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Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×10 3 -fold improved activity against Gram-positive Streptococcus pneumoniae (S. pneumoniae) and Gram-negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31×10 3 -fold reduced human cytotoxicity, resulting in 2.08×10 6 -fold improvements in the therapeutic index. This proof-of-principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs., (© 2022 Wiley-VCH GmbH.)

Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF 3 -phenyl triphenylphosphonium-based PBA conjugate ( 53 ) with improved in vitro and in vivo anticancer activities. Compound 53 exhibited an IC 50 value of 2.22 μM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for cancer therapy.

Calothrixin A ( CAA ) is a dual Topo I and II inhibitor but exhibits poor antiproliferative activities and water solubility. Herein, a library of novel CAA analogues was synthesized. Among them, compound F16 exhibited superior water solubility (>5 mg/mL) as compared to CAA (<5 μg/mL). The mechanism of action studies confirmed that F16 acted as a dual Topo I and II poison. Furthermore, F16 displayed potent antiproliferative activities against high Topo I and II expression cell lines A375 and HCT116, with IC 50 values of 20 and 50 nM, respectively. In xenograft models, F16 reduced the tumor growth at a dose of 10 or 20 mg/kg without apparent effect on the mouse weight, while the clinically used Topo II inhibitor VP-16 dramatically reduced the mouse weight. Collectively, our data demonstrated that F16 could be a promising lead for the development of novel dual Topo I and II antitumor agents.

The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288., (© 2022 by The American Society of Hematology.)

Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC 50 value of 0.09 μM, and reduced various cancer cells proliferation with IC 50 values ranging from 1.1 to 3.8 μM, while show weak effect against non-cancerous L02 cell (IC 50  > 10 μM). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Introduction: Cyclin-dependent kinases 4 and 6 (CDK4/6) along with their upstream/downstream components are pivotal regulators for the cell cycle progression. The dysfunction of CDK4/6 is the common feature and promoting factor in various cancer types. In-depth research on CDK4/6 inhibitors has afforded therapeutic agents, while new challenges and ideas are emerging concomitantly., Areas Covered: This review focuses on patent publications related to CDK4/6 inhibitors which could be utilized for anti-cancer purposes during the period 2015-2019., Expert Opinion: The increasingly comprehensive and thorough understanding of CDK4/6 inhibitors facilitates them to break through the current limitations. Hence the utilization of CDK4/6 inhibitors for cancer therapy in the near future is likely to be performed in diverse forms and for distinct purposes. Selectivity over kinases is still crucial to new agent development but shall be prudently dealt with. The gradually revealing of resistance and adverse events proposed another issue that calls for new tackling strategies.

The purpose of the present study was to evaluate the anti-cancer property of Lobetyolin on colorectal cancer and explore its potential mechanism. Lobetyolin was incubated with HCT-116 cells in the absence or presence of ASCT2 inhibitor Benser or p53 inhibitor Pifithrin-α. The levels of glutamine, glutamic acid, α-ketoglutarate, ATP and GSH were determined to measure the glutamine metabolism. Annexin V-FITC/PI staining and TUNEL assay were applied to estimate the apoptotic condition. The levels of ASCT2 were examined by RT-qPCR, Western blot and immunofluorescence staining. The expressions of cleaved-caspase-3, caspase-3, cleaved-caspase-7, caspase-7, cleaved-PARP, PARP, p53, p21, bax and survivin were detected using Western blot analysis. As a result, the treatment with Lobetyolin effectively induced apoptosis and glutamine metabolism in HCT-116 cells through ASCT2 signalling. The inhibition of ASCT2 reduced the glutamine-related biomarkers and augmented the apoptotic process. We further found that the effect of Lobetyolin on HCT-116 was related to the expressions of p21 and bax, and transportation of p53 to nucleus. The inhibition of p53 by Pifithrin-α promoted the inhibitory effect of Lobetyolin on ASCT2-mediated apoptosis. Lobetyolin also exerted anti-cancer property in nude mice. In conclusion, the present work suggested that Lobetyolin could induce the apoptosis via the inhibition of ASCT2-mediated glutamine metabolism, which was possibly governed by p53., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Nannocystin A is a novel 21-membered macrocyclic lactam that targets eukaryotic translation elongation factor 1α (eEF1A) and displays potent antiproliferative activities. Herein, a series of nannocystin A analogues were synthesized and their structure-activity relationship (SAR) were established based on the MTT assay and western blotting analysis. The SAR enabled us to identify a structurally simplified nannocystin A analogue LQ18, which exhibited potent antiproliferative activities with IC 50 values ranging from 4.3 to 48 nM against the tested cell lines, and inhibited eEF1A1 expression in A549 cell line. LQ18 arrested cell cycle at G2 phase and induced A549 cell apoptosis via up-regulation of caspase-3, caspase-9 and bax protein expressions in a dose-dependent manner, while it significantly decreased the bcl-2 expression. Collectively, these data demonstrated that LQ18 could be a promising lead for the development of structurally novel eEF1A1 inhibitor for cancer treatment., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Aims: CAA45 is a calothrixin A (CAA) analogue with anti-cancer activity at nanomolar concentration. This study aimed to investigate the anti-lung cancer activity of CAA45 and explore its mechanisms of actions., Main Methods: CAA and CAA45 were synthesized and their inhibition on DNA topoisomerase I (Topo I) performed by evaluating the relaxation of supercoiled pBR322 plasmid DNA and their anti-lung cancer capacity determined by cytotoxic assays, cell migration, cell cycle, cell apoptosis, cell autophagy and related signaling proteins expression by western blot., Key Findings: CAA45 significantly inhibited human non-small cancer cell A549 and NCI-H1650 cells growth with IC 50 values of 110 and 230 nM, respectively. In the A549 xenograft models, CAA45 displayed strong antitumor activities at a dose of 10 mg/kg. CAA45 inhibited Topo I activity and caused the cell cycle arrest at S phase, which also reduced A549 cell migration by inhibiting MMP-2 and MMP-9 expressions. Furthermore, CAA45 induced A549 cell apoptosis and autophagy. The apoptosis pathway was involved in the release of cytochrome c and caspase activation. CAA45 also inhibited Akt, activated JNK and up-regulated p53 signals in A549 cells, which may serve as a modulator to induce apoptosis and autophagy in cancer cells., Significance: CAA45 exerted its anti-lung cancer effect via inhibition of Topo I, resulting in cell cycle arrest and cell migration, induction of mitochondria mediated cell apoptosis and autophagy via PI3K/Akt/JNK/p53 pathway. All these observations suggested that CAA45 could be a promising lead for anti-cancer drug discovery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC 50  = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC 50 value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC 50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC 50  = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC 50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC 50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Herein, triphenylphosphonium cation moieties were incorporated into a dichloroacetophenone derivative, leading to the discovery of novel mitochondria-targeted and tumor-specific pyruvate dehydrogenase kinase 1 (PDK1) inhibitors. Biological studies suggested that all these synthesized compounds had significant in vitro activities, in particular compound 1f, which inhibited PDK1 with an EC 50 value of 0.12 μM, and reduced the proliferation of NCI-H1650 cell with an IC 50 value of 0.21 μM, but showed marginal effect against non-cancerous BEAS-2B cell (IC 50  = 3.28 μM). In addition, 1f decreased the extracellular acidification rate and lactate formation, increased reactive oxygen species production, and depolarized the mitochondrial membrane potential of NCI-H1650 cell, which could serve as a potential modulator to reactive mitochondrial oxidative phosphorylation and reprogram the glucose metabolic pathways in cancer cells. Collectively, these data demonstrated that 1f could be a promising lead for the development of therapeutic PDK1 inhibitor in cancer treatment., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1 H NMR, 13 C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC 50  = 2.1 μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cancer cells feature a switch in glucose metabolism from oxidative phosphorylation to cytoplasm-based glycolysis. This altered cellular metabolic pathway meets the survival and proliferation needs for tumor progression. Targeting the metabolic remodeling could offer opportunities for developing effective anticancer therapeutics. Human lactate dehydrogenase (hLDH)5 plays a crucial part in the promotion of glycolysis and is overexpressed in various human tumors, and thus could be a potential anticancer drug target. Here, we briefly discuss the roles of hLDH5 and its connections with cancer metabolism. Then, we review the reported small molecules in light of their binding modes to hLDH5. Finally, possible directions for future development of hLDH5 inhibitors are proposed. We hope that this review will provoke interest in developing hLDH5 inhibitors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of novel azacalix[2]arene[2]pyrimidines were synthesized, and evaluated for their antiproliferative activities against A549, MCF7, SH-SY5Y and CNE human cancer cell lines in vitro by using the CCK-8 assay. A number of compounds showed low micromolar antiproliferative activities against MCF7 cell line. Compound 4j, containing a pyrrolidine moiety, exhibited the strongest inhibitory activity with an IC 50 value of 0.58 μM. Furthermore, breast cancer cells were used to explore the inhibition mechanism of these azacalix[2]arene[2]pyrimidines. The results suggested these compounds were involved in inducing cell apoptosis via up-regulation of caspase-3 and caspase-9 protein expression, and the cell cycle was arrested at the S phase. Our reports here represent the first studies on the biological activities of azacalix[2]arene[2]pyrimidines., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Artemisinin is a potential anticancer agent with an interesting trioxane sesquiterpene structure. In order to improve the biological activity and metabolic stability of artemisinin, a series of novel ring-contracted artemisinin dimers were synthesized. These dimers were evaluated by MTT assay against six cancer cell lines. Most of the dimmers exhibited improved antiproliferative activities over artemisinin. Especially, compound 8b showed the most pronounced anti-cancer activity for PC12 cancer cells with an IC 50 value of 1.56 μM. Thus, PC12 cancer cells were used to further investigate the mechanism of antiproliferation for this series of compounds. Compound 8b arrested cell cycle at G1 phase and induced cell apoptosis via up-regulation of Bad, Bax, caspase-3 and caspase-9 protein expressions while inhibiting the expression of Bcl-xL. The present studies are the first to synthesize the ring-contracted artemisinin as dimers and show that these dimers have potent anti-tumor activities against several cancer cell lines., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A novel synthetic method of 4-substituted aryl-1H-1,2,3-triazoles from arylglyoxaldoxime semicarbazone with sodium dithionite and O2 was found to be safer than the Huisgen azide- alkyne dipolar cycloaddition. A total of 17 new structures of 4-substituted aryl-1H-1,2,3- triazoles were characterized by 1H NMR, 13C NMR, ESI-MS. Subsequently, their in vitro antihepatoma activities were evaluated on human hepatoma QGY-7703, Bel-7402 and SMMC-7721 cell lines and mouse fibroblast cells L-929 by MTS assay. Among them, 5k exhibited excellent activity against QGY-7703 (GI50 = 0.0232 μM), while 5p and 5q displayed good activity (GI50 = 0.103 μM and GI50 = 0.182 μM) against the growth of SMMC-7721 cell lines. Furthermore, 5k, 5p and 5q showed slight selectivity of inhibition on hepatoma cell lines over normal cell line L-929.

Phosphorylated polysaccharide PLEP-1a, with the PO₄³⁻ content of 6.39%, was prepared from LEP-1a by phosphorylation. IR, (13)C NMR and (31)P NMR results of PLEP-1a showed that the original basic structure of the polysaccharide was not changed, and the -H₂PO₃ group was linked at C₆ of LEP-1a. The results of anti-tumor experiments in vivo showed that 100 mg/kg and 400 mg/kg of LEP-1a could significantly improve the food consumption, body weight, tumor inhibition rate and thymus index of S180 sarcoma mice, and increase the levels of SOD, IL-2 and TNF-α in mice blood serum, indicating that LEP-1a had an excellent anti-tumor activity. Furthermore, PLEP-1a had a significantly enhanced inhibitory effect on S180 sarcoma mice than LEP-1a, suggesting that phosphorylation is an effective way of improving the biological activity of LEP-1a., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Fifteen derivatives of 8-oxocoptisine were prepared based on that 8-oxocoptisine showed potent reversing effect against human cancer cells charactering multidrug resistance (MDR). The derivatives were evaluated for their growth inhibition and effects on reversing P-gp-mediated MDR against MCF-7/AMD cells. 12, 13-dinitro-8-oxocoptisine (6c), the most potential candidate with weak growth inhibition, significantly increased the sensitivity of adriamycin (ADM) against MCF-7/ADM cells by 213-fold at 10 μM that was comparable to the reference compound verapamil. The preliminary structure-activity relationships (SARs) of these derivatives were discussed on the basis of the in vitro MDR reversal activities.

Novel 2-aminoanilide histone deacetylase (HDAC) inhibitors were designed to increase their contact with surface residues surrounding the HDAC active site compared to the contacts made by existing clinical 2-aminoanilides such as SNDX-275, MGCD0103, and Chidamide. Their HDAC selectivity was assessed using p21 and klf2 reporter gene assays in HeLa and A204 cells, respectively, which provide a cell-based readout for the inhibition of HDACs associated either with the p21 or klf2 promoter. A subset of the designed compounds selectively induced p21 over klf2 relative to the clinical reference compound SNDX-275. A representative lead compound from this subset had antiproliferative effects in cancer cells associated with induction of acetylated histone H4, endogenous p21, cell cycle arrest, and apoptosis. The p21- versus klf2-selective compounds described herein may provide a chemical starting point for developing clinically-differentiated HDAC inhibitors for cancer therapy., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to target focal adhesion kinase (FAK). A number of these pyrrolopyrimides exhibited low micromolar inhibitory activities against focal adhesion kinase, and their preliminary SAR was established via systematic chemical modifications. The 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines represent a new class of kinase inhibitors.

Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×103‐fold improved activity against Gram‐positive Streptococcus pneumoniae (S. pneumoniae) and Gram‐negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31×103‐fold reduced human cytotoxicity, resulting in 2.08×106‐fold improvements in the therapeutic index. This proof‐of‐principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs. [ABSTRACT FROM AUTHOR]

Hyperthermia as an anticancer method has been paid increasing attention in recent years. Several studies have shown that hyperthermia can kill tumor cells by inducing apoptosis. However, the underlying molecular mechanisms of hyperthermia-induced apoptosis are largely unknown. To investigate the effects and molecular mechanism of hyperthermia on the apoptosis in renal carcinoma 786-O cells, we firstly examined apoptosis and Ku expression in 786-O cell line treated with heat exposure (42°C for 0-4 h). The results showed that hyperthermia induced apoptosis of 786-O cells, and suppressed significantly Ku80 expression, but not Ku70 expression. Next, we knock-down Ku80 in 786-O cells, generating stable cell line 786-O-shKu80, and detected apoptosis, cell survival and cell cycle distribution. Our data showed higher apoptotic rate and lower surviving fraction in the stable cell line 786-O-shKu80 compared with those in control cells, exposed to the same heat stress (42°C for 0-4 h). Moreover, the results also showed suppression of Ku80 led to G2/M phase arrest in the stable cell line 786-O-shKu80 following heat treatment. Together, these findings indicate that Ku80 may play an important role in hyperthermia-induced apoptosis and heat-sensitivity of renal carcinoma cells through influencing the cell cycle distribution. [ABSTRACT FROM AUTHOR]

Objective To investigate the in vitro anticancer effects of 4-ethoxy-2-hydroxy-6-methyl benzoic acid (D6B2) and its combinative anticancer effects with clinical anticancer drug cis-DDP. Methods Human cancer cell lines CNE, Hep G2, HeLa, QBC939 and K562 were used for the in vitro anticancer studies. The anticancer effects were detected by cell counting or MTT assay. Results The inhibitory ratios of D6B2 (25 µM, 50 µM, 100 µM, 150 µM, 200 µM) were 24.94%, 42.11%, 65.74%, 70.22%, 73.11% on CNE; 23.15%, 54.56%, 62.95%, 70.14%, 75.18% on Hep G2; 31.34%, 60.76%, 78.43%, 85.78%, 90.75% on HeLa; 5.97%, 12.05%, 28.44%, 35.28%, 51.31% on QBC939; 18.20%, 35.48%, 46.76%, 58.44%, 57.32% on K562. The IC50 value against CNE, HepG2, HeLa, QBC939 and K562 were 66.9 µM, 60.98 µM, 40.7 µM, 197.07 µM and 120.06 µM, respectively. The inhibitory ratios of D6B2 (25 µM, 50 µM, 100 µM, 150 µM, 200 µM) on HeLa were 7.96%, 9.56%, 10.98%, 14.00%, 17.33% at 24 h; 10.62%, 25.96%, 47.63%, 48.24%, 49.03% at 48 h; 18.08%, 53.68%, 85.55%, 87.86%, 82.07% at 72 h. The CDI value of D6B2 at 25 µM, 50 µM and 100 µM was 0.039, 0.019 and 0.014, respectively, when used with 10 µM DDP. Conclusion D6B2 showed significant in vitro anticancer effects on human cancer cells. Its in vitro anticancer activity was dose-dependent and time-dependent. D6B2 and DDP had synergistic in vitro anticancer effects. [ABSTRACT FROM AUTHOR]

The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis. [ABSTRACT FROM AUTHOR]