An iron-chelating sulfonamide identified from Drosophila-based screening for antipathogenic discovery.

We exploited bacterial infection assays using the fruit fly Drosophila melanogaster to identify anti-infective compounds that abrogate the pathological consequences in the infected hosts. Here, we demonstrated that a pyridine-3-N-sulfonylpiperidine derivative (4a) protects Drosophila from the acute infections caused by bacterial pathogens including Pseudomonas aeruginosa. 4a did not inhibit the growth of P. aeruginosa in vitro, but inhibited the production of secreted toxins such as pyocyanin and hydrogen cyanide, while enhancing the production of pyoverdine and pyochelin, indicative of iron deprivation. Based on its catechol moiety, 4a displayed iron-chelating activity in vitro toward both iron (II) and iron (III), more efficiently than the approved iron-chelating drugs such as deferoxamine and deferiprone, concomitant with more potent antibacterial efficacy in Drosophila infections and unique transcriptome profile. Taken together, these results delineate a Drosophila-based strategy to screen for antipathogenic compounds, which interfere with iron uptake crucial for bacterial virulence and survival in host tissues.

BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion.

Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.

The Chromatin Remodeling Complex CHD1 Regulates the Primitive State of Mesenchymal Stromal Cells to Control Their Stem Cell Supporting Activity.

The primitive state (stemness) of mesenchymal stromal cells (MSCs) is responsible for supporting the function of tissue-specific stem cells to regenerate damaged tissues. However, molecular mechanisms regulating the stemness of MSCs remain unknown. In this study, we found that the primitive state of MSCs is hierarchically regulated by the expression levels of the chromatin remodeling complex, CHD1, with CHD1 expression levels higher in the undifferentiated state, and decreasing upon MSC differentiation. Consistently, CHD1 expression levels decrease during progressive loss of clonogenic progenitors (CFU-F) induced by passage cultures. Moreover, knockdown (KD) of CHD1 decreased CFU-F frequency, whereas CHD1 overexpression increased it. In addition, the expression of stem cell-specific genes was down- or upregulated upon KD or overexpression of CHD1, respectively, accompanied by associated changes in chromatin condensation. Importantly, altering CHD1 expression levels affected the ability of MSCs to support the self-renewing expansion of hematopoietic stem cells (HSCs). Furthermore, CHD1 levels were significantly decreased in MSCs from acute myeloid leukemia or aplastic anemia patients, where CFU-F and HSC-supporting activities are lost. Altogether, these findings show that chromatin remodeling by CHD1 is a molecular parameter that influences the primitive state of MSCs and their stem cell-supporting activity, which controls tissue regeneration.

Anti-leukemic Activity of AIU2008 in FLT3-ITD-positive Acute Myeloid Leukemia.

BACKGROUND/AIM: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in signal transduction underlying survival, proliferation, and differentiation of hematopoietic cells. An internal tandem duplication (ITD) in FLT3 in the juxtamembrane domain is a common mutation causing human acute myeloid leukemia (AML) and activates constitutive signaling. MATERIALS AND METHODS: We evaluated the novel FLT3 inhibitor 5-(4-fluorophenyl)-N-(naphthalen-1-yl)oxazol-2-amine (AIU2008) for the treatment of AML. RESULTS: AIU2008 was designed by modifying FLT3 inhibitor 7c, and showed improved anti-leukemic efficacy in FLT3-ITD-positive AML cells. Specifically, AIU2008 inhibited cell growth and apoptotic death. In addition, AIU2008 down-regulated DNA repair genes involved in homologous recombination and non-homologous end joining. It contributed to the synergistic inhibition of AML cell growth in combination treatment with PARP inhibitors. CONCLUSION: AIU2008 is a promising FLT3 targeting agent, and may be used in combination with PARP inhibitors for the treatment of AML.

A Single-Center Retrospective Analysis of Periprocedural Variables Affecting Local Tumor Progression after Radiofrequency Ablation of Colorectal Cancer Liver Metastases.

Background Local tumor progression (LTP) is associated with poorer survival in patients undergoing radiofrequency ablation (RFA) for colorectal liver metastasis (CLM). An algorithmic strategy to predict LTP may help in selection of patients who would benefit most from RFA for CLM. Purpose To estimate local tumor progression-free survival (LTPFS) following RFA of CLM and develop an algorithmic strategy based on clinical variables. Materials and Methods In this retrospective study, between March 2000 and December 2014, patients who underwent percutaneous RFA for CLM were randomly split into development (60%) and internal validation (40%) data sets. Kaplan-Meier method was used to estimate LTPFS and overall survival (OS) rates. Independent factors affecting LTPFS in the development data set were investigated by using multivariable Cox proportional hazard regression analysis. Risk scores were assigned to the risk factors and applied to the validation data set. Results A total of 365 patients (mean age, 60 years ± 11 [standard deviation]; 259 men) with 512 CLMs were evaluated. LTPFS and OS rates were 85% and 92% at 1 year, 73% and 41% at 5 years, 72% and 30% at 10 years, and 72% and 28% at 15 years, respectively. Independent risk factors for LTP included tumor size of 2 cm or greater (hazard ratio [HR], 3.8; 95% CI: 2.3, 6.2; P < .001), subcapsular tumor location (HR, 1.9; 95% CI: 1.1, 3.1; P = .02), and minimal ablative margin of 5 mm or less (HR, 11.7; 95% CI: 4.7, 29.2; P < .001). A prediction model that used the risk factors had areas under the curve of 0.89, 0.92, and 0.90 at 1, 5, and 10 years, respectively, and it showed significantly better areas under the curve when compared with the model using the minimal ablative margin of 5 mm or less alone. Conclusion Radiofrequency ablation provided long-term control of colorectal liver metastases. Although minimal ablative margin of 5 mm or less was the most dominant factor, the multifactorial approach including tumor size and subcapsular location better predicted local tumor progression-free survival. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Soulen and Sofocleous in this issue.

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors.

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

A Small Compound KJ-28d Enhances the Sensitivity of Non-Small Cell Lung Cancer to Radio- and Chemotherapy.

We previously reported on a poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated KJ-28d), which increased the death of human ovarian cancer BRCA1-deficient SNU-251 cells. In the present study, we further investigated the antitumor activities of KJ-28d in BRCA-proficient non-small cell lung cancer (NSCLC) cells to expand the use of PARP inhibitors. KJ-28d significantly inhibited the growth of NSCLC cells in vitro and in vivo, and induced DNA damage and reactive oxygen species in A549 and H1299 cells. Combined treatment with KJ-28d and ionizing radiation led to increased DNA damage responses in A549 and H1299 cells compared to KJ-28d or ionizing radiation alone, resulting in apoptotic cell death. Moreover, the combination of KJ-28d plus a DNA-damaging therapeutic agent (carboplatin, cisplatin, paclitaxel, or doxorubicin) synergistically inhibited cell proliferation, compared to either drug alone. Taken together, the findings demonstrate the potential of KJ-28d as an effective anti-cancer therapeutic agent for BRCA-deficient and -proficient cancer cells. KJ-28d might have potential as an adjuvant when used in combination with radiotherapy or DNA-damaging agents, pending further investigations.

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells.

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the 'BRCAness'/'DNA-PKness' phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

Fractionated Coptis chinensis Extract and Its Bioactive Component Suppress Propionibacterium acnes-Stimulated Inflammation in Human Keratinocytes.

Coptis chinensis (CC) is widely used in Asian countries to treat inflammatory diseases. We investigated the anti-inflammatory activity of the aqueous fraction separated from CC extract and of berberine, its key bioactive component, in human keratinocytes and the possible molecular mechanisms underlying this. Treating HaCaT keratinocytic cells with heat-killed Propionibacterium acnes induced nitric oxide and proinflammatory cytokine (e.g., tumor necrosis factor-α, interleukin (IL)-1ß, and IL-8) production and their mRNA expression; these effects were suppressed by pretreatment with the aqueous fraction or berberine, which also suppressed the phosphorylation of ERK, JNK, and p38 kinases and the nuclear expression of nuclear factor (NF)-κB p65 in P. acnes-stimulated cells. Thus, the aqueous fraction and berberine effectively exerted anti-inflammatory activities by suppressing mitogen-activated protein kinase and NF-κB signaling pathways in human keratinocytes and may be used for treating P. acnes-induced inflammatory skin diseases.

Validated high-performance liquid chromatography method for the determination of the inhibitor of cancer cell invasion (E)-N-benzyl-6-[2-(3, 4-dihydroxy benzylidene)hydrazinyl]-N-methylpyridine-3-sulfonamide in rat plasma and its application to pharmacokinetic study.

In this study, a reliable method for the quantitation of (E)-N-benzyl-6-[2-(3, 4-dihydroxy benzylidene)hydrazinyl]-N-methylpyridine-3-sulfonamide (JW-55) in rat plasma was developed and validated using high-performance liquid chromatography. Plasma samples were deproteinized; sildenafil was used as an internal standard. Chromatographic separation was achieved using a reversed-phase C18 column. The mobile phase, 0.02 m ammonium acetate buffer:acetonitrile (48:52, v/v), was run at a flow rate of 1.0 mL/min at room temperature, and the column eluent was monitored using an ultraviolet detector at 280 nm. The retention times of JW-55 and sildenafil were ~5.9 and 7.7 min, respectively. The detection limit of JW-55 in rat plasma was 0.03 µg/mL. Pharmacokinetic parameters of JW-55 were evaluated after intravenous and oral administration of JW-55 (10 mg/kg) in rats. After oral administration, the F value was approximately 73.7%.

Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery.

Ex-vivo expanded mesenchymal stromal cells (MSCs) are increasingly used for paracrine support of hematopoietic stem cell (HSC) regeneration, but inconsistent outcomes have hindered ongoing clinical trials. Here, we show that significant heterogeneity in the niche activity of MSCs is created during their culture in various serum-supplemented media. The MSCs cultured under stimulatory or non-stimulatory culture conditions exhibited differences in colony forming unit-fibroblast contents, expression levels of cross-talk molecules (Jagged-1 and CXCL-12) and their support for HSC self-renewal. Accordingly, the enhancing effects of MSCs on hematopoietic engraftment were only visible when HSCs were co-transplanted with MSCs under stimulatory conditions. Of note, these differences in MSCs and their effects on HSCs were readily reversed by switching the cultures, indicating that the difference in niche activity can be caused by distinct functional state, rather than by clonal heterogeneity. Supporting the findings, transcriptomic analysis showed distinct upstream signaling pathways such as inhibition of P53 and activation of ER-stress response gene ATF4 for MSCs under stimulatory conditions. Taken together, our study shows that the niche activity of MSCs can vary rapidly by the extrinsic cues during culture causing variable outcomes in hematopoietic recoveries, and point to the possibility that MSCs can be pre-screened for more predictable efficacy in various cell therapy trials.

The novel anthraquinone derivative IMP1338 induces death of human cancer cells by p53-independent S and G2/M cell cycle arrest.

To identify novel small molecules that induce selective cancer cell death, we screened a chemical library containing 1040 compounds in HT29 colon cancer and CCD18-Co normal colon cells, using a phenotypic cell-based viability assay system with the Cell Counting Kit-8 (CCK-8). We discovered a novel anthraquinone derivative, N-(4-[{(9,10-dioxo-9,10-dihydro-1-anthracenyl)sulfonyl}amino]phenyl)-N-methylacetamide (IMP1338), which was cytotoxic against the human colon cancer cells tested. The MTT cell viability assay showed that treatment with IMP1338 selectively inhibited HCT116, HCT116 p53(-/-), HT29, and A549 cancer cell proliferation compared to that of Beas2B normal epithelial cells. To elucidate the cellular mechanism underlying the cytotoxicity of IMP1338, we examined the effect of IMP1338 on the cell cycle distribution and death of cancer cells. IMP1338 treatment significantly arrested the cell cycle at S and G2/M phases by DNA damage and led to apoptotic cell death, which was determined using FACS analysis with Annexin V/PI double staining. Furthermore, IMP1338 increased caspase-3 cleavage in wild-type p53, p53 knockout HCT116, and HT29 cells as determined using immunoblotting. In addition, IMP1338 markedly induced the phosphorylation of histone H2AX and Chk1 in both cell lines while the combination of 5-fluorouracil (5-FU) and radiation inhibited the viability of HCT116, HCT116 p53(-/-), and HT29 cells compared to 5-FU or radiation alone. Our findings indicated that IMP1338 induced p53-independent cell death through S and G2/M phase arrest as well as DNA damage. These results provide a basis for future investigations assessing the promising anticancer properties of IMP1338.

Recent conjugation strategies of small organic fluorophores and ligands for cancer-specific bioimaging.

Conjugation between various small fluorophores and specific ligands has become one of the main strategies for bioimaging in disease diagnosis, medicinal chemistry, immunology, and fluorescence-guided surgery, etc. Herein, we present our review of recent studies relating to molecular fluorescent imaging techniques for various cancers in cell-based and animal-based models. Various organic fluorophores, especially near-infrared (NIR) probes, have been employed with specific ligands. Types of ligands used were small molecules, peptides, antibodies, and aptamers; each has specific affinities for cellular receptor proteins, cancer-specific antigens, enzymes, and nucleic acids. This review can aid in the selection of cancer-specific ligands and fluorophores, and may inspire the further development of new conjugation strategies in various cellular and animal models.

Inhibition of cancer cell invasion by new ((3,4-dihydroxy benzylidene)hydrazinyl)pyridine-3-sulfonamide analogs.

Rab GTPases regulate various types of intracellular membrane trafficking in all eukaryotes. Since Rab27a and its multiple effectors are involved in exocytosis of lysosome-related organelles and play a major role in malignancy, compounds targeting Rab27a could be likely used to inhibit invasive growth and tumor metastasis. Thus, we designed and synthesized several compounds based on the previously reported Rab27a-targeting synthetic compounds identified by virtual screening, and investigated their anti-metastatic effects in MDA-MB231 and A375 cells. Among the synthesized compounds, (E)-N-(3-chlorophenyl)-6-(2-(3,4-dihydroxy benzylidene)hydrazinyl)pyridine-3-sulfonamide (3d) and (E)-N-benzyl-6-(2-(3,4-dihydroxy benzylidene)hydrazinyl)-N-methylpyridine-3-sulfonamide (3f) significantly inhibited the invasiveness of both tumor cell lines. Compounds 3d and 3f also decreased the levels of signature extracellular matrix marker proteins (fibronectin, collagen, and α-smooth muscle actin) and representative mesenchymal cell markers (N-cadherin and vimentin). Taken together, our results suggest that novel sulfonamide analogs have anti-metastatic activity in breast and melanoma cancer cell lines and may be used as therapeutic agents to treat malignant cancer.

Regulation of mesenchymal stromal cells through fine tuning of canonical Wnt signaling.

Mesenchymal stromal cells (MSCs) have been extensively utilized for various cell therapeutic trials, but the signals regulating their stromal function remain largely unclear. Here, we show that canonical Wnt signals distinctively regulate MSCs in a biphasic manner depending on signal intensity, i.e., MSCs exhibit proliferation and progenitor self-renewal under low Wnt/ß-catenin signaling, whereas they exhibit enhanced osteogenic differentiation with priming to osteoblast-like lineages under high Wnt/ß-catenin signaling. Moreover, low or high levels of ß-catenin in MSCs distinctly regulated the hematopoietic support of MSCs to promote proliferation or the undifferentiated state of hematopoietic progenitors, respectively. A gene expression study demonstrated that different intracellular levels of ß-catenin in MSCs induce distinct transcriptomic changes in subsets of genes belonging to different gene function categories. Different ß-catenin levels also induced differences in intracellular levels of the ß-catenin co-factors, Tcf-1 and Lef-1. Moreover, nano-scale mass spectrometry of proteins that co-precipitated with ß-catenin revealed distinctive spectra of proteins selectively interacting with ß-catenin at specific expression levels. Together, these results show that Wnt/ß-catenin signals can coax distinct transcription milieu to induce different transcription profiles in MSCs depending on the signal intensity and that fine-tuning of the canonical Wnt signaling intensity can regulate the phase-specific functionality of MSCs.

Transarterial chemoembolization vs. radiofrequency ablation for the treatment of single hepatocellular carcinoma 2 cm or smaller.

OBJECTIVES: To compare the effectiveness of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for treating small (≤2 cm) hepatocellular carcinomas (HCCs). METHODS: This retrospective study consisted of 287 patients (mean age, 57.1 years; age range, 29-84 years; 221 men, 66 women; 73.5% with HBV; 100% with liver cirrhosis) with Barcelona Clinic Liver Cancer very early-stage HCC (≤2 cm single HCC) who were initially treated with TACE (n=122) or RFA (n=165). The primary study end point was overall patient survival. Secondary study end points were time to progression and tumor response. RESULTS: The RFA and TACE groups were well balanced in terms of baseline variables. The two groups did not differ significantly in overall survival (P=0.079) or major complication (P>0.999) rates. The respective cumulative survival rates at 1, 3, 5, and 8 years were 97.6, 86.7, 74.5, and 60.0% for RFA and 93.4, 75.4, 63.1, and 51.1% for TACE. Their objective tumor regression (complete or partial response) rates were 100% (165/165) and 95.9% (117/122), respectively (P=0.013). The median times to progression for RFA and TACE were 27.0±3.8 (95% confidence intervals (CIs): 19.6-34.4) and 18.0±2.9 (95% CIs: 12.2-23.8) months, respectively. RFA yielded a significantly longer time to progression (P=0.034). CONCLUSIONS: TACE may be a viable alternative treatment for ≤2 cm HCCs when RFA is not feasible.

Constitutive stabilization of hypoxia-inducible factor alpha selectively promotes the self-renewal of mesenchymal progenitors and maintains mesenchymal stromal cells in an undifferentiated state.

With the increasing use of culture-expanded mesenchymal stromal cells (MSCs) for cell therapies, factors that regulate the cellular characteristics of MSCs have been of major interest. Oxygen concentration has been shown to influence the functions of MSCs, as well as other normal and malignant stem cells. However, the underlying mechanisms of hypoxic responses and the precise role of hypoxia-inducible factor-1α (Hif-1α), the master regulatory protein of hypoxia, in MSCs remain unclear, due to the limited span of Hif-1α stabilization and the complex network of hypoxic responses. In this study, to further define the significance of Hif-1α in MSC function during their self-renewal and terminal differentiation, we established adult bone marrow (BM)-derived MSCs that are able to sustain high level expression of ubiquitin-resistant Hif-1α during such long-term biological processes. Using this model, we show that the stabilization of Hif-1α proteins exerts a selective influence on colony-forming mesenchymal progenitors promoting their self-renewal and proliferation, without affecting the proliferation of the MSC mass population. Moreover, Hif-1α stabilization in MSCs led to the induction of pluripotent genes (oct-4 and klf-4) and the inhibition of their terminal differentiation into osteogenic and adipogenic lineages. These results provide insights into the previously unrecognized roles of Hif-1α proteins in maintaining the primitive state of primary MSCs and on the cellular heterogeneities in hypoxic responses among MSC populations.

Recent updates on the development of ganetespib as a Hsp90 inhibitor.

Heat shock protein 90 (Hsp90) plays a critical role in the maintenance of multiple oncogenic pathways and is a required protein for folding and stability of many oncoproteins that are related to the growth, proliferation, and survival of many kinds of cancers. Ganetespib (STA-9090) is a potent, synthetic, small molecule inhibitor of Hsp90, and its binding to Hsp90 is known to result in the degradation of its client proteins and subsequent death of cancer cells. This article provides a review of ganetespib as one of the leading Hsp90 inhibitors, which is under investigation in a broad range of clinical stages for the treatment of cancer.

Synthesis and structure-activity relationship of (E)-phenoxyacrylic amide derivatives as hypoxia-inducible factor (HIF) 1α inhibitors.

A series of (E)-phenoxyacrylic amide derivatives were synthesized and evaluated as hypoxia inducible factor (HIF) 1α inhibitors. The present structure-activity relationship study on this series identified the morpholinoethyl containing ester 4p as a potent inhibitor of HIF-1α under hypoxic conditions (IC50=0.12 µM in a cell-based HRE reporter assay) in HCT116 cells. The representative compound 4p suppressed hypoxia-induced HIF-1α accumulation and targeted gene expression in a dose-dependent manner. The effect of HIF-1α inhibition by 4p was further demonstrated by its inhibitory activity on in vitro tube formation and migration of cells, which may be valuable for development of novel therapeutics for cancer and tumor angiogenesis.

Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors.

Tumor hypoxia has been recognized as a common feature of solid tumors and a negative prognostic factor for response to treatment and survival of cancer patients. The discovery of hypoxia-inducible factor-1 (HIF-1), a molecular determinant of responses to hypoxia in mammalian cells, has renewed enthusiasm for discovery and development of targeted therapies exploiting the hypoxic tumor microenvironment. HIF-1 activity in tumors depends on availability of the HIF-1α subunit, the levels of which increase under hypoxic conditions and through activation of oncogenes and/or inactivation of tumor suppressor genes. Increased HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to current interest in HIF-1 as promising anticancer drug target. In spite of an ever increasing number of putative small molecule inhibitors of HIF-1, only a few are progressing through preclinical and early clinical development. In this review, we will discuss recent advances in discovery and development of small molecule inhibitors that target the HIF-1 pathway as potential anticancer agents.