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The precise and safe treatment of bioorthogonal prodrug system is hindered by separate administration of prodrug and its activator, which often results in poor therapeutic effects and severe side effects. To address above issues, we herein construct a single bioorthogonal-activated co-delivery system for simultaneous PROTAC prodrug (proPROTAC) delivery and controlled, site-specific activation for tumor-specific treatment. In this co-delivery system (termed AuPLs), prodrug (proPROTAC) and water-soluble Pd-catalyst are first encapsulated by gold nanocubes (AuNCs), which are further coated with a layer of phase-change material (lauric acid/stearic acid, LA/SA). Below 39 °C, the solid state of LA/SA prevents the activation of Pd-mediated bioorthogonal reaction due to the solidification of Pd-catalyst and proPROTAC. Nevertheless, once over 42 °C, the phase change of LA/SA into liquid state, enabled by the photothermal effect of AuNCs, triggers the simultaneous release of proPROTAC and Pd-catalyst and initiates the in situ bioorthogonal reaction for proPROTAC activation. In the tumor-bearing mouse models, the systemic administration of AuPLs results in the accumulation in tumor region, where the photothermal effect activates and controls the tumor-specific bioorthogonal reaction to degrade BRD4 protein, leading to anti-tumor effects with minimized side effects. Overall, the co-delivery proPROTAC and Pd-catalyst and controlled activation by photothermal effects provide a precise way for biorthogonal-based anticancer prodrugs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Limited success has been achieved in ferroptosis-induced cancer treatment due to the challenges related to low production of toxic reactive oxygen species (ROS) and inherent ROS resistance in cancer cells. To address this issue, a self-assembled nanodrug have been investigated that enhances ferroptosis therapy by increasing ROS production and reducing ROS inhibition. The nanodrug is constructed by allowing doxorubicin (DOX) to interact with Fe 2+ through coordination interactions, forming a stable DOX-Fe 2+ chelate, and this chelate further interacts with sorafenib (SRF), resulting in a stable and uniform nanoparticle. In tumor cells, overexpressed glutathione (GSH) triggers the disassembly of nanodrug, thereby activating the drug release. Interestingly, the released DOX not only activates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) to produce abundant H 2 O 2 production for enhanced ROS production, but also acts as a chemotherapeutics agent, synergizing with ferroptosis. To enhance tumor selectivity and improve the blood clearance, the nanodrug is coated with a related cancer cell membrane, which enhances the selective inhibition of tumor growth and metastasis in a B16F10 mice model. Our findings provide valuable insights into the rational design of self-assembled nanodrug for enhanced ferroptosis therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: Ferroptosis is a non-apoptotic form of cell death induced by the iron-regulated lipid peroxides (LPOs), offering a promising potential for effective and safe anti-cancer treatment. However, two significant challenges hinder its clinical application: 1) The easily oxidized nature of Fe2+ and the low concentration of H 2 O 2 leads to a low efficiency of intracellular Fenton reaction, resulting in poor therapeutic efficacy; 2) The instinctive ROS resistance of cancer cells induce drug resistance. Therefore, we developed a simple and high-efficiency nanodrug composed of self-assembling by Fe 2+ sources, H 2 O 2 inducer and ROS resistance inhibitors. This nanodrug can effectively deliver the Fe 2+ sources into tumor tissue, enhance intracellular concentration of H2O2, and reduce ROS resistance, achieving a high-efficiency, precise and safe ferroptosis therapy., 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 © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In the past few decades, chemotherapy has been one of the most effective cancer treatment options. Drug resistance is currently one of the greatest obstacles to effective cancer treatment. Even though drug resistance mechanisms have been extensively investigated, they have not been fully elucidated. Recent genome-wide investigations have revealed the existence of a substantial quantity of long non-coding RNAs (lncRNAs) transcribed from the human genome, which actively participate in numerous biological processes, such as transcription, splicing, epigenetics, the cell cycle, cell differentiation, development, pluripotency, immune microenvironment. The abnormal expression of lncRNA is considered a contributing factor to the drug resistance. Furthermore, drug resistance may be influenced by genetic and epigenetic variations, as well as individual differences in patient treatment response, attributable to polymorphisms in metabolic enzyme genes. This review focuses on the mechanism of lncRNAs resistance to target drugs in the study of tumors with high mortality, aiming to establish a theoretical foundation for targeted therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Zhang et al.)

The practical and facile Mn(OAc) 2 -promoted [3+2] cycloaddition reaction of enaminones with isocyanoacetate was developed, that delivered a diversity of 3-aroyl pyrrole-2-carboxylic esters with broad substrates scope. The most of the newly synthesized compounds exhibit moderate antiproliferative activity against four cancer cells. Notably, compound 2n demonstrate the most potent activity with average IC 50 values of 5.61 μM against four distinct cancer cell lines. Moreover, 2n exhibit favorable anti-migration activity and drug-like properties. The further investigation suggests that compound 2n possesses the ability to inhibit ERK5 activity and exhibits effective binding with the ERK5 protein, making it a promising candidate as a lead compound for a new class of ERK5 inhibitors discovery., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiaopeng Peng reports financial support was provided by Gannan Medical University. Xiaopeng Peng reports a relationship with Gannan Medical University that includes: employment. Xiaopeng Peng has patent pending to No patent. 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 © 2023 Elsevier Inc. All rights reserved.)

Heat shock protein 90, also known as Hsp90, is an extensively preserved molecular chaperone that performs a critical function in organizing various biological pathways and cellular operations. As a potential drug target, Hsp90 is closely linked to cancer. Hsp90 inhibitors are a class of drugs that have been extensively studied in preclinical models and have shown promise in a variety of diseases, especially cancer. However, Hsp90 inhibitors have encountered several challenges in clinical development, such as low efficacy, toxicity, or drug resistance, few Hsp90 small molecule inhibitors have been approved worldwide. Nonetheless, combining Hsp90 inhibitors with other tumor inhibitors, such as HDAC inhibitors, tubulin inhibitors, and Topo II inhibitors, has been shown to have synergistic antitumor effects. Consequently, the development of Hsp90 dual-target inhibitors is an effective strategy in cancer treatment, as it enhances potency while reducing drug resistance. This article provides an overview of Hsp90's domain structure and biological functions, as well as a discussion of the design, discovery, and structure-activity relationships of Hsp90 dual inhibitors, aiming to provide insights into clinical drug research from a medicinal chemistry perspective and discover novel Hsp90 dual inhibitors., 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 © 2023 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment., (© 2023 Wiley-VCH GmbH.)

Exploring multi-targeting chemotherapeutants with advantages over single-targeting agents and drug combinations is of great significance in drug discovery. Herein, we employed phytogenic evodiamine (EVO) and conventional Pt(II) drugs to design and synthesize multi-target EVO-Pt(IV) anticancer prodrugs ( 4 - 14 ). Among them, compound 10 exhibited a 118-fold enhancement in the IC 50 value compared to cisplatin and low toxicity to normal cells. Further studies proved that 10 significantly enhanced intracellular Pt accumulation and DNA damage, perturbed mitochondrial membrane potential, inhibited cell migration and invasion, upregulated reactive oxygen species levels, and induced apoptosis and autophagic cell death. Molecular docking assay revealed that 10 fits perfectly into the extracellular signal-regulated protein kinase (ERK)-1 pocket, which was verified to produce profound ERK suppression. Most strikingly, compound 10 exhibited superior in vivo antitumor efficiency and effectively attenuated systemic toxicity. Our results emphasize that functionalizing platinum drugs with the multi-target EVO could generate synergistically excellent anticancer activity with low toxicity and decreased resistance, which may represent a brand-new cancer therapy modality.

Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by genetic signals or drug interventions. Meanwhile, RCD is closely related to the occurrence and therapy of multiple human cancers. Generally, RCD subroutines are the key signals of tumorigenesis, which are contributed to our better understanding of cancer pathogenesis and therapeutics. Indole alkaloids derived from natural sources are well defined for their outstanding biological and pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, and 3,3'-diindolylmethane, which are currently used in the clinic or under clinical assessment. Moreover, such compounds play a significant role in discovering novel anticancer agents. Thus, here we systemically summarized recent advances in indole alkaloids as anticancer agents by targeting different RCD subroutines, including the classical apoptosis and autophagic cell death signaling pathways as well as the crucial signaling pathways of other RCD subroutines, such as ferroptosis, mitotic catastrophe, necroptosis, and anoikis, in cancer. Moreover, we further discussed the cross talk between different RCD subroutines mediated by indole alkaloids and the combined strategies of multiple agents (e.g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy., (© 2022. The Author(s).)

The combination therapy with different treatment modalities has been widely applied in the clinical applications of cancer treatment. However, it stills a considerable challenge to achieve co-delivery of different drugs because of distinct drug encapsulation mechanisms, low drug loading, and high excipient-related toxicity. Cancer stem cells (CSCs) are closely related to tumor metastasis and recurrence due to high chemoresistance. Herein, we report a stimuli-responsive and tumor-targeted small-molecule self-assembled nanodrug for the combination therapy against CSCs and normal cancer cells. The hydrophobic differentiation-inducing agent (all-trans retinoic acid, ATRA) and hydrophilic anticancer drug (irinotecan, IRI) constitute this amphiphilic nanodrug, which could self-assemble into stable nanoparticles and encapsulate the photothermal agent IR825. Upon cellular uptake, this nanodrug display good release profiles in response to acid and esterase microenvironments by ester linkage. The released drugs not only increase chemotherapy sensitivity by the differentiation of CSCs into non-CSCs, but also exhibit superior cytotoxicity in cancer cells. In addition, IR825 within this nanodrug enables in vivo fluorescence/photoacoustic (PA) imaging allowing for tracking drug distribution. Moreover, the DSPE-PEG-RGD-functionalized nanodrug displayed high tumor accumulation and good biocompatibility, enabling efficient inhibition of tumor growth and tumor metastasis in tumor-bearing mice., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Thymoquinone (TQ) has been reported as an anti-tumour drug widely studied in various tumours, and its mechanism and effect of which has become a focus of current research. However, previous studies from our laboratory and other groups found that TQ showed weak anti-tumour effects in many cancer cell lines and animal models. Therefore, it is necessary to modify and optimize the structure of TQ to obtain new chemical entities with high efficiency and low toxicity as candidates for development of new drugs in treating cancer. Therefore, we designed and synthesized several TQ derivatives. Systematic analysis, including in vitro and in vivo, was conducted on a panel of triple-negative breast cancer (TNBC) cells and mouse model to demonstrate whether TQFL12, a new TQ derivative, is more efficient than TQ. We found that the anti-proliferative effect of TQFL12 against TNBC cells is significantly stronger than TQ. We also demonstrated TQFL12 affects different aspects in breast cancer development including cell proliferation, migration, invasion and apoptosis. Moreover, TQFL12 inhibited tumour growth and metastasis in cancer cell-derived xenograft mouse model, with less toxicity compared with TQ. Finally, mechanism research indicated that TQFL12 increased AMPK/ACC activity by stabilizing AMPKα, while molecular docking supported the direct interaction between TQFL12 and AMPKα. Taken together, our findings suggest that TQFL12, as a novel chemical entity, possesses a better inhibitory effect on TNBC cells and less toxicity in both in vitro and in vivo studies. As such, TQFL12 could serve as a potential therapeutic agent for breast cancer., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

A polysaccharide (ESPS) purified from Eupolyphaga sinensis Walker by ion exchange chromatography and gel chromatography was investigated, including its structure characterization and antitumor activity. The results showed that ESPS was composed of rhamnose, fucose, arabinose, xylose, glucose, and galactose in a molar ratio of 7.4: 3.1: 13.9: 9.3: 39.7: 26.5, with the mean weight (Mw) of 2.14 × 10 4 Da; the main chain of ESPS was mainly composed of → 4) - α - D - Glcp - (1 → and → 3) - β - D - Galp - (1 →, and the side chains were connected to the main chain through the O-6 atom of glucose and O-4 and O-6 atom of galactose. In addition, ESPS promoted the lymphocyte proliferation and inhibited liver cancer cells growth through enhancing lymphocyte activity in vitro, mainly NK cells. Moreover, ESPS markedly stimulated immunity in H22-bearing mice by increasing the spleen and thymus indices and effectively inhibited H22 cell growth in vivo. These data indicated that ESPS was a polysaccharide component possessing high anti-hepatocellular carcinoma activity, representing a potential immunotherapy candidate for the treatment of liver cancer., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists in the present study., (Copyright © 2020. Published by Elsevier B.V.)

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the cause of high rate of mortality. The epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors are used to treat NSCLC, yet their curative effects are usually compromised by drug resistance. This study demonstrates a nanodrug for treating tyrosine-kinase-inhibitor-resistant NSCLC through inhibiting upstream and downstream EGFR signaling pathways. The main molecule of the nanodrug is synthesized by linking a tyrosine kinase inhibitor gefitinib and a near-infrared dye (NIR) on each side of a disulfide via carbonate bonds, and the nanodrug is then obtained through nanoparticle formation of the main molecule in aqueous medium and concomitant encapsulation of a serine threonine protein kinase (Akt) inhibitor celastrol. Upon administration, the nanodrug accumulates at the tumor region of NSCLC-bearing mice and releases the drugs for tumor inhibition, and the dye for fluorescence and optoacoustic imaging. Through suppressing the phosphorylation of upstream EGFR and downstream Akt in the EGFR pathway by gefitinib and celastrol, respectively, the nanodrug exhibits high inhibition efficacy against orthotopic NSCLC in mouse models., (© 2020 Wiley-VCH GmbH.)

The clinical application of mitoxantrone (MTZ), a DNA-intercalating topoisomerase II (topo II) poison, has been largely limited by the risk of secondary tumor and severe myelosuppression. To develop more effective antineoplastic agents with less toxicity, a spectrum of anthraquinone analogues of MTZ were herein designed and synthesized based on the concept of 'enhancing protein backbone-binding', by rationally introducing hydrophobic long fatty acid chain (LFC) and hydrophilic polyamine (PA) components, which are reported to function as effective tumor-targeting tethers. The SAR exploration implicated that in our synthesized molecules, the introduction of both lipophilic LFC and hydrophilic PA fragment is plausibly beneficial to the anti-proliferative potency, with a certain degree of selectivity between the hematopoietic and solid malignant cells, which still need to be further accurately confirmed. Meanwhile, many compounds, the LFC-tethered 5d 2 and PA-bridged 8c in particular, provided satisfactory topo IIα inhibition by acting as DNA non-intercalators, largely attributable to their strong adaptability to three binding regions (pocket I, II and III) and also the generated H-bonding interactions between inhibitors and key residues of topo IIα. In brief, 5d 2 and 8c might be promising hits for further exploitation of more potent topo IIα inhibitors., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bioorthogonal bond-cleavage reactions have emerged as promising tools for manipulating biological processes, still the therapeutic effect of these reactions in vivo needs to be explored. Herein a bioorthogonal-activated prodrug has been developed for bioimaging and therapy, which is composed of a Pd-mediated cleavable propargyl, a coumarin fluorophore and a potent anticancer drug. In vitro investigations show that, the presence of a Pd complex induces the cleavage of propargyl and subsequently trigger the cascade of reactions, thereby activating the coumarin fluorophore for imaging and releasing the anticancer drug for therapy. Both the prodrug and Pd complex were then separately encapsulated into phospholipid liposomes to form a two-component bioorthogonal nanosystem. The lyposomal nanosystem can be readily internalized by HeLa cells and displays strong intracellular fluorescence under one- or two-photon excitation, indicating the release of the active drug in cells as a result of the Pd-mediated bioorthogonal bond-cleavage reaction. More importantly, the nanosystem shows considerable high activity and exerts efficient inhibition towards tumor growth in a mouse model. This work demonstrates that, if properly formulated, a bioorthogonal system can perform well in vivo. This strategy may offer a new approach for designing bioorthogonal prodrugs with imaging and therapeutic capability., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To analyze the kinase mutation ratio, related factors, effectiveness and safety of the second generation drugs for imatinib-resistant patients with chronic myeloid leukemia(CML)., Methods: COX proportional hazard regression model was used for unvariate and multvariate analysis of various factors affecting the kinase mutation and for evaluating the effectiveness and safety of second generation tyrosine kinase inhibitor(TKI)., Results: 13 kinds of mutation were detected in 19 out of 42 cases for 22 times, including 4 times of F359V, 3 times of E255K, 2 time for F359C, F317L, T315I, Y253H, 1 time for D256R, C250R, D276G, F486S, M244V, Y256H and G250E, 3 cases with mixed mutations. The main adverse effects of patients receiving nilotinib were skin rash and fluid retention, while that for patients receiving dasatinib were eyelid edema and elevated bilirubin., Conclusion: The WBC count, spleen enlargement degree, chromosome karyotypes, disease staging, drug used before treatment and time of acheiving CCyR are the related factors of the kinase mutations, but the patients receiving the second generation TKI can survive well.

Chemical investigation of the cultures of marine Streptomyces sp. 182SMLY led to the discovery of two new polycyclic anthraquinones, which were elucidated as N-acetyl-N-demethylmayamycin (1) and streptoanthraquinone A (2) based on the extensive spectroscopic analysis including 2D NMR, HRESIMS, and an electronic circular dichroism (ECD) calculation. Both anthraquinones remarkably suppressed the proliferation of four different glioma cell lines with IC50 values in a range from 0.5 to 7.3 μM and induced apoptosis in the glioma cells. The ratios of IC50 for normal human astrocytes to IC50 for glioma cells were 6.4-53 for 1 and >14-31 for 2. N-acetyl-N-demethylmayamycin (1) also inhibited the growth of methicillin-resistant Staphylococcus aureus with MIC 20.0 μM.

Background: Whether sulfated saponins from Holothuria moebii inhibit the proliferation of colorectal cancer cells and have anti-colorectal tumor effects in animal model has not been investigated., Purpose: To evaluate the cytotoxic and anti-colorectal tumor effects of sulfated saponins from sea cucumber Holothuria moebii., Method: (1) Column chromatography was used to prepare the total and individual saponins and HPLC was applied to define the components of the total saponins; (2) the activity of the total and individual saponins inhibiting the proliferation of human colorectal cancer cells was determined by SRB assay and the apoptosis induced by the saponins was qualified using cytometric analysis with Annexin V-FITC/PI double staining; and (3) the antitumor effects of the sulfated saponins on colorectal CT-26 tumor-bearing Balb/c mice were tested., Results: The total and individual sulfated saponins significantly inhibited the proliferation of four different human colorectal cancer cells with IC50 values ranging from 1.04 to 4.08 μM (or 1.46 to 3.24 μg/ml for total saponins) and induced late apoptosis at an early treatment time in cancer cells. The total saponins (120 mg/kg) had antitumor activity in colorectal CT-26 tumor-bearing Balb/c mice., Conclusion: The sulfated saponins from H. moebii remarkably inhibited the proliferation of different human colorectal cancer cells and had significant anti-colorectal tumor activity in animal model., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Maintaining the self-renewal of embryonic stem cells (ESCs) could be achieved by activating the extrinsic signaling, i.e., the use of leukemia inhibitory factor (LIF), or blocking the intrinsic differentiation pathways, i.e., the use of GSK3 and MEK inhibitors (2i). Here we found that even in medium supplemented with LIF, mESCs still tend to differentiate toward meso-endoderm lineages after long-term culture and the culture spontaneously secretes vascular endothelial growth factors (VEGFs). Blocking VEGF signaling with sunitinib, an anti-cancer drug and a receptor tyrosine kinase (RTK) inhibitor mainly targeting VEGF receptors (VEGFRs), is capable of maintaining the mESCs in the undifferentiated state without the need for feeder cells or LIF. Sunitinib facilitates the derivation of mESCs from blastocysts, and the mESCs maintained in sunitinib-containing medium remain pluripotent and are able to contribute to chimeric mice. Sunitinib also promotes iPSC generation from MEFs with only Oct4. Knocking down VEGFR2 or blocking it with neutralizing antibody mimicks the effect of sunitinib, indicating that blocking VEGF/VEGFR signaling is indeed beneficial to the self-renewal of mESCs. We also found that hypoxia-inducible factor alpha (HIF1α) and endoplasmic reticulum (ER) stress are involved in the production of VEGF in mESCs. Blocking both pathways inhibits the expression of VEGF and prevents spontaneous differentiation of mESCs. Interestingly, LIF may also exert its effect by downregulating HIF1α and ER stress pathways and subsequent VEGF expression. These results indicate the existence of an intrinsic differentiation pathway in mESCs by activating the autocrine VEGF signaling. Blocking VEGF signaling with sunitinib or other small molecules help to maintain the mESCs in the ground state of pluripotency.

We found that artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells. ART arrested the cell cycle in the G2/M phase, which was accompanied by an upregulation of p21. ART upregulated the expression of Beclin1, an initiator of autophagy (type II programmed cell death). In addition, ART stimulated the aggregation of LC3, which is considered to be a marker of autophagosome formation. We further verified the transformation of LC3 from type I into type II. 3-MA, a classical autophagy inhibitor, attenuated ART-induced autophagosome formation, cell growth repression, G2/M arrest, and p21 upregulation. Autophagy induction and p21 upregulation were also repressed by knockdown of Beclin1. Furthermore, ART sensitized breast cancer cells to the chemotherapeutic agent epirubicin through an autophagy-dependent cascade. Our study showed that ART induced autophagy in breast cancer cells and indicated that the anticancer effects of ART were exerted through an autophagy pathway. Moreover, ART sensitized breast cancer cells to epirubicin chemotherapy. Our results provide a basis for further development of ART as a novel therapeutic agent for the treatment of breast cancer.

Background: Cancer relapse, associated with increased drug resistance and rate of metastasis, often follows completion of chemotherapy but the cancer escape mechanisms are still incompletely understood. Percutaneous ethanol injection (PEI) has been used for treating hepatocellular carcinoma (HCC) for decades, while the recurrence after PEI treatment remains a major limitation. Recent evidence mounted that cancer cells could survive from chemical induced apoptosis, suggesting a potential route through which cancer relapse may occur. This study focuses on the consequence of HepG2 recovery from ethanol-induced apoptotic event., Methods: The model of HepG2 recovery from ethanol-induced apoptotic event was established by live cell imaging, BrdU assay and Western blotting. MTT assay, wound healing assay and invasion assay were used to investigate the behavior of HepG2 after recovery., Results: HepG2 cells could recover from ethanol-induced apoptosis. These cells changed their behaviors such as drug resistance, mobility and invasiveness. On average, the recovered HepG2 cell clones were found to be 46% more resistant to ethanol and 84% higher in mobility. The recovered clones became 58.2% more sensitive to 5-fluorouracil., Conclusions: HepG2 cells can recover from ethanol-induced apoptotic event. These cells became more resistant to ethanol and more invasive. Although the recovered cell clones were more resistant to ethanol, they became more sensitive to 5-fluorouracil treatment.

Recent studies suggested that the ovarian cancers with negative excision repair cross-complementation group 1 enzyme (ERCC1) expression have a better response to platinum-based chemotherapy than those with positive ERCC1 expression. The objective of this study was to evaluate whether ERCC1 expression is associated with response to platinum-based chemotherapy in ovarian cancers. MEDLINE, PubMed, Web of Science and CNKI databases were used for searching studies relating to ERCC1 protein expression and response to platinum-based chemotherapy in ovarian cancers. Statistical analysis was based on the method for a fixed effects meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals for ERCC1 protein expression and response to platinum- based chemotherapy were generated. Publication bias was investigated with Begg's test. Five studies involving 306 patients with ovarian cancer were included. Compared to patients with positive ERCC1 expression, those with negative ERCC1 expression had a better response to platinum-based chemotherapy. The pooled OR was 5.264 (95% CI: 2.928 - 9.464, P < 0.001) and publication bias was not found (P = 0.904). The result was similar in both in Asians and Caucasians (P < 0.001 and P = 0.028, respectively). ERCC1 protein expression status is significantly associated with response to platinum-based chemotherapy in ovarian cancers.

Novel chondroitin sulfate A conjugated doxorubicin (CSA-DOX) was synthesized and characterized. The mean diameter of CSA-DOX was 152 nm analyzed by dynamic light scattering (DLS). Further, DOX was physically encapsulated into the CSA-DOX nanoparticles. Total amounts of DOX in three kinds of DOX-loaded CSA-DOX (CSA-DOX/DOX) nanoparticles were from 21.8 to 24.2%. The mean diameters of three CSA-DOX/DOX nanoparticles were in the range of 167–177 nm. The shape of CSA-DOX/DOX nanoparticles was almost spherical. DOX released from DOX-loaded nanoparticles exhibited a biphasic way in phosphate buffered saline (PBS, pH 7.4). Cellular uptake studies exhibited that CSA-DOX and CSA-DOX/DOX nanoparticles could enhance the uptake of DOX into CD44 receptor-positive A549 cells. Moreover, the cytotoxicity of CSA-DOX/DOX nanoparticles against A549 cells significantly improved in contrast with free DOX and CSA-DOX nanoparticles. These results suggested that CSA-DOX copolymer could be a potential carrier for antitumor drug delivery. [ABSTRACT FROM AUTHOR]

Objective: To investigate the potential mechanisms that curcumin reverses 5-fluorouracil (5-FU) multidrug resistance (MDR). Methods: Cell growth and the inhibitory rate of curcumin (2–25 μg/mL) and/or 5-FU (0.05–1000 μg/mL) on human colon cancer HCT-8 and HCT-8/5-FU (5-FU-resistant cell line) were determined using cell counting kit-8 (CCK-8) assay. Apoptosis and cell cycle after 5-FU and/or curcumin treatment were detected by flow cytometry (FCM) and transmission electron microscopy (TEM). The expression of the multidrug resistance related factors p-glycoprotein (P-gp) and heat shock protein 27 (HSP-27) genes and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting (WB), respectively. Results: The inhibitory rate of curcumin or 5-FU on HCT-8 and HCT-8/5-FU cells proliferation at exponential phase were in a dosedependent manner, HCT-8 cell line was more sensitive to curcumin or 5-FU when compared the inhibitory rate of HCT-8/5-FU. The 50% inhibitory concentration (IC50) of combination 5-FU and curcumin (4.0 μg/mL) in HCT-8/5-FU was calculated as 179.26 μg/mL, with reversal fold of 1.85. Another IC50 of combination 5-FU and curcumin (5.5 μg/mL) in HCT-8/5-FU was calculated as 89.25 μg/mL, with reversal fold of 3.71. Synergistic effect of 5-FU and curcumin on HCT-8 and HCT-8/5-FU cells were found. The cell cycle analysis performed by FCM showed that HCT-8 and HCT-8/5-FU cells mostly accumulated at G0/G1 phase, which suggested a synergistic effect of curcumin and 5-FU to induce apoptosis. FCM analysis found that the percentage of apoptosis of cells treated with curcumin, 5-FU and their combination were significantly increased compared to the control group (P<0.05), and the percentage of apoptosis of the combination groups were slightly higher than other groups (P<0.05). The mRNA levels of P-gp (0.28±0.02) and HSP-27 (0.28±0.09) in HCT-8/5-FU cells treated with combination drugs were lower than cells treated with 5-FU alone (P-gp, 0.48±0.07, P=0.009; HSP-27, 0.57±0.10, P=0.007). The protein levels of P-gp (0.25±0.06) and HSP-27 (0.09±0.02) in HCT-8/5-FU cells treated with combination drugs were decreased when compared to 5-FU alone (P-gp, 0.46±0.02, P=0.005; HSP-27, 0.43±0.01, P=0.000). Conclusions: Curcumin can inhibit the proliferation of human colon cancer cells. Curcumin has the ability of reversal effects on the multidrug resistance of human colon cancer cells lines HCT-8/5-FU. Down-regulation of P-gp and HSP-27 may be the mechanism of curcumin reversing the drug resistance of HCT-8/5-FU to 5-FU. [ABSTRACT FROM AUTHOR]

The expression of ubiquitin specific peptidase 22 (USP22) is upregulated in several types of cancer, and has been implicated in tumorigenesis. Pirarubicin (THP), an anthracycline antineoplastic drug, can induce apoptosis of several types of cancer cells. However, the molecular mechanisms underlying the action of THP remain to be elucidated. In the current study, treatment with THP induced HeLa cell apoptosis and decreased USP22 expression in a dose- and time-dependent manner. THP reduced the USP22 promoter-regulated luciferase activity, regardless of the mutation of transcriptional activator MYB or E3 ubiquitin-protein ligase SP1 binding sequences; however, this effect was abrogated by the mutation of cyclic AMP-responsive element-binding protein (CREB) binding sequence in HeLa cells. Furthermore, the inhibition on the USP22 promoter activity by THP was not affected by overexpression of CREB-1 in HeLa cells. Additionally, treatment with THP significantly decreased the phosphorylation of CREB-1 at ser133 in HeLa cells. Quantitative chromatin immunoprecipitation assay revealed that THP significantly inhibited the binding of CREB-1 to the USP22 promoter in HeLa cells. The present study demonstrated that THP decreased USP22 expression and promoted HeLa cell apoptosis partially by inhibiting the phosphorylation of CREB-1. The current results may provide novel insights into the molecular mechanisms underlying the pharmacological effect of THP on cancer cell apoptosis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most prevalent fatal diseases and the incidence of HCC is increasing worldwide. Polymeric micelles with targeting groups have drawn great attention as carriers for drug delivery in HCC therapy. Herein, novel glycyrrhetinic acid modified gelatin (GA-GEL) conjugates with three substitution degrees were synthesized and characterized. Doxorubicin (DOX) was applied as a model drug. DOX-loaded GA-GEL (DOX/GA-GEL) micelles were prepared by an emulsion-solvent evaporation method. The mean diameters of DOX/GA-GEL micelles were in the range of 195–235 nm. The encapsulation efficiency of DOX/GA-GEL micelles was 63.6%–96.2%, and the loading content was 8.3%–12.5%. Drug release from DOX-loaded micelles exhibited a biphasic manner in phosphate buffer solution (PBS) at pH 7.4. DOX/GA-GEL could be efficiently accumulated into human liver cancer HepG2 cells. The IC50 values of DOX/GA-GEL-2 and DOX·HCl in HepG2 cells were 0.33 and 0.66 μg/mL, respectively. In vivo imaging analysis demonstrated that the fluorescence signals of DiR-labeled GA-GEL-2 micelles were mainly distributed in liver and H22 orthotopic tumor, indicating that GA-GEL had the liver-targeting activity. Compared to DOX·HCl, DOX/GA-GEL-2 exhibited better antitumor activity in H22 orthotopic mice. Therefore, these results indicated that GA-GEL could be used as carrier of hydrophobic drug for targeting HCC. [ABSTRACT FROM AUTHOR]

The polysaccharide SEP has been reported to activate NK and T cells via TLR2/4. Here, the combination of gemcitabine (GEM) and SEP against HepG-2 was investigated. SEP apparently enhanced antitumor activity of gemcitabine against liver cancer through stimulating NKG2D and DAP10/Akt pathway to activate NK cells. The NKG2D upregulation could improve the sensitivity of NK-92 cells targeting to its ligand MICA expressed on HepG-2 cells. Meanwhile, GEM up-regulated MICA expression and attenuated soluble MICA secretion through inhibiting ADAM10 expression, which in turn enhanced the cytotoxicity of NK-92 cells against cancer cells. SEP remarkably enhanced GEM antitumor activity with an inhibitory rate of 79.1% in an H22-bearing mouse model. Moreover, SEP reversed atrophy and apoptosis caused by GEM in both spleen and bone marrow through suppressing ROS secretion in vivo. The data indicated that the combination of SEP and GEM is a potential chemo-immunotherapy strategy for liver cancer treatment clinically. [ABSTRACT FROM AUTHOR]

For folate receptor (FR) targeted anticancer therapy, novel folic acid (FA) conjugated cholesterol-modified glycol chitosan (FCHGC) micelles were synthesized and characterized by ¹H NMR, dynamic light scattering, transmission electron microscopy, and fluorescence spectroscopy. The degree of substitution was 1.4 FA groups and 7.7 cholesterol groups per 100 sugar residues of glycol chitosan. The critical aggregation concentration of FCHGC micelles in aqueous solution was 0.0169mg/ml. The doxorubicin (DOX)-loaded FCHGC (DFCHGC) micelles were prepared by an emulsion/solvent evaporation method. The DFCHGC micelles were almost spherical in shape and their size increased from 282 to 320 nm with the DOX-loading content increasing from 4.53 to 11.4%. DOX released from DOX-loaded micelles displayed sustained release behavior. The targeted micelles encapsulated DOX showed significantly greater cytotoxicity against FR-positive HeLa cells than the nontargeted DOX-loaded micelles and free DOX. These results suggested that FCHGC micelles could be a potential carrier for targeted drug delivery. [ABSTRACT FROM AUTHOR]

In this study, 5-fluorouracil-1-acetic acid was chemically conjugated with poly(glycerol-sebacate) (PGS) to form a unitary polymer poly(glycerol-sebacate- (5-fluorouracil-1-acetic acid)) (PGS-5-FU-CH2COOH). The structure, the in vitro antitumor activity of 5-FU-CH2COOH, the in vitro degradation, the drug release, and antitumor activity as well as the in vivo degradation and tissue biocompatibility of PGS-5-FU-CH2COOH were investigated. The 5-FU-CH2COOH inhibited HeLa (human cervical cancer cell line) and SGC-7901 (human gastric adenocarcinoma cell line) tumor cells with a half maximal inhibitory concentration (IC50) of 0.196 and 0.267 μM, respectively, after a 3-day incubation. The in vitro drug release profiles of PGS-5-FU-CH2COOH exhibited a biphasic release with an initial exponential phase in the first week and then the second constant linear phase. An in vitro antitumor assay of the PGS-5-FU-CH2COOH polymer showed significant cytotoxicity against tumor cells. The implanted PGS-5-FU-CH2COOH degraded completely in 1 month after implantation. The antitumor activity and improved drug release profile of PGS-5-FU-CH2COOH indicate its potential as an implantable polymer for cancer therapy. [ABSTRACT FROM PUBLISHER]

Pancreatic cancer is a devastating disease characterized by low sensitivity to conventional chemotherapeutic treatment that has a poor prognosis. Therefore, novel effective chemotherapeutic regimens need to be developed. In this study, we analyzed the combined cytotoxic effect of triptolide and hydroxycamptothecin (HCPT) on pancreatic cancer cell line PANC-1 by using 3-(4.5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) and fluorescence- activated cell sorting (FACS) assays. Our results showed that the sensitivity of a combined therapy using triptolide and HCPT was higher than that of triptolide or HCPT alone and that activation of caspase-9/caspase-3 and inhibition of nuclear factor-kappaB (NF-κB) signaling pathway may contribute to the synergistic cytotoxic effect of this combination therapy. Therefore, our observations provided evidence supporting the clinical applications of the combination chemotherapy using triptolide and HCPT for treating pancreatic cancer. [ABSTRACT FROM AUTHOR]