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Photodynamic therapy (PDT) plays a crucial role in treating cancer and major infectious diseases. However, the hypoxic microenvironment and deep-seated tumors often compromise the effectiveness of photosensitizers (PSs). PSs primarily generate type-II reactive oxygen species (ROS), which are limited under hypoxic conditions. Pyridinium salts frequently exhibit critical dark toxicity in vitro . Moreover, PDT alone often fails to achieve optimal anti-tumor effects compared to its combined application with photothermal therapy (PTT). To address these issues, we replaced pyridinium with quinolinium, significantly reducing dark toxicity. Additionally, the incorporation of benzophenone enhanced ROS generation, achieving a synergistic effect of type-I and type-II PDT. Fine-tuning the conjugated structure enhanced the donor-acceptor (D-A) intensity, while the stretching vibrations of carbon-carbon double bonds and carbon-nitrogen triple bonds red-shifted the excitation wavelength to the near-infrared (NIR) region and improved the photothermal conversion efficiency (PCE). This strategy provides a molecular design approach for achieving synergy between PDT and PTT. The synthesized four NIR-emitting aggregation-induced emission quinolinium salts exhibited mitochondrial targeting ability and low dark toxicity. Among them, FCN-TPAQ-BP showed excellent ROS generation capability, a PCE of 39.2%, good biocompatibility, and low dark toxicity, making it an ideal candidate for enhancing PDT's antitumor efficacy.

With the rapid development of nanotechnology and nanomedicine, there are great interests in employing nanomaterials to improve the efficiency of disease diagnosis and treatment. The clinical translation of hafnium oxide (HfO 2 ), commercially namedas NBTXR3, as a new kind of nanoradiosensitizer for radiotherapy (RT) of cancers has aroused extensive interest in researches on Hf-based nanomaterials for biomedical application. In the past 20 years, Hf-based nanomaterials have emerged as potential and important nanomedicine for computed tomography (CT)-involved bioimaging and RT-associated cancer treatment due to their excellent electronic structures and intrinsic physiochemical properties. In this review, a bibliometric analysis method is employed to summarize the progress on the synthesis technology of various Hf-based nanomaterials, including HfO 2 , HfO 2 -based compounds, and Hf-organic ligand coordination hybrids, such as metal-organic frameworks or nanoscaled coordination polymers. Moreover, current states in the application of Hf-based CT-involved contrasts for tissue imaging or cancer diagnosis are reviewed in detail. Importantly, the recent advances in Hf-based nanomaterials-mediated radiosensitization and synergistic RT with other current mainstream treatments are also generalized. Finally, current challenges and future perspectives of Hf-based nanomaterials with a view to maximize their great potential in the research of translational medicine are also discussed., (© 2023 Wiley-VCH GmbH.)

Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. Z HER2 -ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAF-based conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-over-expressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of Z HER2 -ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting Z Taq -ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of Z HER2 -ABD-mcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects., Competing Interests: Declaration of Competing Interest Anna Orlova and Vladimir Tolmachev own shares in Affibody AB (Solna, Sweden). The other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Tropomyosin receptor kinase (TRK) is a successful target for the treatment of various cancers caused by NTRK gene fusions. Herein, based on a rational drug design strategy, we designed and synthesized 35 aminopyrimidine derivatives that were shown to be TRKA inhibitors in the enzyme assay, among which compounds C3, C4, and C6 showed potent inhibitory activities against TRKA with IC 50 values of 6.5, 5.0, and 7.0 nM, respectively. In vitro antiproliferative activity study showed that compound C3 significantly inhibited the proliferation of KM-12 cells but had weak inhibitory effect on MCF-7 cells and HUVEC cells. The preliminary druggability evaluation showed that compound C3 exhibited favorable liver microsomal and plasma stabilities and had weak or no inhibitory activity against cytochrome P450 isoforms at 10 µM. Compounds C3, C4, and C6 were also selected for ADME (absorption, distribution, metabolism, and elimination) properties prediction and molecular docking studies. Inhibition experiments showed that compound C3 was not selective for TRK subtypes. All results indicated that compound C3 was a useful candidate for the development of TRK inhibitors., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TRKA) selectivity- and metabolic stability-guided structure-activity relationship (SAR) exploration were carried out to discover a highly potent (IC 50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability ( t 1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.

Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase involved in regulating cell mitosis and centriole duplication, and has emerged as a therapeutic target for treating multiple cancers. At first, the design and in vitro validation of PLK4 inhibitors (12a-12e, 17a-17f, 22a-22e) bearing 1H-pyrazolo[3,4-b]pyridine scaffold was described and lead compound 22a (IC 50  = 0.106 μM) was identified. Then, selectivity- and activity-guided development of a series of potent and selective type-II PLK4 inhibitors using a homology model approach was carried out. Further structure-based optimization resulted in a potent type-II PLK4 inhibitor 29u (IC 50  = 0.026 μM), which exhibited outstanding selectivity in a panel of 47 kinases at a single concentration of 1.0 μM. Furthermore, compound 29u significantly inhibited the proliferation of breast cancer cell line MCF-7 with an IC 50 value of 1.52 μM, while it exhibited no inhibitory effect on normal cell lines (L02 and HUVECs). Meanwhile, the clone formation, senescence and migration abilities of compound 29u were evaluated using MCF-7 cells. The detailed biological evaluation revealed that compound 29u could arrest cell division in S/G2 phase by inhibiting PLK4, and then affect the expression of downstream signalling pathway proteins regulated by PLK4. Moreover, the in vitro preliminary evaluation of the drug-like properties of compound 29u exhibited outstanding plasma stability, moderate liver microsomal stability, and low risk of drug-drug interactions (DDIs). The current discovery will support the further development of compound 29u as a lead compound for PLK4-targeted anticancer drug discovery and as a useful chemical probe for the further biological research of PLK4., 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 © 2022 Elsevier Masson SAS. All rights reserved.)

FAK mediated tumour cell migration, invasion, survival, proliferation and regulation of tumour stem cells through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. At present, the development of FAK PROTACs has become one of the hotspots in current pharmaceutical research to solve above problems. Herein, we designed and synthesised a series of FAK-targeting PROTACs consisted of PF-562271 derivative 1 and Pomalidomide. All compounds showed significant in vitro FAK kinase inhibitory activity, the IC 50 value of the optimised PROTAC A13 was 26.4 nM. Further, A13 exhibited optimal protein degradation (85% degradation at 10 nM). Meantime, compared with PF-562271, PROTAC A13 exhibited better antiproliferative activity and anti-invasion ability in A549 cells. More, A13 had excellent plasma stability with T 1/2 >194.8 min. There are various signs that PROTAC A13 could be useful as expand tool for studying functions of FAK in biological system and as potential therapeutic agents.

Background: Triple-negative breast cancer (TNBC), the subtype of breast cancer with the highest mortality rate, shows clinical characteristics of high heterogeneity, aggressiveness, easy recurrence, and poor prognosis, which is due to lack of expression of estrogen, progesterone receptor and human epidermal growth factor receptor 2. Currently, neoadjuvant chemotherapy (NAT) is still the major clinical treatment for triple-negative breast cancer. Chemotherapy drugs can be divided into platinum and non-platinum according to the presence of metal platinum ions in the structure. However, which kind is more suitable for treating TNBC remains to be determined., Methods: The relevant randomized clinical trials (RCTs) that explore the effectiveness of chemotherapy regimens containing platinum-based drugs (PB) or platinum-free drugs (PF) in treating TNBC patients were retrieved through PubMed, EMBASE, Cochrane Library, CNKI, and other literature platforms, above research findings, were included in the meta-analysis. The incidence of overall remission rate (ORR), pathological complete remission rate (pCR), overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and adverse events (AE) were compared between the two groups., Results: In this study, 12 clinical trials with a total of 4580 patients were included in the analysis. First, the ORR in 4 RCTs was, PB vs PF = 52% vs 48% (RR = 1.05, 95% CI: 0.91-1.21, P = 0.48); the pCR in 5 RCTs was, PB vs PF = 48% vs 41% (RR = 1.38, 95% CI: 0.88-2.16, P = 0.17). CI: 0.88-2.16, P = 0.17; the other 2 RCTs reported significantly higher DFS and OS rates in the PB group compared with the PF group, with the combined risk ratio for DFS in the PB group RR = 0.22 (95% CI:0.06-0.82, P = 0.015); the combined risk ratio for DFS in the PF group RR = 0.15 (95% CI. 0.04-0.61, P = 0.008); OS rate: PB vs PF = 0.046 vs 0.003; secondly, 2 RCTs showed that for patients with BRCA-mutated TNBC, the pCR rate in the PB and PF groups was 18% vs 26%, 95% CI: 2.4-4.2 vs 4.1-5.1; meanwhile, the median subject in the PB group The median PFS was 3.1 months (95% CI: 2.4-4.2) in the PB group and 4.4 months (95% CI: 4.1-5.1) in the PC group; finally, the results of the clinical adverse effects analysis showed that platinum-containing chemotherapy regimens significantly increased the incidence of adverse effects such as thrombocytopenia and diarrhea compared with non-platinum regimens, while the incidence of adverse effects such as vomiting, nausea, and neutropenia was reduced. The incidence of adverse reactions was reduced., Conclusion: Compared with non-platinum drugs, platinum drugs significantly improved clinical treatment effective indexes, such as PCR, ORR, PFS, DFS, and OS rate in the treatment of TNBC patients without BRCA mutant may cause more serious hematological adverse reactions. Accordingly, platinum-based chemotherapy should be provided for TNBC patients according to the patient's special details., (© 2022. The Author(s).)

Serine/threonine-protein kinase polo-like kinase 4 (PLK4) is a mitosis-associated protein kinase that plays a vital role in the duplication of centrioles in dividing cells and is considered a promising target of synthetic lethality in TRIM37-amplified breast cancer. Herein, based on a rational drug design strategy, we described a series of pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors and dissected the relevant structure-activity relationships (SARs). Most compounds showed potent suppressive activities against PLK4, with IC 50 values of < 10 nM. Among them, compound 24j (PLK4 IC 50  = 0.2 nM) displayed potent enzyme inhibition and good selectivity in a panel of 35 kinases. At the cellular level, compound 24j exhibited notable antiproliferative activities against MCF-7, BT474, and MDA-MB-231 cells, with IC 50 values of 0.36, 1.35, and 2.88 μM, respectively. Compound 24j killed TRIM37-amplified breast cancer cells. Moreover, we evaluated the clone formation, proliferation, cycle arrest, and migration abilities of compound 24j using MCF-7 cells. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 24j showed remarkable plasma stability, moderate liver microsomal stability, and weak inhibitory activity against the main subtypes of human cytochrome P450. Based on in vivo pharmacokinetic studies in Sprague Dawley rats, compound 24j exhibited a relatively high plasma clearance and a low F value (8.03%). Overall, these results support the further development of compound 24j as a potential lead compound to treat TRIM37-amplified breast cancer., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The intracellular non-receptor tyrosine protein kinase Focal adhesion kinase (FAK) is a key signalling regulator, which mediates tumor survival, invasion, metastasis, and angiogenesis through its kinase catalytic functions and non-kinase scaffolding functions. Previous efforts have clarified that it is crucial to address both FAK kinase and scaffolding functions instead of just inhibiting FAK kinase activity because it may be insufficient to completely block FAK signaling. Proteolysis targeting chimera (PROTAC) technology is a method of targeting a specific protein and inducing its degradation in the cell, which can simultaneously eliminate both kinase-dependent enzymatic functions and scaffolding functions. In current study, we designed and synthesized a series of novel FAK PROTACs and the optimal PROTAC B5 exhibited potent FAK affinity with an IC 50 value of 14.9 nM. Furthermore, in A549 cells, PROTAC B5 presented strong FAK degradation activity (86.4% degradation @ 10 nM), powerful antiproliferative activity (IC 50  = 0.14 ± 0.01 μM) and inhibited cell migration and invasion in a concentration-dependent manner. Additionally, the in vitro preliminary drug-like properties evaluation of PROTAC B5 showed outstanding plasma stability and moderate membrane permeability. Together, current results provided a promising FAK PROTAC B5 as lead compound for cancer-related drug discovery and FAK-degradation functions exploration in biological systems., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Synthetic lethality in DNA repair pathways is an important strategy for the selective treatment of cancer cells without harming healthy cells and developing cancer-specific drugs. The synthetic lethal interaction between the mismatch repair (MMR) protein, MutL homolog 1 (MLH1), and the mitochondrial base excision repair protein, DNA polymerase γ (Pol γ) was used in this study for the selective treatment of MLH1 deficient cancers. Germline mutations in the MLH1 gene and aberrant MLH1 promoter methylation result in an increased risk of developing many cancers, including nonpolyposis colorectal and endometrial cancers. Because the inhibition of Pol γ in MLH1 deficient cancer cells provides the synthetic lethal selectivity, we conducted a comprehensive small molecule screening from various databases and chemical drug library molecules for novel Pol γ inhibitors that selectively kill MLH1 deficient cancer cells. We characterized these Pol γ inhibitor molecules in vitro and in vivo, and identified 3,3'-[(1,1'-Biphenyl)-4',4'-diyl)bis(azo)]bis[4-amino-1-naphthalenesulfonic acid] (congo red; CR; Zinc 03830554) as a high-affinity binder to the Pol γ protein and potent inhibitor of the Pol γ strand displacement and one-nucleotide incorporation DNA synthesis activities in vitro and in vivo. CR reduced the cell proliferation of MLH1 deficient HCT116 human colon cancer cells and suppressed HCT116 xenograft tumor growth whereas it did not affect the MLH1 proficient cell proliferation and xenograft tumor growth. CR caused mitochondrial dysfunction and cell death by inhibiting Pol γ activity and oxidative mtDNA damage repair, increasing the production of reactive oxygen species and oxidative mtDNA damage in MLH1 deficient cells. This study suggests that the Pol γ inhibitor, CR may be further evaluated for the MLH1 deficient cancers' therapy., Competing Interests: MM, BuE and BaE are co-inventors on a patent application (WO2020005171). The competing interest does not alter our adherence to PLOS ONE policies on sharing data and materials.

Tropomyosin receptor kinase (TRK) is an ideal target for treating cancers caused by the NTRK gene fusion. In this study, more than 60 2,4-diaminopyrimidine derivatives were prepared to understand the structure-activity relationship and confirm the rationality of the pharmacophore model reported previously. Among them, compound 19k was found to be a potent pan-TRK inhibitor that inhibits the proliferation of Km-12 cell lines. Additionally, compound 19k induced the apoptosis of Km-12 cells in a concentration-dependent manner. Western blot analysis revealed that compound 19k inhibited the phosphorylation of TRK to block downstream pathways. Compound 19k also possessed outstanding plasma stability and liver microsomal stability in vitro, with half-lives greater than 289.1 min and 145 min, respectively. Pharmacokinetic studies indicated that the oral bioavailability of compound 19k is 17.4%. These results demonstrate that compound 19k could serve as a novel lead compound for overcoming NTRK-fusion cancers., 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. Published by Elsevier Masson SAS.)

LSD1 was the first histone demethylase identified by Professor Shi Yang and his team members in 2004. LSD1 employs FAD as its cofactor, which catalyzes the demethylation of H3K4 and H3K9. It is aberrantly overexpressed in different types of cancers and is associated with the growth, invasion, and metastasis of cancer cells. The knockout or inhibition of LSD1 could effectively suppress tumor development, and thus, it has become an attractive molecular target for cancer therapy. Moreover, many LSD1 inhibitors have been developed in preclinical and clinical trials to treat solid tumors and hematological malignancy. This study made an extensive review of the research obtained from the literature retrieval of electronic databases, such as PubMed, Web of Science, RCSB PDB, ClinicalTrials.gov, and EU clinical trials register. This review summarizes recent studies on the advances of LSD1 inhibitors in the literature, covering January 2015 to June 2021. It focuses on the function of LSD1 in tumor cells, summarizes the crystal structures of Homo sapiens LSD1, reviews the structural characteristics of LSD1 inhibitors, compares the screening methods of LSD1 inhibitors, and proposes guidelines for the future exploitation of LSD1 inhibitors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC 50  = 0.065 μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC 50 values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development., 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.)

The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O 2 self-supply, self-sufficient singlet oxygen ( 1 O 2 ), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H 2 O 2 ) into O 2 to alleviate tumor hypoxia. The production of O 2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.

Gas therapy as a burgeoning and promising research field has attracted considerable attention in biomedicine due to its high therapeutic efficacy, biocompatibility, and biosafety. However, the lack of tumor site accumulation and controlled release of therapeutic gas molecules limited the therapeutic efficacy. Therefore, the development of gas-releasing nanoplatforms to realize tumor targeting and controllable release is highly desired. The structural diversity and tailorability and ultrahigh surface area make metal-organic frameworks (MOFs) find potential applications in the delivery and release of gas or gas releasing molecules (GRMs). In this Frontier article, we provide an overview of the recent developments achieved in gas-involving cancer therapy using MOFs or MOF-based materials. The main emphasis is focused on the design of multifunctional MOF-based nanoplatforms for the delivery and release of therapeutic gas molecules, and emphasizing their synergistic mechanism against tumor. Moreover, the challenges, future trends, and prospects of gas-related cancer therapy are also discussed.

D-a-tocopheryl polyethylene glycol succinate (TPGS) as a FDA-approved safe adjuvant has shown an excellent application in the targeting delivery of antitumor drugs and overcoming multidrug resistance. Beside, TPGS can result in apoptogenic activity toward many tumor types because it can induce mitochondrial dysfunction. Therefore, TPGS can serve as an antineoplastic agent. However, the current research on the selective antitumor activity of TPGS is ignored. To reveal the issue, herein we develop a mitochondria-targeting drug-free TPGS nanomicelles with the hydrodynamic diameter of about 100 nm and outstanding serum stability by weak interaction-driven self-assembly of the amphiphilic TPGS polymer. Moreover, such drug-free TPGS nanomicelles intravenously injected into tumor-bearing mice exhibit long blood circulation time, superior tumor enrichment, and inhibit the tumor growth via inducing excessive reactive oxygen species (ROS) generation within tumor cells. Further in vitro and in vivo researches jointly demonstrate that drug-free TPGS nanomicelles have more significant antitumor effect on HeLa cells compared with that of other tumor cells. On the contrary, drug-free TPGS nanomicelles display the low toxicity toward normal cells and tissues. Taken together, these new findings confirm that TPGS drug-free nanomicelles represent simple, multifunctional, safe, and efficient antineoplastic agents, which can be expected to bring new light on the development of drug-free polymers for tumor therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Carrier-free nanoparticles (NPs) via chemotherapeutic drug-drug conjugate assembly are a promising alternative for tumor chemotherapy. However, these NPs are still hindered via their nonspecific internalization into certain healthy cells and tissues. Herein, dual-acting methotrexate (MTX) and mannose (MAN) were conjugated via a hydrolyzable ester bond to synthesize a MTX-MAN conjugate as one molecule, which could be directly self-assembled into stimulus-responsive carrier-free NPs (MTX-MAN NPs) in aqueous solution. Such carrier-free MTX-MAN NPs with an accurate drug to sugar ratio could achieve on-demand drug release by dual stimuli of lysosomal acidity and esterase. Besides, MTX-MAN NPs could be dual-recognized by tumor cells in vitro and specifically by tumors in vivo. Moreover, the large proportion of MAN located on the NPs' surface could exert a shielding effect to avoid phagocytosis of macrophages, leading to long blood circulation. Therefore, the MTX-MAN NPs sharply reduced the drug dosage and decreased the toxicity to normal cells and tissues. Further in vitro and in vivo studies consistently confirmed that the MTX-MAN NPs exhibited superior tumor accumulation and highly synergistic chemotherapeutic effects. Furthermore, we found for the first time that MAN could enhance the antitumor activity of MTX. Considering that bi-functional MTX and MAN are approved via the FDA, and MAN is highly biosafe, the dual-self-recognizing, stimulus-responsive, and carrier-free MTX-MAN NPs might be a simple, selective, and safe chemotherapeutic strategy.

A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of ∼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC 50 ) of 6.3 μM, which is much lower than 17.8 μM for G-BCP and 28.9 μM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Cancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.

Block copolymer prodrugs (BCPs) have emerged as one of the most promising anticancer drug delivery strategies, which can self-assemble into nanoparticles with optimal physicochemical properties including sizes, morphologies, surface properties, and integration of multifunction for improved in vivo applications. Moreover, the utility of stimuli-responsive linkages to conjugate drugs onto the polymer backbones can achieve efficient and targeting drug release. Several BCP micellar delivery systems have been pushed ahead into the clinical trials, which showed great promising potentials for cancer therapy. In recent years, various novel and more efficient BCP systems have been developed for better in vivo performance. In this focus article, we focus on the recent advances of BCPs including the synthesis, self-assembly, and applications for cancer therapy. The synthetic methods are first introduced, and the self-assembly of BCPs for in vivo anticancer applications is discussed along the line of varying endogenous stimuli-responsive linkages including amide or ester bonds, pH, reduction, and oxidation-responsive linkages. Finally, conclusions along with the brief future perspectives are presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2019 Wiley Periodicals, Inc.)

Background: Cancer is one of the leading causes of mortality globally. To cope with cancer, it is necessary to develop anticancer drugs. Bioactive natural products, i.e. diarylheptanoids, have gained significant attention of researchers owing to their intriguing structures and potent biological activities. In this article, considering the development of anticancer drugs with enhanced selectivity towards cancerous cells, a series of Cyclic Diarylheptanoids (CDHs) are designed, synthesized and evaluated their biological activity., Objective: To establish an easy route for the synthesis of diarylheptanoids, and evaluate their antiproliferative, and topoisomerase-I & -IIα inhibitory activities, for developing potential anticancer drugs among CDHs., Methods: Diarylheptanoids were synthesized from reported linear diarylheptanoids using the classical Ullmann reaction. Antibacterial activity was evaluated by the filter paper disc diffusion method. Cell viability was assessed by measuring mitochondrial dehydrogenase activity with a Cell Counting Kit (CCK-8). Topoisomerases I and II (topo-I and -IIα) inhibitory activity was measured by the assessment of relaxation of supercoiled pBR322 plasmid DNA. IFD protocol of Schrodinger Maestro v11.1 was used to characterize the binding pattern of studied compounds with the ATPase domain of the human topo-IIα., Results: The synthesized CDHs were evaluated for their biological activities (antibacterial, antiproliferative, and topoisomerase-I & -IIα inhibitory activities, respectively). Leading to obtain a series of anticancer agents with the least inhibitory activities against different microbes, improving their selectivity for cancer cells. In brief, most of the synthesized CDHs had excellent antiproliferative activity against T47D (human breast cancer cell line). Pterocarine possessed the strongest activity (2i; IC50 = 0.63µM) against T47D. The cyclic diarylheptanoid 2b induced 30% inhibition of topoisomerase-IIα activity at 100μM compared with the reference of etoposide, which induced 72% inhibition. Among the tested compounds, galeon (2h) displayed very low activity against four bacterial strains. Compounds 2b, 2h, and 2i formed hydrogen bonds with Thr215, Asn91, Asn120, Ala167, Lys168 and Ile141 residues, which are important for binding of ligand compound to the ATPase binding site of topoisomerase IIα by acting as ATP competitive molecule validated by docking study. In silico Absorption, Distribution, Metabolism and Excretion (ADME) analysis revealed the predicted ADME parameters of the studied compounds which showed recommended values., Conclusion: A series of CDHs were synthesized and evaluated for their antibacterial, antiproliferative, and topo-I & -IIα inhibitory activities. SARs study, molecular docking study and in silico ADME analysis were conducted. Five compounds exhibited excellent and selective antiproliferative activity against the human breast cancer cell line (T47D). Among them, a compound 2h showed topo-IIα activity by 30% at 100µM, which represented a moderate intensity of inhibition compared with etoposide. Three of them formed hydrogen bonds with Thr215, Asn91, Asn120, and Ala167 residues, which are considered as crucial residues for binding to the ATPase domain of topoisomerase IIα. According to in silico drug-likeness property analysis, three compounds are expected to show superiority over etoposide in case of absorption, distribution, metabolism and excretion., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The long history of discovery and recently encouraging studies of the anti-cancer effect of aspirin promise a closer step to widely used aspirin-based medication in cancer therapy. To resolve the poor water-solubility of aspirin and low encapsulation efficiency of exosomes for further developing a new delivery of aspirin as anti-cancer treatment, our nanoamorphous exosomal delivery platform was established. In this study, the anti-tumour effects of nanoamorphous aspirin-loaded exosomes with exosomes derived from breast and colorectal cancer cells, were comprehensively studied using both in vitro and in vivo models. These exosomes displayed enhanced cellular uptake via both clathrin-dependent and -independent endocytosis pathways, and significantly improved cytotoxicity of aspirin to breast and colorectal cancer cells, accompanied by the enhanced apoptosis and autophagy. Remarkably, this nanoamorphous exosomal platform endowed aspirin with the unprecedented cancer stem cell eradication capacity. Further animal study demonstrated that this developed exosomal system was able to efficiently deliver aspirin to in vivo tumours. The active targeting of these exosomes to tumour was further improved by conjugating an aptamer specifically targeting EpCAM protein. Hence, this nanoamorphous structured exosome system effectively transformed aspirin into a potential cancer stem cell killer with distinguished properties for clinical translation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recently, chemotherapy is still widely exploited to treat the residual, infiltrative tumor cells after surgical resection. However, many anticancer drugs are limited in clinical application due to their poor water-solubility (hydrophibic) and stability, low bioavailability, and unfavorable pharmacokinetics. Herein, an amphiphilic stearic acid-O-carboxymethyl chitosan (SA-CMC) conjugate was synthesized by amide linkage of SA to the backbone of CMC polymer and then self-assembled into nanoparticles (SA-CMC NPs) with the hydrodynamic particle size of ~100 nm. Subsequently, Paclitaxel (PTX) as a potent and broad-spectrum anticancer drug was loaded into SA-CMC NPs by a probe sonication combined with dialysis method. Owing to the multi-hydrophobic inner cores, the prepared PTX-SA-CMC NPs showed a considerable drug-loading capacity of ~19 wt% and a biphasic release behavior with an accumulative release amount in the range of 70-90% within 72 h. PTX-SA-CMC NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of acid, PTX-SA-CMC NPs showed exceptional instability by pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with Cremophor EL-based free PTX treatment, PTX-SA-CMC NPs under pH-stimuli accomplished highly efficient apoptosis in cancer cells and effectively suppression of tumors by chemotherapy. Overall, PTX-SA-CMC NPs integrating imaging capacity might be a simple yet feasible PTX nanosystem for tumor-targeted delivery and cancer therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Colorectal carcinoma (CRC) is one of the most common cancers with high metastatic potential, explaining why identifying new drug candidates that inhibit tumour metastasis is an urgent need. The aim of this study was to evaluate the biological activities of pectolinarigenin (PEC, a natural flavonoid present in Cirsium chanroenicum) in CRC in vitro and in vivo and to determine its underlying mechanism of action. Here, we observed that treatment with PEC could inhibit cell viability and induce apoptosis in cancer cells in a concentration- and time-dependent manner. The occurrence of apoptosis was associated with activation of caspase-3 and Bax and decreased expression of Bcl-2. In addition, PEC markedly impaired CRC cell migration and invasion by downregulating the expression of matrix metalloproteinase (MMP-9) and phosphorylated-Stat3 Tyr705 . Moreover, our studies showed that PEC inhibited abdominal metastasis models of murine colorectal cancer. In addition, histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, MMP9-positive cells and p-Stat3 Tyr705 cells upon treatment with PEC compared to control samples. Furthermore, PEC reduced the number of myeloid-derived suppressor cells (MDSCs) in the blood and tumours, which was accompanied by the increased infiltration of CD8 + T cells in the blood. Taken together, our findings suggested that PEC could be used as a natural drug to inhibit CRC metastasis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Despite their great potential, the nano-sized extracellular vesicles are yet to become effective delivery systems for poorly water-soluble drugs. Here, we present a novel platform of exosomes as a drug delivery system by engineering of a poorly water-soluble drug into a poloxamer-based molecular nanostructured dispersion composed of a hydrophilic and a hydrophobic moiety for an enhanced anticancer efficacy. For the first time, aspirin was loaded into exosomes as an anticancer agent via a one-step fabrication combining the nano-matrix formation of the nanostructured dispersion and exosomes loading. Our approach could transform crystalline aspirin to a nanoamorphous form in the nano-matrix structured exosomes, leading to increased drug encapsulation efficiency for exosomes, improved dissolution and strongly enhanced cytotoxicity of aspirin to cancer cells. Interestingly, cytotoxicity of aspirin to both breast and colorectal cancer cells could be strongly enhanced by the nanoamorphous aspirin-loaded exosomes, and this cytotoxic effect was more pronounced to parental cells of the exosomes, reminiscent of homing effect. Hence, this study has pioneered a novel nanoplatform of nanoamorphous exosomal delivery system to transform an anti-inflammatory drug into a potent anti-cancer agent., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Down-regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All-trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti-tumor T-cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma-inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down-regulated during murine melanoma growth. Rarres2 -/- mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor-infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up-regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor-infiltrating NK cells, which was completely abrogated in Rarres2 -/- mice and Cmklr1 -/- mice, suggesting a dependency of NK cell recruitment on the chemerin-CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild-type mice and Cmklr1 -/- mice, lack of CMKLR1 partially abrogated the melanoma-inhibitory effect of atRA. This may be due to the inability to enhance tumor-infiltrating NK cells in Cmklr1 -/- mice following atRA treatment. Collectively, our study suggests that down-regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti-tumor NK cell immunity and identifies a new anti-tumor mechanism of atRA by up-regulating chemerin to enhance CMKLR1-dependent NK cell recruitment., (© 2019 John Wiley & Sons Ltd.)

In efforts to develop effective anticancer therapeutics with greater selectivity toward cancerous cell and reduced side-effects, such as emetic effects due to detrimental action of the drug toward the intestinal flora, a series of linear diarylheptanoids (LDHs) were designed and synthesized in 7 steps with good-to-moderate yields. All synthesized compounds were evaluated for their antibacterial, antiproliferative, and topoisomerase-I and -IIα inhibitory activity. Overall, all compounds showed little to no activity against the bacterial strains tested. Most of the synthesized compounds showed good antiproliferative activity against human breast cancer cell lines (T47D); specifically, the IC 50 values of compounds 6a, 6d, 7j, and 7e were 0.09, 0.64, 0.67, and 0.99 μM, respectively. Among the tested compounds, 7b inhibited topo-I by 9.3% (camptothecin 68.8%), 7e and 7h inhibited topo-IIα by 38.4 and 47.4% (etoposide 76.9%), respectively, at the concentration of 100 μM. These results suggest that a set of promising anticancer agents can be obtained by reducing inhibitory actions on different microbes to provide enhanced selectivity against cancerous cells.

We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC 50  = 25 nM) and cellular potency (A549 IC 50  = 0.58 μM, HCT116 IC 50  = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Cisplatin is a platinum-based chemotherapy drug that is widely used to treat various types of malignancies. Although the involvement of circadian clock in cisplatin metabolism and excretion has been reported, the effect of cisplatin on circadian rhythm remains unclear. In the present study, we investigated the effects of cisplatin on clock genes expression in mouse peripheral tissues. Cisplatin induced severe nephrotoxicity, as revealed by the significant increase of blood urea nitrogen and serum creatinine levels. Moreover, cisplatin circadian time-dependently induced p21 expression in the liver, heart and kidney, with the highest increase during the dark phase. In addition, cisplatin altered the clock genes expression in the liver, heart and kidney in a tissue- and gene-specific manner. Interesting, the expression of D site of the albumin promoter binding protein (Dbp), a gene involved in detoxification and drug metabolism, was consistently suppressed in the liver, heart and kidney after cisplatin treatment, implying a role of DBP in the toxicity of cisplatin., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Relative to normal cells, tumor cells lack adequate capability of reactive oxygen scavenging. Thus, tumor cells can be selectively killed by increasing the concentration of reactive oxygen species in tumor tissue. In this report, we construct an integrated multifunctional polymeric nanoparticle which can selectively improve hydrogen peroxide (H 2 O 2 ) levels in tumor tissue and convert them into more active hydroxyl radicals by Fenton reaction. First, the diblock copolymers containing polyethylene glycol (PEG) and poly(glutamic acid) modified by β-cyclodextrin (β-CD) were synthesized. The block copolymer, ferrocenecarboxylic acid hexadecyl ester (DFc), and ascorbyl palmitate (PA) were coassembled in aqueous solution to obtain stable core-shell micelles through the inclusion complexation between β-CD moieties in the block copolymer and ferrocene (Fc) groups from DFc. After intravenous injection, the particles achieved significant accumulation in tumor tissue where ascorbic acid at the pharmacological concentration promotes the production of H 2 O 2 , and subsequently Fenton reaction was catalyzed by Fc groups to produce hydroxyl radicals to efficiently kill cancer cells and suppress tumor growth. The micellar systems possess great potentials toward cancer therapy through synergistic H 2 O 2 production and conversion into hydroxyl radicals specifically in tumor tissue.

The intrinsic or acquired cisplatin resistance of cancer cells frequently limits the final therapeutic efficacy. Detoxification by the high level of intracellular glutathione (GSH) plays critical roles in the majority of cisplatin-resistant cancers. In this report, we designed an amphiphilic diblock copolymer composed of poly(ethylene glycol) (PEG) and polymerized phenylboronic ester-functionalized methacrylate (PBEMA), PEG-b-PBEMA, which can self-assemble into micelles in aqueous solutions to load hydrophobic cisplatin prodrug (Pt(IV)). Pt(IV)-loaded PEG-b-PBEMA micelles (PtBE-Micelle) reverse cisplatin-resistance of cancer cells through improving cellular uptake efficiency and reducing intracellular GSH level. We found that the cellular uptake amount of platinum from PtBE-Micelle was 6.1 times higher than that of free cisplatin in cisplatin-resistant human lung cancer cells (A549R). Meanwhile, GSH concentration of A549R cells was decreased to 32% upon treatment by PEG-b-PBEMA micelle at the phenyl borate-equivalent concentration of 100μM. PtBE-Micelle displayed significantly higher cytotoxicity toward A549R cells with half maximal inhibitory concentration (IC 50 ) of cisplatin-equivalent 0.20μM compared with free cisplatin of 33.15μM and Pt(IV)-loaded PEG-b-poly(ε-caprolactone) micelles of cisplatin-equivalent 0.75μM. PtBE-Micelle can inhibit the growth of A549R xenograft tumors effectively. Accordingly, PEG-b-PBEMA micelles show great potentials as drug delivery nanocarriers for platinum-based chemotherapy toward cisplatin-resistant cancers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3-aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block-poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taking paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10 -3  g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (∼40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH-sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy based on thiolactone chemistry represents an efficient approach to construct multifunctional BCPs for better therapeutic efficacy via addressing multiple physiological barriers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H 2 O 2 ) production by the catalysis of GOD in theraNR increases tumor oxidative stress significantly. Meanwhile, high levels of H 2 O 2 induce self-destruction of theraNR releasing quinone methide (QM) to deplete glutathione and suppress the antioxidant ability of cancer cells. Finally, theraNR efficiently kill cancer cells and ablate tumors via the synergistic effect., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

New tetramic acid derivatives, (±)-conipyridoins A-D (1-4), conipyridoins E (5) and F (6), and new 4-hydroxy-2-pyridone alkaloids (±)-didymellamide E (7), (+)-didymellamide B (8), (+)-N-hydroxyapiosporamide (9), and didymellamides F-H (10-12) were isolated and identified from the solid culture of the fungus Coniochaeta cephalothecoides. Chiral resolution of 1, 2, 3, 4, and 7 gave five pairs of enantiomers: 1a/1b, 2a/2b, 3a/3b, 4a/4b, and 7a/7b, respectively. Stereochemistry of 1a and 1b, and 2a and 2b was established and confirmed by the single-crystal X-ray diffraction and electronic circular dichroism (ECD) methods. Absolute configuration in 3a, 3b, 4a, 4b, 7a, and 7b was assigned by ECD calculations. Compounds 1-6 possess an unprecedented chemical skeleton featuring a decalin ring and a tetramic acid moiety. Compound 11 significantly inhibited the growth of Candida albicans and Aspergillus fumigatus with minimum inhibitory concentration (MIC) of 3.13 and 1.56 μM, respectively, and was further confirmed to be a new chitin synthesis inhibitor. Compound 5 exhibited the strongest activity against the growth of both Staphylococcus aureus and MRSA with MIC value of 0.97 μM. In the light of a co-occurrence of 3-acyl tetramic acids and biogenetically related pyridine alkaloids, the biosynthetic pathway for 1-12 was postulated.

All-trans retinoic acid (atRA), the main biologically active metabolite of vitamin A, has been implicated in immunoregulation and anti-cancer. A recent finding that vitamin A could decrease the risk of melanoma in humans indicates the beneficial role of atRA in melanoma. However, it remains unknown whether topical application of atRA could inhibit melanoma growth by influencing tumour immunity. We demonstrate topical application of tretinoin ointment (atRA as the active ingredient) effectively inhibited B16F10 melanoma growth. This is accompanied by markedly enhanced CD8 + T-cell responses, as evidenced by significantly increased proportions of effector CD8 + T cells expressing granzyme B, tumour necrosis factor-α, or interferon-γ, and Ki67 + proliferating CD8 + T cells in atRA-treated tumours compared with vaseline controls. Furthermore, topical atRA treatment promoted the differentiation of effector CD8 + T cells in draining lymph nodes (DLN) of tumour-bearing mice. Interestingly, atRA did not affect tumoral CD4 + T-cell response, and even inhibited the differentiation of interferon-γ-expressing T helper type 1 cells in DLN. Importantly, we demonstrated that the tumour-inhibitory effect of atRA was partly dependent on CD8 + T cells, as CD8 + T-cell depletion restored tumour volumes in atRA-treated mice, which, however, was still significantly smaller than those in vaseline-treated mice. Finally, we demonstrated that atRA up-regulated MHCI expression in B16F10 cells, and DLN cells from tumour-bearing mice had a significantly higher killing rate when culturing with atRA-treated B16F10 cells. Hence, our study demonstrates that topical atRA treatment effectively inhibits melanoma growth partly by promoting the differentiation and the cytotoxic function of effector CD8 + T cells., (© 2017 John Wiley & Sons Ltd.)

Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600-fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus-suppressed inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Summay: Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of SKOV3 cancer cells. Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 31 days after tumor inoculation. Number of tumor vessels and Ki-67 index were calculated. Results SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the ovarian cancer cells in untreated control group (P = 0.001). Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37 μmol/L. Treatment with alofanib in combination with paclitaxel/carboplatin resulted in tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated significant effect (inhibiting growth by 80 % and by 53 % in comparison with vehicle and chemotherapy group alone, respectively (P < 0.001). Alofanib decreased number of vessels in tumor (-49 %; P < 0.0001) and number of Ki-67-positive SKOV3 cells (-42 %, P < 0.05). There were tumor necrosis and cell degeneration in alofanib group. Conclusions We suggest that FGFR2 inhibition has potent effects on ovarian cancer growth in preclinical studies.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers cancer cell death via its association with death receptors on the cell membrane, but exerts negligible side effects on normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients exhibited resistance to TRAIL treatment in clinical trials, and the mechanism varies. In this study, we described for the first time that toosendanin (TSN), a triterpenoid derivative used in Chinese medicine for pain management, could significantly sensitize human primary NSCLC cells or NSCLC cell lines to TRAIL-mediated apoptosis both in vitro and in vivo, while showing low toxicity against human primary cells or tissues. The underlying apoptotic mechanisms involved upregulation of death receptor 5 (DR5) and CCAAT/enhancer binding protein homologous protein, which is related to the endoplasmic reticulum stress response, and is further associated with reactive oxygen species generation and Ca 2+ accumulation. Surprisingly, TSN also induced autophagy in NSCLC cells, which recruited membrane DR5, and subsequently antagonized the apoptosis-sensitizing effect of TSN. Taken together, TSN can be used to sensitize tumors and the combination of TRAIL and TSN may represent a useful strategy for NSCLC therapy; moreover, autophagy serves as an important drug resistance mechanism for TSN.

Reverse transcription quantitative polymerase chain reaction (RT-qPCR) has become a frequently used strategy in gene expression studies. The relative quantification method is an important and commonly used method for the evaluation of RT-qPCR data. The key of this method is to identify an applicable internal control gene because the usage of different internal control genes may lead to distinct conclusions. Herein, we report the validation of 12 common housekeeping genes for RT-qPCR for gene expression analysis in the Oral squamous cell carcinoma (OSCC) cell line (KB and Tca-8113) treated by 5 kinds of Chemotherapy Drugs. The gene expression stability and applicability of the 12 housekeeping gene candidates were determined using the geNorm, NormFinder, and BestKeeper software programs. Comprehensive analyzing the results of the three software, ALAS1/GAPDH, ALAS1 and GUSB were suggested to be the most stable candidate genes for the study of both KB and Tca-8113 cell line together, KB cell line, and Tca-8113 cell line, respectively. This study provides useful information to normalize gene expression accurately for the investigation of target gene profiling in cell lines of OSCC. Further clarification of tumor molecular expression markers with our recommended housekeeping genes may improve the accuracy of diagnosis and estimation of prognostic factors as well as provide novel personalized treatments for OSCC patients.

A series of novel 2,4,5-trisubstituted 1,3-thiazole derivatives containing hydrazide-hydrazine, and carboxamide moiety including 46 compounds T were synthesized, and evaluated for their antitumor activity in vitro against a panel of five human cancer cell lines. Eighteen title compounds T displayed higher inhibitory activity than that of 5-Fu against MCF-7, HepG2, BGC-823, Hela, and A549 cell lines. Especially, T1, T26 and T38 exhibit best cytotoxic activity with IC50 values of 2.21μg/mL, 1.67μg/mL and 1.11μg/mL, against MCF-7, BCG-823, and HepG2 cell lines, respectively. These results suggested that the combination of 1,3-thiazole, hydrazide-hydrazone, and carboxamide moiety was much favorable to cytotoxicity activity. Furthermore, the flow cytometry analysis revealed that compounds T1 and T38 could induce apoptosis in HepG2 cells, and it was confirmed T38 led the induction of cell apoptosis by S cell-cycle arrest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Natural killer (NK)-lysin, a broad-spectrum antimicrobial peptide, has antitumor and antibactericidal activities against both gram-positive and gram-negative bacteria. In this study the recombinant porcine NK-lysin was expressed and purified in the Pichia pastoris system, and then 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to assess its anticancer activity in vitro. The results showed that the recombinant porcine NK-lysin possesses potent antitumor activity against the human hepatocellular carcinoma cell line SMMC-7721 in a time- and dose-dependent manner, but has negligible hemolysis activity against human erythrocytes. Scanning electronic microscopy was used to directly observe the ultrastructure of SMMC-7721 cells treated with NK-lysin; untreated cells showed lamellipodia and filopodia scattered with the cell surface, with good cell-cell contacts among neighboring cells. In contrast, treated tumor cells exhibited marked alterations in cell morphology, and cell-cell contacts disappeared among neighboring cells. Compared with the untreated tumor cells, the tumor cells treated with NK-lysin for 12 and 24 hr were suppressed for the expression of fascin 1. Thus, the recombinant porcine NK-lysin potentially could be developed as a therapeutic agent for inhibiting tumor growth.

Engineering design of plasmonic nanomaterials as on-demand theranostic nanoagents with imaging, drug carrier, and photothermal therapy (PTT) functions have profound impact on treatment of cancer. Here, a facile 'one-pot' template-free hydrothermal route was firstly developed for synthesis of plasmonic oxygen deficiency molybdenum oxide hollow nanospheres functionalized by poly(ethylene glycol) (PEG-MoO(3-x) HNSs). The as-prepared PEG-MoO(3-x) HNSs not only have good biocompatibility but also exhibit obvious localized surface plasmon resonance (LSPR) absorption in the near-infrared (NIR) region. Especially, due to its intrinsic mesoporous properties and effective photothermal conversion efficiency upon 808-nm NIR laser irradiation, the PEG-MoO(3-x) HNSs can be applied as a pH/NIR laser dual-responsive camptothecin (CPT) drug delivery nanoplatform for chemotherapy as well as PTT to cancer cells. A remarkably improved synergistic therapeutic effect to pancreatic (PANC-1) tumor-bearing mice was obtained compared to the result of chemotherapy or PTT alone. Apart from its application for drug delivery, the PEG-MoO(3-x) HNSs can also be employed as an effective contrast nanoagent for photoacoustic (PAT) imaging because of its high NIR absorption, making it promising as a theranostic nanoagent for PAT imaging-guided chemo-photothermal combinational cancer therapy in the nanomedicine field., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.

Mounting evidence suggests that microRNAs (miRNAs) play important roles in the development of cancer by targeting expression of tumor-related genes. In the present study, downregulation of miR-193b was observed in hepatocellular carcinoma (HCC) tissues and HCC cell lines by quantitative RT-PCR analyses, suggesting that miR-193b is a tumor-suppressor in HCC. More importantly, miR-193b significantly enhanced the cytotoxicity of cisplatin in HepG2 cells by targeting Mcl-1. Knockdown of the Mcl-1 gene by specific siRNA exhibited a function similar to miR-193b on sensitizing HepG2 cells to cisplatin-inducing cytotoxicity. Furthermore, the miR-193b-induced sensitization of HepG2 cells to cisplatin cytotoxicity was abolished by the transfection of Mcl-1 expression plasmid that lacked the 3'-untranslated region (3'-UTR). In addition, activation of caspase-3 was needed for sensitization by miR-193b to cisplatin-mediated cell death. Thus, the present study revealed the downregulation of miR-193b in HCC cells and illustrated a synergistic effect on cisplatin-induced apoptosis by targeting Mcl-1.

Multi-drug resistance (MDR) is a major cause of failure in cancer chemotherapy. Tocopheryl polyethylene glycol 1000 succinate (TPGS) has been extensively investigated for overcoming MDR in cancer therapy because of its ability to inhibit P-glycoprotein (P-gp). In this work, TPGS was for the first time used as a new surface modifier to functionalize NaYbF4:Er upconversion nanoparticles (UNCPs) and endowed the as-prepared products (TPGS-UCNPs) with excellent water-solubility, P-gp inhibition capability and imaging-guided drug delivery property. After the chemotherapeutic drug (doxorubicin, DOX) loading, the as-formed composites (TPGS-UCNPs-DOX) exhibited potent killing ability for DOX-resistant MCF-7 cells. Flow-cytometric assessment and Western blot assay showed that the TPGS-UCNPs could potently decrease the P-gp expression and facilitate the intracellular drug accumulation, thus achieving MDR reversal. Moreover, considering that UCNPs process efficient upconversion emission and Yb element contained in UCNPs has strong X-ray attenuation ability, the as-obtained composite could also serve as a dual-modal probe for upconversion luminescence (UCL) imaging and X-ray computed tomography (CT) imaging, making them promising for imaging-guided cancer therapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Umbelliferones have gained significant attention due to their tumor-inhibitory effects in vitro. This study was undertaken to examine the impact of umbelliferones in an invertebrate model organism, Bombyx mori, to assess the underlying antimicrobial activities via antioxidation in vivo. Oral administration of 4 mM 4-methylumbelliferone (4-MU), a model umbelliferone drug, in B. Mori larvae caused a rapid increase in reactive oxygen species, such as hydrogen peroxide (H2O2) and antimicrobial activity in the digestive tract. In addition, a significant increase in total antioxidant capacity as well as superoxide anion radical-inhibiting activity and reduced glutathione were detected. The antioxidant defense system was activated following induction of H2O2, resulting in a significant rise in catalase (50-66 %) and glutathione peroxidase (175 %) activities, which were helpful in defending digestive tract cells against oxidative injury. These results help in understanding the anticancer mechanism of 4-MU based on its antioxidation in organisms.

This study investigated the active components and the anti-tumor efficacy and mechanisms of the flavonoids from Docynia delavayi (Franch.) Schneid. (DDS). MTT assay was used to examine the growth inhibitory effects of the four flavonoids, including chrysin, quercetin, naringenin, and avicularin that were isolated from the rhizome of DDS, on human hematomas cell (HepG2), esophageal carcinoma cell (EC109), human cervical adenocarcinoma cell (Hela), human colon adenocarcinoma cell (SW480), and African green monkey kidney cell (Vero cells). The anti-tumor mechanism of chrysin on HepG2 was further investigated by the methods of fluorescence staining, flow cytometry, and immunoblotting. The results showed that the inhibitory activity of chrysin was much stronger than the other three flavonoids on HepG2, EC109, Hela, and SW480 cells for 48 h treatment in vitro. Moreover, no inhibiting effect of chrysin on the proliferation of normal cells (Vero cells) was observed. Further study revealed that chrysin caused HepG2 cell shrinkage, membrane blebbing, and apoptotic body formation, all of which were typical characteristics of apoptosis programmed cell death. Flow cytometric analysis demonstrated that chrysin increased the sub G0/G1 population, which indicated the increased cell apoptosis, thus preventing cells from entering the S phase as the population in G2/M or S phase declined; whereas in G0/G1 phase, it increased. In addition, immunoblot results showed that chrysin significantly increased the expression levels of caspase-3 and Bax proteins, and it decreased the expression level of B-cell lymphoma/leukemia-2 (Bcl-2) protein. These findings indicate that chrysin is the major flavonoid present in DDS, and it induces HepG2 cell death via apoptosis, probably through the participation of caspase-3, Bax, and Bcl-2 proteins.