperone
activity by IDF-11774 suppresses HIF-1α refolding and stimulates
HIF-1α degradation. Taken together, these findings indicate
that IDF-11774-derived chemical probes successfully identified IDF-11774’s
target molecule, HSP70, and elucidated the mode of action of IDF-11774
in inhibiting HSP70 chaperone activity and stimulating HIF-1α
degradation in cancer cells
Identification of targets of the HIF-1 inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes
No full textWe developed a hypoxia-inducible factor-1 (HIF-1) inhibitor, IDF-11774, as a clinical candidate for cancer therapy. To understand the mechanism of action of IDF-11774, we attempted to isolate target proteins of IDF-11774 using bioconjugated probes. Multifunctional chemical probes containing sites for click conjugation and photoaffinity labeling were designed and synthesized. After fluorescence and photoaffinity labeling of proteins, two-dimensional electrophoresis (2DE) was performed to isolate specific molecular targets of IDF-11774. Heat shock protein (HSP) 70 was identified as a target protein of IDF-11774. We revealed that IDF-11774 inhibited HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotide-binding domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate (OCR) and ATP production, thereby increasing intracellular oxygen tension. This result suggests that the inhibition of HSP70 chaperone activity by IDF-11774 suppresses HIF-1α refolding and stimulates HIF-1α degradation. Taken together, these findings indicate that IDF-11774-derived chemical probes successfully identified IDF-11774's target molecule, HSP70, and elucidated the mode of action of IDF-11774 in inhibiting HSP70 chaperone activity and stimulating HIF-1α degradation in cancer cells.open
The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth
No full textAbstractHIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.</jats:p
Abstract 1164: A novel hypoxia-inducible factor-1 inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth
No full textAbstract
HIF-1 is associated with poor patient prognosis and therapeutic resistance of cancer. We have developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, as a clinical candidate for cancer therapy. Under hypoxic condition, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells. IDF-11774 suppressed the angiogenesis of cancer cells by reducing the expression of HIF-1 target genes. Moreover, IDF-11774 reduced glucose uptake, leading sensitizing cell growth on low glucose condition. IDF-11774 also decreased the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Metabolic profile of IDF-11774-treated cells revealed low levels of NAD+, lactate, and intermediates in glycolysis and tricarboxylic acid (TCA) cycle. More importantly, we observed elevated AMP and diminished ATP level, leading high AMP/ATP ratio. Apparently, phosphorylation of AMPK increased, leading inhibition of mTOR signaling in cells. In vivo xenograft assays demonstrated that IDF11774 has significant anti-cancer efficacy by targeting cancer metabolism in mouse models containing the KRAS, PTEN or VHL mutation, which often occurs in many malignant cancers. Collectively, IDF-11774 suppresses the hypoxia-induced HIF-1α accumulation, thereby repressing tumor growth by regulating cancer metabolism.
Citation Format: Misun Won, Hyun Seung Ban, Kyeong Lee, Hongsub Lee, Bo-Kyung Kim, Hwan Mook Kim, Ravi Naik, Song-Kyu Park, Joon-Tae Park, Inhyub Kim, Miso Nam, Geum-Sook Hwang. A novel hypoxia-inducible factor-1 inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1164. doi:10.1158/1538-7445.AM2017-1164</jats:p
Composition for preventing or treating cancer comprising IDF-11774 and autolysosome formation inhibitor
No full text본 발명은 IDF-11774 및 자가용해소체 형성 저해제를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명의 약학적 조성물은 암세포의 성장 및 생존을 억제하는 효능이 탁월하여 암을 효과적으로 예방 및 치료할 수 있다. 구체적으로 본 발명의 약학적 조성물은 IDF-11774 및 자가용해소체 형성 저해제를 병용함으로써, 암세포에서 자가용해소체(autolysosome)의 형성을 억제하여 암세포에 대한 아폽토시스(apoptosis)를 유도하는 우수한 시너지 효과를 발휘하는 효능이 있어, 암의 예방 및 치료에 다양하게 활용될 수 있다. 이 때 Bcl-2 가 시너지 효능을 예측할 수 있는 바이오마커로 활용될 수 있다.국
IDF-11774 Induces Cell Cycle Arrest and Apoptosis by Inhibiting HIF-1α in Gastric Cancer
No full textHypoxia-inducible factor-1 alpha (HIF-1α) is a regulatory factor of intracellular oxygen supersession. The expression or increased activity of HIF-1α is closely related to various human cancers. Previously, IDF-11774 was demonstrated to inhibit HSP70 chaperone activity and suppress the accumulation of HIF-1α. In this study, we aimed to determine the effects of IDF-11774 on gastric cancer cell lines. Treatment with IDF-11774 was found to markedly decrease the proliferation, migration, and invasion of the gastric cancer cell lines. Furthermore, the phosphorylation levels of extracellular signal-regulated kinase 1/2, p38, and Jun N-terminal kinase in the mitogen-activated protein kinase signaling pathways were markedly increased in a dose-dependent manner, ultimately promoting apoptosis via the induction of cell cycle arrest. Our findings indicate that HIF-1α inhibitors are potent drugs for the treatment of gastric cancer
Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer
No full textBACKGROUND: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation.
METHODS: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library.
RESULTS: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression.
CONCLUSIONS: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.restrictio
Share of open access journal articles published by Berlin authors from 2019: data
No full textThe publication output from nine research institutions from Berlin (Germany) was analysed and the share of open access for journal articles published in 2019 was determined. Journal articles whose authors are affiliated with at least one of the nine institutions were analysed.
The data description includes: description of provided files and respective sheets, list of data fields and their source, data re-use cases. The data described here were retrieved from multiple bibliographic databases. Due to license terms raw data from individual databases cannot be provided for download.
Data was aggregated, normalised and analysed with a Python script which is available at https://github.com/tuub/oa-eval (code documentation in English). For a detailed description of the retrieval process and the analysis steps see the report (https://doi.org/10.14279/depositonce-11774). Search queries and the respective download settings for these databases are included in the data file
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