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Marine natural products and their analogues have as of now been acknowledged as an important source of bioactive molecules for the treatment of cancer. Rubrolides, a unique group of γ -butenolides derived from marine microorganisms, have shown strong cytotoxic activity against various tumor cells. In this study, we synthesized and characterized 21 rubrolide analogues (including 16 new compounds) and investigated their antitumor activities in order to screen more active molecules and elucidate their mechanism of action. Primary MTT assay showed that compounds 1 and 4 - 9 all exhibited excellent antiproliferative activities. In particular, compound 7 showed broad-spectrum cytotoxic activity against six tumor cell lines, with IC 50 values mostly ranging from 2.5 to 0.2 μM. Further mechanistic studies revealed that compound 7 could penetrate HCT116 and Hela cells, localize in the endoplasmic reticulum, and upregulate the PERK-eIF2α-CHOP pathway, inducing ER stress and increasing intracellular reactive oxygen species (ROS) levels to ultimately trigger apoptosis in tumor cells. Additionally, compound 7 was found to upregulate Cyclin B1 protein expression, causing cell cycle reticulum at the G 2 /M phase. In vivo studies further demonstrated that liposomal delivery of compound 7 exhibited a potent antitumor efficacy against Hela xenograft tumors. Based on these results, marine-derived rubrolide analogues show significant potential as novel lead compounds for antitumor drug development.

A total of 19 resveratrol derivatives, including 12 imines and 7 amines, were synthesized, among which compounds 1, 5, 6, 7', 11', and 13 are new compounds. The anti-inflammatory and antitumor activities of these compounds were evaluated in vitro. The results revealed that compounds 1, 6, 8', 12, and 12' exhibited significant inhibitory effects (> 50%) on NO production at the concentration of 10 μM and their NO production inhibitory activities have a significant concentration-dependent ability. Additionally, compounds 8' and 12' showed promising COX-2 inhibitory activity, and the molecular docking analysis indicated their stable binding to multiple amino acid residues within the active pocket of COX-2 through hydrogen bonding. Moreover, compound 12' exhibited inhibitory effects on various tumor cell lines and induced apoptosis in MCF-7 breast cancer cells, which was not observed with resveratrol alone. Therefore, the N-substituted structural modification of resveratrol would have possibly enhanced the bioactivity of resveratrol and facilitated its application., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

A plethora of studies have reported the associations between microbiota and multiple diseases, leading to the development of at least four databases to demonstrate microbiota-disease associations, i.e., gutMDisorder, mBodyMap, Gmrepo, and Amadis. Moreover, gut microbiota mediates drug efficacy and toxicity, whereas a comprehensive database to elucidate the microbiota-drug associations is lacking. Here, we report an open-access knowledge base, MADET (Microbiomics of Anticancer Drug Efficacy and Toxicity), which harbors 483 manually annotated microbiota-drug associations from 26 studies. MADET provides user-friendly functions allowing users to freely browse, search, and download data conveniently from the database. Users can customize their search filters in MADET using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy), and cancer type (e.g., lung cancer) with different types of experimental evidence of microbiota-drug association and causation. We have also enabled user submission to further enrich the data documented in MADET. The MADET database is freely available at https://www.madet.info. We anticipate that MADET will serve as a useful resource for a better understanding of microbiota-drug associations and facilitate the future development of novel biomarkers and live biotherapeutic products for anticancer therapies. IMPORTANCE Human microbiota plays an important role in mediating drug efficacy and toxicity in anticancer treatment. In this work, we developed a comprehensive online database, which documents over 480 microbiota-drug associations manually curated from 26 research articles. Users can conveniently browse, search, and download the data from the database. Search filters can be customized using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy), and cancer type (e.g., lung cancer), with different types of experimental evidence of microbiota-drug association. We anticipate that this database will serve as a convenient platform for facilitating research on microbiota-drug associations, including the development of novel biomarkers for predicting drug outcomes as well as novel live biotherapeutic products for improving the outcomes of anticancer drugs.

Over the last decade, mounting evidence has revealed the key roles of gut microbiota in modulating the efficacy and toxicity of anticancer drugs, via mechanisms such as immunomodulation and microbial enzymatic degradation. As such, human microbiota presents as an exciting prospect for developing biomarkers for predicting treatment outcomes and interventional approaches for improving therapeutic effects. In this review, we analyze the current knowledge of the interplays among gut microorganisms, host responses and anticancer therapies (including cytotoxic chemotherapy and targeted therapy), with an emphasis on the immunomodulation function of microbiota which facilitates the efficacy of immune checkpoint inhibitors. Moreover, we propose several microbiota-modulating strategies including fecal microbiota transplantation and probiotics, which can be pursued to optimize the use and development of anticancer treatments. We anticipate that future clinical and preclinical studies will highlight the significance of human microbiome as a promising target towards precision medicine in cancer therapies. FUNDING: National Key Research and Development Program of China (2020YFA0907800), Shenzhen Science and Technology Innovation Program (KQTD20200820145822023) and National Natural Science Foundation of China (31900056 and 32000096)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The response rate of most anti-cancer drugs is limited because of the high heterogeneity of cancer and the complex mechanism of drug action. Personalized treatment that stratifies patients into subgroups using molecular biomarkers is promising to improve clinical benefit. With the accumulation of preclinical models and advances in computational approaches of drug response prediction, pharmacogenomics has made great success over the last 20 years and is increasingly used in the clinical practice of personalized cancer medicine. In this article, we first summarize FDA-approved pharmacogenomic biomarkers and large-scale pharmacogenomic studies of preclinical cancer models such as patient-derived cell lines, organoids, and xenografts. Furthermore, we comprehensively review the recent developments of computational methods in drug response prediction, covering network, machine learning, and deep learning technologies and strategies to evaluate immunotherapy response. In the end, we discuss challenges and propose possible solutions for further improvement., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nanotechnology is an emerged field to develop the plant mediated metal based nanodrugs by green method. In this current study, the zinc oxide metal based nanoparticles were developed using (Clausena lansium (Lour.) Skeels) Peel aqueous extracts and zinc nitrate. The C.L extract zinc nanoparticleswere indicated by the sharp peak seen at 350 nm utilizing the Ultraviolet-Visible spectroscopy (UV-Vis). The high peaks indicate the presence of phytochemicals and its functional groups in ZnONPs were studied by the Fourier Transform Infrared Spectroscopy (FT-IR). The X-Ray Diffraction analysis (XRD) explores the pattern and structure of ZnONPs as spherical and base-centered monoclinic crystalline shapes. The C.L extract with Zn nanoparticles were spherical in nature and the size of the synthesized particles were about 28.42 nm respectively. The autophagy (Beclin-1, LC3-I, LC3-II and ATG4B) and apoptotic (Bax, Bcl-2 and Caspase-3) proteins were regulated by the treatment with ZnONPs in SH-SY5Y neuroblastoma cells. The DNA loss or damage was occurred in the ZnONPs treatment and it was performed using Comet assay. The ZnONPs treatment generates the ROS in the cells and decreased its stability and viability. Addition of NAC prevents ROS in the cultured SH-SY5Y cells and prevents the cells from the apoptosis. We concluded that the ZnONPs potentially kills the neuroblastoma cells by producing the intracellular ROS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma (HCC) represents a valuable treatment target. Recent studies have developed a highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM concentrations of CZ415 efficiently inhibited survival and induced apoptosis in HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes. Mechanistic studies showed that CZ415 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in HepG2 cells. Meanwhile, activation of mTORC1 (p-S6K1) and mTORC2 (p-AKT, Ser-473) was almost blocked by CZ415. In vivo studies revealed that oral administration of CZ415 significantly suppressed HepG2 xenograft tumor growth in severe combined immuno-deficient (SCID) mice. Activation of mTORC1/2 was also largely inhibited in CZ415-treated HepG2 tumor tissue. Together, these results show that CZ415 blocks mTORC1/2 activation and efficiently inhibits HCC cell growth in vitro and in vivo., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising result in cancer therapy and induces apoptosis in a wide variety of tumor cells, without causing toxicity to normal cells. However, many tumor cells including acute myeloid leukemia (AML) showed certain degrees of resistance to TRAIL and the mechanism remains largely unknown. Embelin is a potent XIAP inhibitor which has been shown to inhibit the proliferation of tumor cells and cause cell apoptosis. In this study, we investigated the effects of Embelin on the TRAIL-induced apoptosis and the underlying mechanism. Here, we chose an adenovirus vector as the expression vector for TRAIL, which was named Ad-TRAIL. The results in vitro showed that the co-treatment of Embelin and Ad-TRAIL has synergistically suppressed the proliferation of AML cells. Embelin has the ability to enhance TRAIL-induced apoptosis and activate caspase pathway. More interestingly, we found that the underlying mechanism for these talent skills of Embelin is through reducing the TRAIL-mediated activation of NF-κB and decreasing its transcriptional activity. Furthermore, our results in vivo suggest that combined therapy of Embelin and Ad-TRAIL caused significant growth inhibition of HL-60 xenograft tumors. Our results suggested that Embelin could sensitize AML cell to TRAIL through the repression of NF-κB signal pathway in vitro and in vivo, and combined therapy of Ad-TRAIL and Embelin may be the attractive candidate for clinical application in treatment of AML.

Eleven cyclic diarylheptanoids were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. 13-Oxomyricanol and myricanone showed the highest activity and also exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that certain diarylheptanoids might be valuable antitumor promoters and/or chemopreventors.