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The Wnt/β-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/β-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/β-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/β-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: To systematically evaluate the efficacy and safety of antiemetic regimen with aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) and provide updated information for clinical practice., Methods: Pubmed, Embase, the Cochrane Library, and 3 Chinese literature databases were systematically searched. Randomized controlled trials comparing standard regimen (5-hydroxytryptamine-3 receptor antagonist and glucocorticoid) with aprepitant triple regimen (aprepitant plus the standard regimen) for preventing CINV were screened. Literature selection, data extraction, and quality evaluation were performed by 2 reviewers independently. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in the meta-analysis using RevMan 5.3 software., Results: A total of 51 randomized controlled trials were finally included in the systematic review. Compared with the standard regimen, the aprepitant triple regimen significantly improved the complete response in the overall (OR 1.88, 95% CI 1.71-2.07), acute (OR 1.96, 95% CI 1.65-2.32) and delayed (OR 1.96, 95% CI 1.70-2.27) phases, regardless of emetogenic risk of chemotherapy. Aprepitant could also significantly enhance the proportions of patients who have no emesis, nausea, or use of rescue medication respectively in the overall, acute and/or delayed phases. Aprepitant was found to be associated with decreased risk of constipation (OR 0.85, 95% CI 0.74-0.97), but increased the incidence of hiccup (OR 1.26, 95% CI 1.05, 1.51). There were no statistically significant differences between the 2 groups on other safety outcomes., Conclusion: The aprepitant triple regimen is effective for the prevention of CINV in patients being treated with moderately or highly emetogenic chemotherapy, and has a significant tendency to reduce the risk of constipation and increase the incidence of hiccup.

Medicinal inorganic chemistry has been largely stimulated by the clinic success of platinum anticancer drugs. An array of metal-based drugs (e.g. platinum, gold, bismuth, and silver) are currently used clinically for the treatment of various diseases. Integrating multiomics approaches, particularly metalloproteomics, with other biochemical characterizations enables comprehensive understanding of cellular responses of metallodrugs, which in turn will guide the rational design of a new drug and modification of the presently used drugs. This review aims to summarize the recent progress in this area. We will describe the technology platforms and their applications for uncovering the mechanisms of action of metallodrugs, for which remarkable advances have been achieved recently. Moreover, we will also highlight the application of newly generated knowledge for the development of novel therapeutic strategies., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.

Histone H3.3 was identified as an arsenic-binding protein of S-dimethylarsino-glutathione (ZIO-101, darinaparsin®) in leukemia cells by GE-ICP-MS. Such a binding results in TRAIL-induced apoptosis. We further validate histone H3.3 as a vital target for ZIO-101, offering new information on the mode of action of arsenic-based anticancer agents.

Stimuli-responsive drug delivery systems have been developed to enhance the tumor-targeting drug transportation and minimize the severe side effects along with the chemotherapy. In this study, a near-infrared (NIR) light triggered drug delivery system was developed based on the amphiphilic chitosan derivative-coated single-wall carbon nanotubes (CNT) encapsulated in the thermo/pH sensitive nanogel (CS/PNIPAAm@CNT). The PEG diacrylate (Mw = 250 Da) was applied in the present work to tune the nanoparticles with the phase transition temperature at ∼ 38 °C, which was an attempt to match the prerequisite for the in vivo applications. Owing to the π-π stacking, hydrophobic interaction and the opportunity of Schiff-base formation between chitosan and doxorubicin (DOX), the nanoparticles possessed a relative high drug loading capacity (∼ 43%). The DOX loaded CS/PNIPAAm@CNT released DOX faster at 40 °C than at 25 °C, meanwhile faster at pH 5.0 in comparison with that at pH 7.4. Moreover, the rapid and repetitive release of DOX was observed when the DOX-loaded CS/PNIPAAm@CNT was irradiated under NIR light. Furthermore, DOX-loaded CS/PNIPAAm@CNT upon NIR irradiation showed significantly greater cytotoxicity in HeLa cells owing to NIR-triggered increase in temperature and enhanced DOX release. Confocal laser scanning microscopy (CLSM) was utilized to demonstrate the enhanced cell uptake of the as prepared nanoparticles and the faster drug release under the NIR irradiation and lower pH. All the results suggest that multifunctional DOX-loaded CS/PNIPAAm@CNT nanocomposite is a promising therapeutic nanocarrier for intracellular drug delivery with great potential for targeted cancer therapy., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

As a novel histone deacetylase inhibitor (HDACi), LAQ824 (LAQ) effectively inhibits the proliferation of hematological malignancies and solid tumors. However, phase II trials of LAQ in solid tumors were terminated due to dose-dependent toxicity. Furthermore, LAQ has been shown to induce the activation of the Notch signaling pathway in hematopoietic stem cells, which is associated with tumor progression and drug resistance in colon and breast cancers. Therefore, in this study, we investigated the strategy of LAQ combined with a Notch signaling pathway inhibitor to treat solid tumors. We used RT-PCR and Western blot methods to demonstrate that LAQ upregulated the Notch signaling pathway in solid tumor cell lines at the molecular level. The combination of LAQ and a Notch signaling pathway inhibitor was shown by a Chou–Talalay assay to have a synergistic effect in inhibiting solid tumor cell line proliferation in vitro. We also demonstrated that the combination of LAQ and a Notch signaling pathway inhibitor significantly inhibited the growth of tumor cells in vivo using an allograft tumor model. This study indicates that inhibition of the Notch signaling pathway provides a valuable strategy for enhancing solid tumor sensitivity to LAQ. [ABSTRACT FROM AUTHOR]

Platinum resistance represents a huge difficulty in ovarian cancer treatment, resulting in disease recurrence and deaths in patients. However, platinum-resistant, recurrent diseases still lack fundamentally effective treatment. Herein, four platinum(IV) (Pt(IV)) prodrugs were developed from the most widely used cisplatin (CisPt) and oxaliplatin (OxaPt), which were subsequently loaded with human serum albumin (HSA) to form nanoparticles (NP1-NP4). We found that NP1, also named Abplatin(iv), showed the best anticancer activity in six ovarian cancer cell lines of various pathological types. Hence, Abplatin(iv) was further evaluated in terms of translational potential. We established patient-derived cells (PDCs) and patient-derived organoids (PDOs) and observed enhanced antitumor effects of Abplatin(iv) in these ex vivo models. Furthermore, in mice bearing orthotopic ovarian cancer, intraperitoneal administration of Abplatin(iv) resulted in targeted drug accumulation in tumors and decreased tumor burden more effectively than CisPt, without causing any detectable side effects. In addition, by analyzing single-cell transcriptome sequencing results, we found a phenotypic shift toward stem-like cells in ovarian cancers undergoing chemotherapy. Therefore, cancer stem cells (SKOV3–3rd) mimicking such persistent tumor cells in postchemotherapeutic residual lesions were established. Abplatin(iv) exhibited a significantly improved antitumor effect on SKOV3–3rd cells both in vitro and in vivo. Finally, RNA sequencing revealed that Abplatin(iv) worked by boosting cell ferroptosis compared with CisPt. Taken together, Abplatin(iv) exhibits low systemic toxicity and high anticancer activity. In particular, it shows robust efficacy against platinum-resistant ovarian cancer derived from patients, indicating its great clinical translation potential. [Display omitted] • Abplatin(iv), an albumin nanoparticle with Pt(IV) prodrugs, exhibits low systemic toxicity and high anti-cancer activity; • Abplatin(iv) boosts cell ferroptosis to improved anti-tumor effect; • Abplatin(iv) holds great clinical translation potential. [ABSTRACT FROM AUTHOR]