Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

Synthesis, Anti-Inflammatory Activities, and Molecular Docking Study of Novel Pyxinol Derivatives as Inhibitors of NF-κB Activation.

Pyxinol, an active metabolite of ginsenosides in human hepatocytes, exhibits various pharmacological activities. Here, a series of C-3 modified pyxinol derivatives was designed and virtually screened by molecular docking with the key inflammation-related proteins of the nuclear factor kappa B (NF-κB) pathway. Some of the novel derivatives were synthesized to assess their effects in inhibiting the production of nitric oxide (NO) and mitochondrial reactive oxygen species (MtROS) in lipopolysaccharide-triggered RAW264.7 cells. Derivative 2c exhibited the highest NO and MtROS inhibitory activities with low cytotoxicity. Furthermore, 2c decreased the protein levels of interleukin 1ß, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2 and suppressed the activation of NF-κB signaling. Cellular thermal shift assays indicated that 2c could directly bind with p65 and p50 in situ. Molecular docking revealed that 2c's binding to the p65-p50 heterodimer and p50 homodimer was close to their DNA binding sites. In summary, pyxinol derivatives possess potential for development as NF-κB inhibitors.

Polyacrylate-graft-polypyrrole Copolymer as Intrinsically Elastic Electrodes for Stretchable Supercapacitors.

Constructing elastic electrodes with high mechanical and electrochemical stability remains a challenge in developing flexible supercapacitors. Instability of elastic composite electrodes stems from detachment of noncovalently associated electroactive components from elastic substrates under cyclic deformations. Herein, a novel all-organic copolymer consisting of polypyrrole grafted from a polyacrylate elastomer is proposed as elastic electrodes for stretchable supercapacitors. The single copolymer is obtained by graft polymerization in the swollen state, characterized by a wrinkled polypyrrole coating covalently attached on an elastic core. The copolymer is intrinsically elastic and maintains structural integrity under bending, twisting, and stretching deformations to ensure stable electrochemical performance. In addition, the grafted polypyrrole aggregates densely under the constraint of the backbone and gives a competitive conductivity of 41.6 S cm-1. A stretchable supercapacitor is constructed using the copolymer as electrodes and an acid hydrogel as an electrolyte, resulting in a specific capacitance of 430 mF cm-2. The supercapacitor delivers a capacitance retention of 100% after 1000 stretching-releasing cycles, exhibiting mechanical and electrochemical reliability under elastic deformations.

A Transformer-Embedded Multi-Task Model for Dose Distribution Prediction.

Radiation therapy is a fundamental cancer treatment in the clinic. However, to satisfy the clinical requirements, radiologists have to iteratively adjust the radiotherapy plan based on experience, causing it extremely subjective and time-consuming to obtain a clinically acceptable plan. To this end, we introduce a transformer-embedded multi-task dose prediction (TransMTDP) network to automatically predict the dose distribution in radiotherapy. Specifically, to achieve more stable and accurate dose predictions, three highly correlated tasks are included in our TransMTDP network, i.e. a main dose prediction task to provide each pixel with a fine-grained dose value, an auxiliary isodose lines prediction task to produce coarse-grained dose ranges, and an auxiliary gradient prediction task to learn subtle gradient information such as radiation patterns and edges in the dose maps. The three correlated tasks are integrated through a shared encoder, following the multi-task learning strategy. To strengthen the connection of the output layers for different tasks, we further use two additional constraints, i.e. isodose consistency loss and gradient consistency loss, to reinforce the match between the dose distribution features generated by the auxiliary tasks and the main task. Additionally, considering many organs in the human body are symmetrical and the dose maps present abundant global features, we embed the transformer into our framework to capture the long-range dependencies of the dose maps. Evaluated on an in-house rectum cancer dataset and a public head and neck cancer dataset, our method gains superior performance compared with the state-of-the-art ones. Code is available at https://github.com/luuuwen/TransMTDP.

Circ_0020123 plays an oncogenic role in non-small cell lung cancer depending on the regulation of miR-512-3p/CORO1C.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes responsible for cancer-associated death globally. The aim of this study was to illustrate the function of circular RNA_0020123 (circ_0020123) in NSCLC progression and its associated mechanism. METHODS: RNA and protein expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot assay. Cell proliferation, migration, invasion, angiogenesis, apoptosis and autophagy were analyzed to assess the role of circ_0020123/microRNA-512-3p (miR-512-3p)/coronin 1C (CORO1C) axis in NSCLC cells. Tumorigenesis in nude mice was analyzed to determine the in vivo role of circ_0020123. The intermolecular target relation was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Circ_0020123 expression was aberrantly upregulated in NSCLC tissues and cell lines. Circ_0020123 interference markedly restrained cell proliferation, migration, invasion, angiogenesis and autophagy and induced cell apoptosis of NSCLC cells. Circ_0020123 knockdown suppressed xenograft tumor growth in vivo. Circ_0020123 acted as a molecular sponge for miR-512-3p. Circ_0020123 silencing-induced effects in NSCLC cells were largely reversed by the knockdown of miR-512-3p. miR-512-3p interacted with the 3' untranslated region (3'UTR) of CORO1C. CORO1C overexpression largely reversed miR-512-3p accumulation-induced influences in NSCLC cells. Circ_0020123 positively regulated CORO1C expression by sponging miR-512-3p in NSCLC cells. CONCLUSION: Circ_0020123 aggravated NSCLC progression by binding to miR-512-3p to induce CORO1C expression, which provided new potential targets for the treatment of NSCLC.

circTLK1 facilitates the proliferation and metastasis of renal cell carcinoma by regulating miR-495-3p/CBL axis.

Renal cell carcinoma (RCC) is a common urological malignancy. Circular RNAs (circRNAs) have been confirmed to play an important regulatory role in various cancers. This study aimed to investigate the role and potential mechanism of circTLK1 (hsa_circ_0004442) in RCC. The levels of circTLK1, Cbl proto-oncogene (CBL), and microRNA-495-3p (miR-495-3p) were detected by quantitative reverse transcription polymerase chain reaction or western blot. Cell proliferation, cycle arrest and apoptosis, migration, and invasion were assessed by colony formation, flow cytometry, scratch, and transwell assays. The levels of E-cadherin and Vimentin were measured by western blot. The targeting relationship between miR-495-3p and miR-495-3p or CBL was verified by dual-luciferase reporter assay. Tumor growth in vivo was evaluated by xenograft assay. The results found that circTLK1 and CBL were up-regulated in RCC tissues and cells. Silencing of circTLK1 or CBL inhibited proliferation and metastasis and accelerated apoptosis in RCC cells. In addition, circTLK1 directly bound to miR-495-3p, and CBL was the target of miR-495-3p. circTLK1 sponged miR-495-3p to increase CBL expression. Moreover, knockdown of circTLK1 suppressed tumor growth in vivo. In conclusion, down-regulation of circTLK1 restrained proliferation and metastasis and promoted apoptosis in RCC cells by modulating miR-495-3p/CBL axis.

VEGFR2 inhibition hampers breast cancer cell proliferation via enhanced mitochondrial biogenesis.

Objective: Vascular endothelial growth factor (VEGF), apart from its predominant roles in angiogenesis, can enhance cancer cell proliferation, but its mechanisms remain elusive. The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation. Methods: VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor, Ki8751, and the breast cancer cell lines, MCF-7 and MDA-MB-231, using flow cytometry, mass spectrometry, immunoblotting, and confocal microscopy. Data were analyzed using one-way analysis of variance followed by Tukey's multiple comparison test. Results: VEGF blockade by Ki8751 significantly reduced cancer cell proliferation, and enhanced breast cancer cell apoptosis. Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins, suggesting the involvement of mitochondrial biogenesis. Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells, induced endomitosis, and arrested cancer cells in the high aneuploid phase. VEGFR2 knockdown by shRNAs showed similar effects to those of Ki8751, confirming the specificity of Ki8751 treatment. Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species (ROS) production, which induced cancer cell apoptosis. Furthermore, Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α, and translocated PGC1α into the nucleus. The PGC1α alterations increased mitochondrial transcription factor A (TFAM) expression and subsequently increased mitochondrial biogenesis. Conclusions: VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis, ROS production, and cell apoptosis. These findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production.

Paneth cell-derived growth factors support tumorigenesis in the small intestine.

Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit. PC depletion in Apc Min mice impaired adenoma development in the small intestine and led to decreased Wnt3 expression in small bowel adenomas. To determine if PC-derived Wnt3 was required for adenoma development, we examined tumor formation after PC-specific ablation of Wnt3 We found that this was sufficient to decrease small intestinal adenoma formation; moreover, organoids derived from these tumors displayed slower growth capacity. Overall, we report that PC-derived Wnt3 is required to sustain early tumorigenesis in the small bowel and identify a clear role for PC-derived Wnt production in intestinal pathology.

Irreversible epidermal growth factor receptor inhibitor Z25h exhibits pronounced inhibition on non-small cell lung adenocarcinoma cell line Hcc827.

The epidermal growth factor receptor (EGFR) signaling is frequently activated in lung cancer. In our previous study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-tyrosine kinase inhibitors to overcome acquired EGFR-T790M resistance. In this study, we selected the most promising compound Z25h to further investigate its effects and the underlying mechanism against non-small cell lung adenocarcinoma cells in vitro. Four different non-small cell lung adenocarcinoma cell lines were selected to test the antiviability profile of Z25h, and Hcc827 was the most sensitive to the drug treatment. Z25h caused cell cycle arrest at G0-G1 phase, and triggered strong early apoptosis in Hcc827 cells at 0.1 µM and late apoptosis in A549, H1975 and H1299 cells at 10 µM by 48 h treatment. Z25h inhibited the activation of EGFR and its downstream PI3K/AKT/mTOR pathway in the four tested cell lines, leading to the inhibition of cellular biosynthetic and metabolic processes and the promotion of apoptotic process. However, the effect of Z25h on mitogen-activated protein kinase pathway varies from cell lines. In addition, Z25h sensitized H1975 cells to X-ray radiation, and it also enhanced the radiation effect on A549 cells, while no obvious effect of Z25h was observed on the cell viability inhibition of H1299 cells induced by radiation. Hereby, Z25h might be considered as a potential therapeutic drug candidate for non-small cell lung adenocarcinoma treatment.

Platelet factor 4 enhances CD4+ T effector memory cell responses via Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis.

BACKGROUND: Cell metabolism drives T cell functions, while platelets regulate overall CD4+ T cell immune responses. OBJECTIVE: To investigate if platelets influence cell metabolism and thus regulate CD4+ T effector memory cell (Tem) responses. METHODS: Human CD4+ Tem cells were activated with αCD3/αCD28 and cultured without or with platelets or platelet-derived mediators. RESULTS: Polyclonal stimulation induced rapid and marked Th1 and Treg cell activation of CD4+ Tem cells. Platelet co-culture enhanced Th1 response transiently, while it persistently enhanced Treg cell activation of Tem cells, with an enhancement that plateaued by day 3. Platelet factor 4 (PF4) was the key platelet-derived mediator regulating CD4+ Tem cell responses, which involved cellular metabolisms as indicated by mass spectrometric analyses. PF4 exerted its effects via its receptor CXCR3, attenuated Akt activity, and reduced PGC1α phosphorylation, and resulted in elevations of PGC1α function and mitochondrial transcription factor A (TFAM) synthesis. The latter increased mitochondrial biogenesis, and subsequently enhanced Th1 and Treg responses. Consistent with these observations, inhibition of mitochondrial function by rotenone counteracted the enhancements by recombinant PF4, and TFAM overexpression by TFAM-adenovirus infection mimicked PF4 effects. Furthermore, increased mitochondrial mass elevated oxygen consumption, and enhanced adenosine triphosphate and reactive oxygen species production, which, in turn, stimulated Th1 (T-bet) and Treg (FoxP3) transcription factor expression and corresponding CD4+ T effector cell responses. CONCLUSIONS: Platelets enhance CD4+ T cell responses of Tem cells through PF4-dependent and Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis. Hence, PF4 may be a promising intervention target of platelet-regulated immune responses.

Effects and Mechanisms of Autophagy Induced by Solubilized-Cholesterol in Hepatocytes: A Comparative Study Among Solvents.

Cholesterol, the principal sterol in mammalian cells, has been reported to play a role in the pathogenesis of several diseases through autophagy. Due to its insoluble characteristic, all in vitro cholesterol experiments are performed using dimethyl sulphoxide, methyl-ß-cyclodextrin, and ethanol co-solvents. To investigate whether the types of solvents have different effects on cholesterol-induced cell behaviors, we analyzed the effects and mechanisms of autophagy induced by solubilized-cholesterol in hepatic cells. We found that both solubilized-cholesterol and involved solvents could induce autophagy. Solubilized-cholesterol could further enhance the LC3-II expression with or without the pre-treatment with lysosomal blockers compared with the single-solvent groups, indicating that cholesterol could sensitize cells to solvents-induced autophagy. Besides, solubilized-cholesterol and single-solvent treatment could repress the activation of AKT-mTOR pathway. Furthermore, cholesterol solubilized in methyl-ß-cyclodextrin could induce apoptosis while other solubilized-cholesterol or single solvent groups could not, suggesting that different dissolve methods may affect the cytotoxic of cholesterol. These results strongly suggest that the effect of solvent should be taken into consideration in further in vitro cholesterol studies.

Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4.

BACKGROUND: Succinate is a Krebs cycle intermediate whose formation is enhanced under metabolic stress, and for which a selective sensor GPR91 has been identified on various cell types including platelets. Platelet-derived eicosanoids play pivotal roles in platelet activation/aggregation, which is key to thrombus formation and progression of atherothrombosis. OBJECTIVES: This study aims to decipher the molecular mechanism(s) and potential involvement of eicosanoids in succinate enhanced platelet activation/aggregation. METHODS: We used liquid chromatography-mass spectrometry (LC-MS)/MS-based lipid mediator profiling to identify eicosanoids regulated by succinate. We ran light transmittance aggregometry and flow cytometry to assess platelet aggregation, P-selectin expression, and platelet-polymorphonuclear leukocyte (PMN) adherence. Various pharmacological tools were used to assess the contributions of GPR91 signalling and eicosanoids in platelet aggregation. RESULTS: Succinate and two types of synthetic non-metabolite GPR91 agonists-cis-epoxysuccinate (cES) and Cmpd131-potentiated platelet aggregation, which was partially blocked by a selective GPR91 antagonist XT1. GPR91 activation increased production of 12-hydroxy-eicosatetraenoic acid (12-HETE), thromboxane (TX) A2 , and 12-hydroxy-heptadecatrienoic acid (12-HHT) in human platelets, associated with phosphorylation of cytosolic phospholipase A2 (cPLA2 ), suggesting increased availability of free arachidonic acid. Blocking 12-HETE and TXA2 synthesis, or antagonism of the TXA2 receptor, significantly reduced platelet aggregation enhanced by GPR91 signalling. Moreover, platelet-PMN suspensions challenged with succinate exhibited enhanced transcellular biosynthesis of leukotriene C4 (LTC4 ), a powerful proinflammatory vascular spasmogen. CONCLUSION: Succinate signals through GPR91 to promote biosynthesis of eicosanoids, which contribute to platelet aggregation/activation and potentially vascular inflammation. Hence, GPR91 may be a suitable target for pharmacological intervention in atherothrombotic conditions.

Risk factors for anxiety and depression in Chinese patients undergoing surgery for endometrial cancer.

This study analyzed risk factors for anxiety and depression in 714 patients who received surgery for endometrial cancer. Our data indicate that the incidence of postoperative anxiety and depression in 714 patients with endometrial cancer was 15.55% and 32.77%, respectively. Univariate and logistic regression analysis showed postoperative pain (odds ratio (OR) = 3.166, P = 0.000) and combined liver disease (OR = 2.318, P = 0.001) were independent risk factors for postoperative anxiety. Additionally, CD4+/CD8+ (OR = 0.513, P = 0.042) and natural killer (NK) cell ratios (OR = 0.692, P = 0.021) were independent protective factors for postoperative anxiety. As for depression, low literacy (OR = 1.943, P = 0.042), postoperative pain (OR = 2.671, P = 0.001), high clinical stage (OR = 3.469, P = 0.009), and combined liver disease (OR = 4.865, P = 0.000) were independent risk factors for postoperative depression. CD4+/CD8+ (OR = 0.628, P = 0.002) and NK cell ratio (OR = 0.710, P = 0.013) were independent protective factors for postoperative depression. In conclusion, patients with endometrial cancer have a higher incidence of postoperative anxiety and depression where postoperative pain, liver disease, and decreased immune function are risk factors for both anxiety and depression in these patients.

A new xanthatin analogue 1ß-hydroxyl-5α-chloro-8-epi-xanthatin induces apoptosis through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition in human hepatocellular carcinoma.

1ß-hydroxyl-5α-chloro-8-epi-xanthatin (XTT), a sesquiterpene lactone isolated from Xanthium sibiricum, possessed potent cytotoxicity on cancer cells in vitro. The objective of this study was to investigate the anti-tumor effect and underlying mechanisms of XTT on human hepatocellular carcinoma (HCC). Firstly, XTT inhibited the cell growth and induced apoptosis in human HCC cells, which was associated with the induction of Bax and cleaved-caspase-3, inhibition of Bcl-2 and survivin expression. Importantly, XTT induced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), and depletion of glutathione (GSH) in HCC cells through covalently modification of GSH. Furthermore, XTT caused obvious activation of extracellular regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and inactivation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) in HCC cells. ROS scavenger N-acetyl cysteine abrogated the effects of XTT on ERK/p38 MAPK activation and JAK2/STAT3 inhibition, and rescued HCC cells from XTT-induced apoptosis. Additionally, inhibitors of ERK/p38 MAPKs or activator of JAK2/STAT3 partially abolished XTT-mediated effect. In summary, XTT inhibited cell growth and induced apoptosis in HCC cells through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition by GSH depletion. These findings also show the therapeutic potential of XTT in HCC.

Astragalus polysaccharides exerts anti-infective activity by inducing human cathelicidin antimicrobial peptide LL-37 in respiratory epithelial cells.

Astragalus polysaccharides (APS), one of the major active components in Astragalus membranaceus, is an effective immunomodulator used in the treatment of immunological diseases in China. However, the anti-infective action and mechanism of APS is not fully known. In the present study, we found that APS induced the expression of human cathelicidin antimicrobial peptide LL-37, a key host anti-infective molecule, in both mRNA and protein levels in respiratory epithelial cells HBE16 and A549. Furthermore, the lysate and supernatant from APS-treated HBE16 cells both exhibited an obvious antibacterial action, which was partially neutralizated by LL-37 monoclonal antibody. In addition, APS also significantly elevated the phosphorylation of p38 MAPK and JNK and caused the degradation of IκBα. Specific inhibitors of p38 MAPK, JNK, or NF-κB obviously abolished APS-induced LL-37 synthesis and antibacterial activity, respectively. Taken together, our results confirmed the enhancement of APS on LL-37 induction and antibacterial action in respiratory epithelial cells, which may be attributed to activation of p38 MAPK/JNK and NF-κB pathways. Furthermore, these results also supported the clinical application of APS in the treatment of infectious diseases.

FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors.

Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3ß-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1-selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3ß/FBW7-dependent Mcl-1 degradation in killing of colorectal cancer cells by Hsp90 inhibitors and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy. Mol Cancer Ther; 16(9); 1979-88. ©2017 AACR.

Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H-cheromene derivatives as histone deacetylaes inhibitors.

As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho-aminoanilides 9b, 9c, 10b, 10c, 11b, and the α-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho-aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2.

Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells.

The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multikinase inhibitor drugs, where it relied upon GSK3ß phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the antiangiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other prosurvival proteins to maintain cell survival, which was abolished by small-molecule Mcl-1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1-targeting agents that can overcome drug resistance. Cancer Res; 77(9); 2512-21. ©2017 AACR.

Natural products as zinc-dependent histone deacetylase inhibitors.

Zinc-dependent histone deacetylases (HDACs), a family of hydrolases that remove acetyl groups from lysine residues, play an important role in the regulation of multiple processes, from gene expression to protein activity. The dysregulation of HDACs is associated with many diseases including cancer, neurological disorders, cellular metabolism disorders, and inflammation. Molecules that act as HDAC inhibitors (HDACi) exhibit a variety of related bioactivities. In particular, HDACi have been applied clinically for the treatment of cancers. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small-molecule chemotypes, including a number of natural products. This review provides a systematic introduction of natural HDACi, with an emphasis on their enzyme inhibitory potency, selectivity, and biological activities, highlighting their various binding modes with HDACs.