A Novel Tetramethylpyrazine Chalcone Hybrid- HCTMPPK, as a Potential Anti-Lung Cancer Agent by Downregulating MELK.

Purpose: Lung adenocarcinoma currently ranks the leading causes of cancer-related mortality worldwide. Many anti-inflammation herbs, like tetramethylpyrazine, have shown their anti-tumor potentials. Here, we evaluated the role of a novel chalcone derivative of tetramethylpyrazine ((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1, HCTMPPK) in lung adenocarcinoma. Methods: The effects of HCTMPPK on cell proliferation, apoptosis, and invasion were investigated by in-vitro assays, including CCK-8, colony formation assay, flow cytometry, transwell assay, and wound-healing assay. The therapeutic potential of HCTMPPK in vivo was evaluated in xenograft mice. To figure out the target molecules of HCTMPPK, a network pharmacology approach and molecular docking studies were employed, and subsequent experiments were conducted to confirm these candidate molecules. Results: HCTMPPK effectively suppressed the proliferative activity and migration, as well as enhanced the apoptosis of A549 cells in a concentration-dependent manner. Consistent with this, tumor growth was inhibited by HCTMPPK significantly in vivo. Regarding the mechanisms, HCTMPPK down-regulated Bcl-2 and MMP-9 and up-regulating Bax and cleaved-caspase-3. Subsequently, we identified 601 overlapping DEGs from LUAD patients in TCGA and GEO database. Then, 15 hub genes were identified by PPI network and CytoHubba. Finally, MELK was verified to be the HCTMPPK targeted site, through the molecular docking studies and validation experiments. Conclusion: Overall, our study indicates HCTMPPK as a potential MELK inhibitor and may be a promising candidate for the therapy of lung cancer.

Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer.

Purpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.

Discovery of N-(4-((6-(3,5- Dimethoxyphenyl)-9H-purine derivatives as irreversible covalent FGFR inhibitors.

Fibroblast growth factor receptor (FGFR) is an attractive target for cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, III-30 showed the most potent effect on enzyme activity inhibition and anti-proliferative activity against the tested cancer cell lines. Significantly, III-30 could inhibit the enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote cancer cell apoptosis and inhibit cancer cell invasion and metastasis. Moreover, III-30 had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells.

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

Exploring the Role of Galectins in Cancer : In Vitro and In Vivo Approaches.

Galectins have been linked to tumorigenesis since 1975, even before this family of proteins was given its name. Since then, hundreds of papers have analyzed the role of different galectins in cancer development and progression, deciphering their involvement in many different pathological events, from the regulation of cell cycle, to angiogenesis, metastasis, and immune attack evasion. Importantly, the tumor galectin profile is often altered in many cancers and aberrant levels of some of the members of this family have been considered in diagnosis and frequently correlated with patient prognosis and clinicopathological characteristics. In this chapter, we summarize most frequent techniques employed in cancer research to interrogate the role of galectins, using Gal-1 to illustrate one member of the family and pancreatic cancer as an experimental model. We will cover from techniques employed to detect their expression (tissue and blood samples) to the most frequent tools used to change expression levels and the cell line-based in vitro studies and murine preclinical models used to explore their role in tumor progression and/or clinical translation.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

"Sustained irrigation" effect enhanced the accumulation and retention of ultra-long circulating nanoparticles in tumor.

The development of ultra-long circulating nanodrug delivery systems have showed distinct advantage in maintaining the long-lasting tumor retention. Although the relationship between extended tumor retention and ultra-long plasma half-life was apparent, there was still a lack of experimental evidence to reveal the enhancement mechanism. Herein, we proposed a concept of "Sustained Irrigation" effect ("SI" effect) to elucidate that it was through sustained blood irrigation that the ultra-long circulating nanoparticles achieved long-lasting tumor retention. Besides, in order to intuitively verify the "SI" effect, we developed an "ON-OFF-ON" fluorescence switch technology. The ultra-long circulating delivery nanoparticle was constructed by encapsulating the protein with hydrophilic polymer shell. Nanoparticles with ultra-long plasma half-life (t1/2>40 h) fabricated by this method were employed as models for demonstrating the "SI" effect. The recovery of Cy5.5 fluorescence after the laser quenching meant the "fresh" Cy5.5-labeled nanoparticles were entering tumor, which confirmed the ultra-long circulating nanoparticles in blood could sustainedly irrigate to tumor. Our finding revealed the key mechanism by which ultra-long circulating NDDSs enhanced the tumor accumulation and retention, and provided experimental support for the development of ultra-long circulating delivery system in clinic.

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors.

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.

Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D -driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of ß-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling.

Short divalent ethacrynic amides as pro-inhibitors of glutathione S-transferase isozyme Mu and potent sensitisers of cisplatin-resistant ovarian cancers.

The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione S-transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min-1. In cisplatin-resistant SK-OV-3, COC1, SGC7901 and A549 cells, GSTM activities probed by 15 nM BDEA or EDEA revealed 5-fold and 1.0-fold increases in cisplatin-resistant SK-OV-3 and COC1 cells, respectively, in comparison with the susceptible parental cells. Being tolerable by HEK293 and LO2 cells, BDEA at 0.2 µM sensitised resistant SK-OV-3 and COC1 cells by ∼3- and ∼5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 µM sensitised resistant SK-OV-3 and A549 cells by ∼5- and ∼7-fold, respectively. EDEA at 1.7 µg/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 µg/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers.

Gut microbiota influenced the xenograft MC38 tumor growth potentially through interfering host lipid and amino acid metabolisms, basing on the integrated analysis of microbiome and metabolomics.

Gut microbiota is associated with tumor progress and host metabolic disorder, but whether gut microbiota regulation can affect cancer growth through interfering host metabolism maintains unknown yet. Here, we used combined antibiotics (ABX) to build an extremely altered gut microbiota ecosystem and study its influence on the xenograft MC38 tumor as well as the associations of the effects with host metabolisms. The MC38 tumor bearing mouse was treated with ABX (vancomycin, neomycin and imipenem-cilastatin) to build the extremely altered microbiota ecosystem, the gut microbiota diversity alteration was determined by 16S rRNA based gene sequencing. The effects of the altered microbiota on tumor were assessed by cell apoptosis and growth rate of the tumor. The potential metabolic biomarkers and involved metabolism pathways were screened out by UPLC-QTOF-MS/MS based untargeted metabolomics and KEGG analysis respectively. The correlations between key metabolites and microbiota were analyzed by Spearman correlation analysis. Compared with the un-treated mice, the tumor growth of ABX-treated mice was significantly suppressed, and the cell apoptosis was obviously promoted. The gut microbiota diversity was decreased significantly with the dominant bacteria phylum Bacteroidetes and Firmicutes replaced by Proteobacteria, which involved 14 significantly altered bacteria genera. Four potential targeted metabolism pathways, including sphingolipid, glycerophospholipid, arginine-proline and primary bile acid metabolism, were screened out, and the involved key metabolites such as ceramide, phosphatidylethanolamine, phosphatidylcholine, taurocholic acid and L-proline were correlated significantly with the altered bacteria genera. Through the integrated analysis of microbiome and metabolomics, it was revealed that gut microbiota regulation may inhibit the xenograft MC38 tumor growth potentially by interfering host lipid and amino acid metabolisms, such as sphingolipid, glycerophospholipid, primary bile acid and arginine-proline metabolisms in this case.

Polyoxometalate Modified by Zeolite Imidazole Framework for the pH-Responsive Electrodynamic/Chemodynamic Therapy.

Electrodynamic therapy (EDT) and chemodynamic therapy (CDT) have the potential for future tumor treatment; however, their underlying applications are greatly hindered owing to their inherent drawbacks. The combination of EDT and CDT has been considered to be an effective way to maximize the superiorities of these two ROS-based methodologies. However, the development of novel nanomaterials with "one-for-all" functions still remains a big challenge. In this work, the polyoxometalate nanoparticles (NPs) were decorated using the zeolite imidazole framework (POM@ZIF-8) in order to integrate the EDT with CDT. The resulting POM@ZIF-8 NPs can effectively induce the generation of reactive oxygen species (ROS) via a catalytic reaction on the surface of POM NPs induced by an electric field (E). At the same time, POM@ZIF-8 NPs can catalyze the intracellular H2O2 into ROS via a Fenton-like reaction, thereby achieving the combination of EDT and CDT. Besides, since ZIF-8 is acid-responsive, it can protect normal tissues and avoid side effects. Of great note is that the cytotoxicity and the apoptosis rate of the POM@ZIF-8+E group (80%) were found to be significantly higher than that of the E group (55%). As a result, a high tumor inhibition phenomenon can be observed both in vitro and in vivo. The present study thus provides an alternative concept for combinational therapeutic modality with exceptional efficacy.

Synthesis and biological evaluation of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives as novel, potent of ALK5 receptor inhibitors.

The transforming growth factor type ß receptor I (TGF-ß R1, also known as activin-like kinase 5 or ALK5) plays a significant role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis. Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. Herein, a novel series of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives was synthesized and identified as ALK5 inhibitors. Among them, compound 8h inhibited ALK5 autophosphorylation and NIH3T3 cell activity with IC50 values of 25 nM and 74.6 nM, respectively. Compound 8h also showed favorable pharmacokinetic profile and ameliorated hERG inhibition. More importantly, 30 mg/kg oral administration of 8h could significantly induce tumour growth inhibition in CT26 xenograft model without obvious toxicity.

Complement C1q binding protein regulates T cells' mitochondrial fitness to affect their survival, proliferation, and anti-tumor immune function.

T cells survival, proliferation, and anti-tumor response are closely linked to their mitochondrial health. Complement C1q binding protein (C1QBP) promotes mitochondrial fitness through regulation of mitochondrial metabolism and morphology. However, whether C1QBP regulates T cell survival, proliferation, and anti-tumor immune function remains unclear. Our data demonstrated that C1QBP knockdown induced the accumulation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential to impair T cell mitochondrial fitness. At the same time, C1QBP insufficiency reduced the recruitment of the anti-apoptotic proteins, including Bcl-2 and Bcl-XL, and repressed caspase-3 activation and poly (ADP-ribose) polymerase cleavage, which consequently accelerated the T cell apoptotic process. In contrast, C1QBP knockdown rendered T cells with relatively weaker proliferation due to the inhibition of AKT/mTOR signaling pathway. To investigate the exact role of C1QBP in anti-tumor response, C1QBP+/- and C1QBP+/+ mice were given a subcutaneous injection of murine MC38 cells. We found that C1QBP deficiency attenuated T cell tumor infiltration and aggravated tumor-infiltrating T lymphocytes (TIL) exhaustion. Moreover, we further clarified the potential function of C1QBP in chimeric antigen receptor (CAR) T cell immunotherapy. Our data showed that C1QBP+/- CAR T cells exhibited relatively weaker anti-tumor response than the corresponding C1QBP+/+ CAR T cells. Given that C1QBP knockdown impairs T cells' anti-apoptotic capacity, proliferation as well as anti-tumor immune function, development of the strategy for potentiation of T cells' mitochondrial fitness through C1QBP could potentially optimize the efficacy of the related immunotherapy.

Calcium-activated nucleotides 1 (CANT1)-driven nuclear factor-k-gene binding (NF-ĸB) signaling pathway facilitates the lung cancer progression.

Dysregulation of calcium-activated nucleotides 1 (CANT1) has been observed in different organs. Thus, its biological function in cancer has increasingly attracted researchers. The current work aims to study the CANT1 role in lung cancer and understand the underlying pathological mechanisms. High amplification of CANT1 was observed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared to normal tissues. The high-CANT1 patients showed a dismal prognosis in comparison with the low-CANT1 patients. Highly expressed CANT1 was significantly associated with the N stage of LUSC patients. Ectopic expression of CANT1 conspicuously increased the proliferation and viability of A549 cells. Conversely, CANT1 depletion resulted in adverse effects in H1299 cells. CANT1 depletion also resulted in the retardation of tumor growth in vivo. Mechanically, we found that CANT1 could elevate NF-ĸB (nuclear factor-k-gene binding) transcriptional activity in a concentration-dependent manner. This regulatory relationship was also established by the Western blot technique. Inhibiting NF-ĸB can significantly blunt the increased NF-κ-B Inhibitor-α (IκBα) expression caused by CANT1 overexpression in A549 cells. In conclusion, highly amplified CANT1 promotes the proliferation and viability of lung cancer cells. We also elucidate a new signaling axis of CANT1-NF-ĸB in lung cancer. This approach might be a promising strategy for lung cancer treatment.

Self-assembled chitosan derived microparticles inhibit tumor angiogenesis and induce apoptosis in Ehrlich-ascites-tumor bearing mice.

Self-assembled microparticles from chitosan (SAMC) was prepared by depolymerization induced by potassium persulfate. Particle size distribution data showed averaged around 5 µm size and SEM indicated the sequential formation of "RBC" shaped particles. Soluble SAMC consists of 'deacetylated' residues as revealed by 13C NMR. SAMC showed antitumor efficacy in human breast cancer cell lines through mitigation in cell proliferation, colony formation and cell migration. Anti-tumor and anti-angiogenic properties of SAMC was found in vivo Ehrlich ascites tumor (EAT) bearing mice model resulting in tumor growth inhibition (EAT control, 17.4 ml; SAMC treated, 6.8 ml) and improved survival potency (15 days). Moreover, the decrease in ascites VEGF secretion (EAT control, 1354 ng; SAMC treated, 351 ng) accompanied with reduction in neovessel formation. Apoptosis induction by SAMC was confirmed by DNA fragmentation, caspase activities and fluorescence staining methods respectively. SAMC may be a safe candidate for anti-tumor dietary supplement production in food industry.

Novel 5-fluorouracil sensitizers for colorectal cancer therapy: Design and synthesis of S1P receptor 2 (S1PR2) antagonists.

Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (KD = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.

PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation.

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility.

FNC inhibits non-small cell lung cancer by activating the mitochondrial apoptosis pathway.

BACKGROUND: Previously, we published that 4'-azid-2'-deoxy-2'-fluorarabinoside (FNC), a novel cytosine nucleoside analog, has good anti-viral and anti-tumor activity. OBJECTIVE: This study aimed to further explore the role and molecular mechanism of FNC in non-small cell lung cancer (NSCLC). METHODS: FNC was tested in the NSCLC H460 cell line, the Lewis mouse model, and the H460 cell xenograft model. The effects of FNC were assessed by cell viability, transwell migration, and wound scratch analyses of cell migration and invasion. Apoptosis was assessed by flow cytometry. Proteins expression was assessed by western blot and immunohistochemistry staining (IHC). RESULTS: FNC inhibits the proliferation and metastasis of H460 cells in a time- and dose-dependent manner. FNC treatment showed efficacy and low toxicity in the Lewis mouse lung cancer model as well as in the H460 cell xenograft model. Further, FNC induced H460 cell apoptosis through the activation of the mitochondrial pathway. Notably, FNC inhibited invasion by increasing E-cadherin protein and reducing the protein expression of VEGF, MMP-2, MMP-9, and CD31. CONCLUSION: FNC inhibits NSCLC by activating the mitochondrial apoptosis pathway and regulating the expressions of multiple proteins related to cell adhesion and invasion, highlighting its potential as an NSCLC therapeutic.

Identification of new halogen-containing 2,4-diphenyl indenopyridin-5-one derivative as a boosting agent for the anticancer responses of clinically available topoisomerase inhibitors.

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F-, Cl-, Br-, CF3- and OCF3-)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl-, Br-, and CF3- groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.