Britannin is an active compound derived from Inula japonica Thunb. that possess a wide range of pharmacological activities. However, the mechanism underlying its influence on colorectal cancer (CRC) is not clear. This study aimed to explore the mechanism of britannin in treating colorectal cancer. We employed network pharmacology and single-cell RNA sequencing to assess the potential mechanism of britannin in CRC therapy. In vivo and in vitro experiments were conducted to confirm the effect of britannin on CRC cells and tumor environment. Network pharmacology analysis identified 36 britannin-related genes associated with CRC. Key signaling pathways, including the PI3K-Akt pathway, PD-L1 expression, and HIF-1 signaling, were implicated in britannin's anti-CRC effects. CIBERSORT and scRNA-seq analyses revealed that britannin affects tumor cells, macrophages, and endothelial cells, with a particular impact on macrophage polarization. In vitro assays confirmed that britannin suppressed CRC cell proliferation, promoted apoptosis, and inhibited AKT phosphorylation. In vivo, britannin significantly suppressed tumor growth and modulated the tumor microenvironment by inhibiting M1 macrophage polarization. Britannin may inhibit colorectal by directly inhibiting colon cancer cells and modulating macrophage polarization.

Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.

Britanin is a bioactive sesquiterpene lactone known for its potent anti-inflammatory and anti-oxidant properties. It also exhibits significant anti-tumor activity, suppressing tumor growth in vitro and in vivo. The current body of research on Britanin includes thirty papers predominantly related to neoplasms, the majority of which are gastrointestinal tumors that have not been summarized before. To drive academic debate, the present paper reviews the available research on Britanin in gastrointestinal tumors. It also outlines novel research directions using data not directly concerned with the digestive system, but which could be adopted in future gastrointestinal research. Britanin was found to counteract liver, colorectal, pancreatic, and gastric tumors, by regulating proliferation, apoptosis, autophagy, immune response, migration, and angiogenesis. As confirmed in pancreatic, gastric, and liver cancer, its most commonly noted molecular effects include nuclear factor kappa B and B-cell lymphoma 2 downregulation, as well as Bcl-2-associated X protein upregulation. Moreover, it has been found to induce the Akt kinase and Forkhead box O1 axis, activate the AMP-activated protein kinase pathway, elevate interleukin-2 and peroxisome proliferator-activated receptor-γ levels, reduce interleukin-10, as well as downregulate matrix metalloproteinase-9, Twist family bHLH transcription factor 1, and cyclooxygenase-2. It also inhibits Myc-HIF1α interaction and programmed death ligand 1 transcription by interrupting the Ras/ RAF/MEK/ERK pathway and mTOR/P70S6K/4EBP1 signaling. Future research should aim to unravel the link between Britanin and acetylcholinesterase, mast cells, osteolysis, and ischemia, as compelling data have been provided by studies outside the gastrointestinal context. Since the cytotoxicity of Britanin on noncancerous cells is significantly lower than that on tumor cells, while still being effective against the latter, further in-depth studies with the use of animal models are merited. The compound exhibits pleiotropic biological activity and offers considerable promise as an anti-cancer agent, which may address the current paucity of treatment options and high mortality rate among patients with gastrointestinal tumors.

Apoptosis is a programmed cell death comprising two signaling cascades including the intrinsic and extrinsic pathways. This process has been shown to be involved in the therapy response of different cancer types, making it an effective target for treating cancer. Cancer has been considered a challenging issue in global health. Cancer cells possess six biological characteristics during their developmental process known as cancer hallmarks. Hallmarks of cancer include continuous growth signals, unlimited proliferation, resistance to proliferation inhibitors, apoptosis escaping, active angiogenesis, and metastasis. Sesquiterpene lactones are one of the large and diverse groups of planet-derived phytochemicals that can be used as sources for a variety of drugs. Some sesquiterpene lactones possess many biological activities such as anti-inflammatory, anti-viral, anti-microbial, anti-malarial, anticancer, anti-diabetic, and analgesic. This review article briefly overviews the intrinsic and extrinsic pathways of apoptosis and the interactions between the modulators of both pathways. Also, the present review summarizes the potential effects of sesquiterpene lactones on different modulators of the intrinsic and extrinsic pathways of apoptosis in a variety of cancer cell lines and animal models. The main purpose of the present review is to give a clear picture of the current knowledge about the pro-apoptotic effects of sesquiterpene lactones on various cancers to provide future direction in cancer therapeutics.

Lung cancer is a harmful type of malignancy and the leading cause of cancer-associated mortality. It is therefore imperative to develop novel drugs effective for treating this cancer. The Traditional Chinese Medicine compound Britannin has been previously reported to inhibit the development of certain cancers, such as pancreatic, breast and liver cancer. Moreover, Kruppel-like factor 5 (KLF5) has been identified an on oncogene in lung cancer. In the present study, the possible regulatory effects and underlying mechanism of Britannin in lung cancer were investigated. A549 and 16HBE cells were treated with different concentrations of Britannin. Subsequently, Cell counting kit-8, EdU staining and colony formation assays were used to detect the proliferative ability of these cells. Cell migration was detected by wound healing and Transwell assays, respectively. XF96 extracellular flux analyzer was used to analyze the extent of extracellular acidification and oxygen consumption rate in cells, whereas assay kits were used to detect glucose and lactic acid levels in the cell supernatant. The targeting effect between Britannin and the KLF5 protein was investigated using molecular docking technology. The protein expression levels of KLF5 in cells challenged with Britannin was detected by western blotting. Finally, overexpression of KLF5 in A549 cells was performed before cell proliferation, migration and the glycolysis rate were measured to explore the regulatory effects of Britannin. Britannin was found to inhibit the proliferation, migration and glycolysis of lung cancer cells, during which the protein expression levels of KLF5 were decreased. This suggests that Britannin regulated the expression of KLF5 in A549 cells. Overexpression of KLF5 reversed the inhibitory effects of Britannin on the proliferation, migration and glycolysis in lung cancer cells. In conclusion, these results suggest that Britannin can inhibit cell proliferation, migration and glycolysis by downregulating KLF5 expression in lung cancer cells.

Forkhead box protein 3a (FOXO3a) is a transcription factor that regulates various downstream targets upon its activation, leading to the upregulation of tumor suppressor and apoptotic pathways. Hence, targeting FOXO3a is an emerging strategy for cancer prevention and treatment. Recently, Natural Bioactive Compounds (NBCs) have been used in drug discovery for treating various disorders including cancer. Notably, several NBCs have been shown as potent FOXO3a activators. NBCs upregulate FOXO3a expressions through PI3K/Akt, MEK/ERK, AMPK, and IκB signaling pathways. FOXO3a promotes its anticancer effects by upregulating the levels of its downstream targets, including Bim, FasL, and Bax, leading to apoptosis. This review focuses on the dysregulation of FOXO3a in carcinogenesis and explores the potent FOXO3a activating NBCs for cancer prevention and treatment. Additionally, the review evaluates the safety and efficacy of NBCs. Looking ahead, NBCs are anticipated to become a cost-effective, potent, and safer therapeutic option for cancer, making them a focal point of research in the field of cancer prevention and treatment.

The pharmacological effects of natural product therapy have received sigificant attention, among which terpenoids such as sesquiterpene lactones stand out due to their biological activity and pharmacological potential as anti-tumor drugs. Inula sesquiterpene lactones are a kind of sesquiterpene lactones extracted from Inula species. They have many pharmacological activities such as anti-inflammation, anti-asthma, anti-tumor, neuroprotective and anti-allergic. In recent years, more and more studies have proved that they are important candidate drugs for the treatment of a variety of cancers because of its good anti-tumor activity. In this paper, the structure, structure-activity relationship, antitumor activities, mechanisms and targets of Inula sesquiterpene lactones reported in recent years were reviewed in order to provide clues for the development of novel anticancer drugs.

The above article, published online on 19 September 2022 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/jbt.23211), has been retracted by agreement between the authors, the journal Editor in Chief, Hari Bhat, and Wiley Periodicals, LLC. The article is being retracted at the authors' request because some of the data underlying this article refer to a different cell line from the one reported in it. As a result, the article's conclusions do not accurately reflect the full data and cannot be considered reliable.

Gastric cancer is one of the most common and deadliest malignancies in the world. Therefore, there is an urgent need to develop new and effective agents to reduce mortality. The plants of genus Inula have gained the attention of researchers worldwide as a rich source of potent medicinal compounds.

This study explores the anti-cancer activity of Britannin, a sesquiterpene lactone isolated from Inula aucheriana DC., and its molecular mechanism in gastric cancer cells, AGS and MKN45.

Cytotoxicity was evaluated through the MTT assay following 24 h, 48 h, and 72 h treatment with different concentrations of Britannin. Apoptosis rate and caspase-3 activity were measured 24 h after treatment by Britannin. . Western blotting was performed to determine the expression of the NF-κB, IκBα, and PPARγ proteins. Moreover, quantitative RT-PCR was applied to measure the expression of NF-κB target genes.

We showed that Britannin induced cell growth inhibition and apoptosis in gastric cancer cells. Britannin caused an elevation in mRNA and protein levels of PPARγ. The involvement of PPARγ was more confirmed using GW9662, a PPARγ inhibitor. Suppression of NF-κB was demonstrated by western blot analysis. Down-regulation of MMP-9, TWIST-1, COX-2, and Bcl-2 and up-regulation of Bax were also observed in gastric cancer cells.

These results imply that activation of the PPARγ signaling pathway through suppression of NF-κB underlies the anti-cancer properties of Britannin in gastric cancer. Therefore, Britannin could be considered as a promising anti-cancer candidate for further evaluation.

Britannin, a Sesquiterpene Lactone isolated from Inula aucheriana, has recently gained attraction in the therapeutic fields due to its anti-tumor properties. This study was designed to evaluate the effect of this agent on Acute Lymphoblastic Leukemia (ALL) cell lines, either as a monotherapy or in combination with Vincristine (VCR).

To determine the anti-leukemic effects of Britannin on ALL-derived cell lines and suggest a mechanism of action for the agent, we used MTT assay, Annexin-V/PI staining, ROS assay, and real-time PCR analysis. Moreover, by using a combination index (CI), we evaluated the synergistic effect of Britannin on Vincristine. We found that unlike normal Peripheral Blood Mononuclear Cells (PBMCs) and L929 cells, Britannin reduced the viability of NALM-6, REH, and JURKAT cells. Among tested cells, NALM-6 cells had the highest sensitivity to Britannin, and this agent was able to induce p21/p27-mediated G1 cell cycle arrest and Reactive Oxygen Specious (ROS)-mediated apoptotic cell death in this cell line. When NALM-6 cells were treated with Nacetyl-L-Cysteine (NAC), a scavenger of ROS, Britannin could induce neither apoptosis nor reduce the survival of the cells suggesting that the cytotoxic effect of Britannin is induced through ROS-dependent manner. Moreover, we found that a low dose of Britannin enhanced the effect of Vincristine in NALM-6 cells by inducing apoptotic cell death via altering the expression of apoptotic-related genes.

Overall, our results proposed a mechanism for the cytotoxic effect of Britannin, either as a single agent or in combination with Vincristine, in NALM-6 cells.