Development and validation of a nomogram to predict overall survival in patients with glioma: a population-based study.

AIM: The objective is to investigate the prognostic factors associated with gliomas and to develop and assess a predictive nomogram model connected to survival that may serve as an additional resource for the clinical management of glioma patients. METHOD: From 2010 to 2015, participants included in the study were chosen from the Surveillance Epidemiology and End Results (SEER) database. Gliomas were definitively diagnosed in each of them. They were divided into the training group and the validation cohort at random (7/3 ratio) using a random number table. To identify the independent predictive markers for overall survival (OS), Cox regression analysis was utilized. Subsequently, the training cohort's survival-related nomogram predictive model for OS was created by incorporating the fundamental patient attributes. Following that, the training cohort's model underwent internal validation. The nomogram model's authenticity and reliability were assessed through the computation of receiver operating characteristic (ROC) curves and concordance index (C-index). To evaluate the degree of agreement between the observed and predicted values in the training and validation cohorts, calibration plots were created. RESULT: Age, primary site, histological type, surgery, chemotherapy, marital status, and grade were the independent predictive factors for OS in the training cohort, according to Cox regression analysis. Moreover, the nomogram model for predicting 1-year, 3-year, and 5-year OS was built using these variables. The C-indexes of OS for glioma patients in the training cohort and internal validation cohort were found to be 0.779 (95% CI=0.769-0.789) and 0.776 (95% CI=0.760-0.792), respectively, according to the results. The ROC curves also demonstrated good discrimination. Additionally, calibration plots demonstrated a fair amount of agreement. CONCLUSIONS: In summary, the nomogram prediction model of OS demonstrated a moderate level of reliability in its predictive performance, offering valuable reference data to enable doctors to quickly and easily determine the survival likelihood of patients with gliomas.

Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Virtual screening combined with experimental verification reveals the potential mechanism of Fuzitang decoction against Gouty Arthritis.

Background: and Purpose: Fuzitang decoction (FZT), a classic prescription of traditional Chinese medicine (TCM), has excellent efficacy in treating gouty arthritis (GA). However, the underlying molecular mechanism remains obscure. In the present study, we aimed to explore the underlying mechanisms of FZT in treating GA by virtual screening combined with experimental verification. Methods: In this study, the active components of FZT and their corresponding targets were screened from the TCMSP database and TargetNet database. Then, the potential targets of FZT against GA were retrieved from multiple databases to generate a network. Protein-protein interaction, herbal-component-target, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were applied to identify potential targets and related signaling pathways. Furthermore, molecular docking simulation was applied to identify the interactions between the drug and targets. Finally, in vitro experiments were conducted to validate the potential targets and signaling pathways. Results: In the present study, several crucial components, including kaempferol, luteolin, catechin, deoxyandrographolide, and perlolyrine in FZT, were obtained through network pharmacology, and several potential targets to treat GA were developed, such as PPARG, CYP3A4, PTGS2 (known as COX2), VEGFA, and CYP1A1. Experimental validation suggested that deoxyandrographolide significantly suppressed the expression of IL-1ß, COX2, NLRP3 and IL-6 in inflammatory monocyte cells. Conclusions: Our results identified a novel anti-inflammatory compound, deoxyandrographolide, which helps to explain the potential mechanism of FZT in treating GA and provides evidence to support FZT's clinical use.

Comprehensive analysis of the oncogenic and immunological role of FAP and identification of the ceRNA network in human cancers.

Fibroblast activation protein-alpha (FAP) is a transmembrane serine protease involving in tissue remodeling. Previous studies report that FAP is highly expressed in certain tumors and participated in oncogenesis. However, there is still lack of systematic and in-depth analysis of FAP based on clinical big data. Here, we comprehensively map the FAP expression profile, prognostic outcome, genetic alteration, immune infiltration across over 30 types of human cancers through multiple datasets including TCGA, CPTAC, and cBioPortal. We find that FAP is up-regulated in most cancer types, and increased FAP expression is associated with advanced pathological stages or poor prognosis in several cancers. Furthermore, FAP is significantly correlated with the infiltration of cancer-associated fibroblasts, macrophages, myeloid dendritic cells, as well as endothelia cells. Immunosuppressive checkpoint proteins or cytokines expression, microsatellite instability and tumor mutational burden analysis also indicate the regulation role of FAP in tumor progression. Gene enrichment analysis demonstrates that ECM-receptor interaction as well as extracellular matrix and structure process are linked to the potential mechanism of FAP in tumor pathogenesis. The ceRNA network is also constructed and identified the involvement of LINC00707/hsa-miR-30e-5p/FAP, LINC02535/hsa-miR-30e-5p/FAP, LINC02535/hsa-miR-30d-5p/FAP, as well as AC026356.1/hsa-miR-30d-5p/FAP axis in tumor progression. In conclusion, our study offers new insights into the oncogenic and immunological role of FAP from a pan-cancer perspective, providing new clues for developing novel targeted anti-tumor strategies.

Periplocin inhibits hepatocellular carcinoma progression and reduces the recruitment of MDSCs through AKT/NF-κB pathway.

AIMS: We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS: Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING: Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE: These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.

Therapy resistance in neuroblastoma: Mechanisms and reversal strategies.

Neuroblastoma is one of the most common pediatric solid tumors that threaten the health of children, accounting for about 15% of childhood cancer-related mortality in the United States. Currently, multiple therapies have been developed and applied in clinic to treat neuroblastoma including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, the resistance to therapies is inevitable following long-term treatment, leading to treatment failure and cancer relapse. Hence, to understand the mechanisms of therapy resistance and discover reversal strategies have become an urgent task. Recent studies have demonstrated numerous genetic alterations and dysfunctional pathways related to neuroblastoma resistance. These molecular signatures may be potential targets to combat refractory neuroblastoma. A number of novel interventions for neuroblastoma patients have been developed based on these targets. In this review, we focus on the complicated mechanisms of therapy resistance and the potential targets such as ATP-binding cassette transporters, long non-coding RNAs, microRNAs, autophagy, cancer stem cells, and extracellular vesicles. On this basis, we summarized recent studies on the reversal strategies to overcome therapy resistance of neuroblastoma such as targeting ATP-binding cassette transporters, MYCN gene, cancer stem cells, hypoxia, and autophagy. This review aims to provide novel insight in how to improve the therapy efficacy against resistant neuroblastoma, which may shed light on the future directions that would enhance the treatment outcomes and prolong the survival of patients with neuroblastoma.

Autophagy in Cancer Immunotherapy.

Autophagy is a stress-induced process that eliminates damaged organelles and dysfunctional cargos in cytoplasm, including unfolded proteins. Autophagy is involved in constructing the immunosuppressive microenvironment during tumor initiation and progression. It appears to be one of the most common processes involved in cancer immunotherapy, playing bidirectional roles in immunotherapy. Accumulating evidence suggests that inducing or inhibiting autophagy contributes to immunotherapy efficacy. Hence, exploring autophagy targets and their modifiers to control autophagy in the tumor microenvironment is an emerging strategy to facilitate cancer immunotherapy. This review summarizes recent studies on the role of autophagy in cancer immunotherapy, as well as the molecular targets of autophagy that could wake up the immune response in the tumor microenvironment, aiming to shed light on its immense potential as a therapeutic target to improve immunotherapy.

Evodiamine as the Active Compound of Evodiae fructus to Inhibit Proliferation and Migration of Prostate Cancer through PI3K/AKT/NF-κB Signaling Pathway.

Evodiae fructus (EF) is a traditional Chinese medicine which is widely used for the treatment of obesity, inflammation, cardiovascular disease, and diseases of the central nervous system. Recent studies have demonstrated the anticancer property of EF, but the active compounds of EF against prostate cancer and its underlying mechanism remain unknown. In this study, a network pharmacology-based approach was used to explore the multiple ingredients and targets of EF. Through protein-protein interaction (PPI), Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the potential targets and corresponding ingredients of EF against prostate cancer cells were obtained. CCK8 and colony formation assays were performed to evaluate the antiproliferative effect of the active compounds on DU145 cells. Cell cycle analysis, Annexin V-FITC/PI staining assay, and Hoechst 33258 staining assay were used to explore the way of evodiamine-induced cell death. The capacities of cell migration after evodiamine treatment were evaluated by wound-healing assay. PharmMapper database was used to predict the potential targets of evodiamine against cancer cell migration. Western blot assay was performed to investigate the signaling pathway through which evodiamine inhibits cell proliferation and migration. The binding of evodiamine to PI3K and AKT was verified by molecular docking. As a consequence, 24 active compounds and 141 corresponding targets were obtained through a network pharmacology-based approach. The results of PPI analysis, GO enrichment, and KEGG pathway enrichment indicated that molecules in the PI3K/AKT/NF-κB signaling pathway were the potential targets of EF against prostate cancer, and evodiamine was the potential active compound. In vitro study demonstrated that evodiamine displays antiproliferative effect on DU145 cells obviously. Evodiamine induces G2/M cell cycle arrest by Cdc25c/CDK1/cyclin B1 signaling. Additionally, evodiamine also promotes mitochondrial apoptosis and inhibits cell migration through PI3K/AKT/NF-κB signaling in DU145 cells. In conclusion, evodiamine is the active compound of EF to inhibit proliferation and migration of prostate cancer through PI3K/AKT/NF-κB signaling pathway, indicating that evodiamine may serve as a potential lead drug for prostate cancer treatment.

The MicroRNA-Based Strategies to Combat Cancer Chemoresistance via Regulating Autophagy.

Chemoresistance frequently occurs in cancer treatment, which results in chemotherapy failure and is one of the most leading causes of cancer-related death worldwide. Understanding the mechanism of chemoresistance and exploring strategies to overcome chemoresistance have become an urgent need. Autophagy is a highly conserved self-degraded process in cells. The dual roles of autophagy (pro-death or pro-survival) have been implicated in cancers and chemotherapy. MicroRNA (miRNA) is a class of small non-coding molecules that regulate autophagy at the post-transcriptional level in cancer cells. The association between miRNAs and autophagy in cancer chemoresistance has been emphasized. In this review, we focus on the dual roles of miRNA-mediated autophagy in facilitating or combating chemoresistance, aiming to shed lights on the potential role of miRNAs as targets to overcome chemoresistance.

ß-estradiol Induces Mitochondrial Apoptosis in Cervical Cancer through the Suppression of AKT/NF-κB Signaling Pathway.

BACKGROUND: Cervical cancer is the fourth most prevalent gynecological cancer worldwide, which threatens women's health and causes cancer-related mortality. In the search for effective anticervical cancer drugs, we discovered that ß-estradiol (E2), a potent drug for estrogen deficiency syndrome treatment, displays the most potent cytotoxicity against HeLa cells. OBJECTIVE: This study aims to evaluate the growth inhibitory effect of ß-estradiol on HeLa cells and explore its underlying mechanisms. METHODS: CCK-8 assay was used to evaluate the cytotoxicity of 6 compounds against HeLa cells. Flow cytometric analysis and Hoechst 33258 staining assay were performed to detect cell cycle arrest and apoptosis induction. The collapse of the mitochondrial potential was observed by the JC-1 staining assay. The expression levels of proteins were examined by western blotting. RESULTS: ß-Estradiol, at high concentration, displays potent cytotoxicity against HeLa cells with an IC50 value of 18.71 ± 1.57 µM for 72 h treatment. ß-Estradiol induces G2/M cell cycle arrest through downregulating Cyclin B1 and p-CDK1. In addition, ß-estradiol-induced apoptosis is accompanied by the loss of mitochondrial potential, activation of the Caspase family, and altered Bax/Bcl-2 ratio. ß-Estradiol markedly decreased the expression level of p-AKT and p-NF-κB. CONCLUSION: This study demonstrated that ß-estradiol induces mitochondrial apoptosis in cervical cancer through the suppression of AKT/NF-κB signaling pathway, indicating that ß-estradiol may serve as a potential agent for cervical cancer treatment.

New Insights Into the Regulatory Roles of Extracellular Vesicles in Tumor Angiogenesis and Their Clinical Implications.

Angiogenesis is required for tumor growth and development. Extracellular vesicles (EVs) are important signaling entities that mediate communication between diverse types of cells and regulate various cell biological processes, including angiogenesis. Recently, emerging evidence has suggested that tumor-derived EVs play essential roles in tumor progression by regulating angiogenesis. Thousands of molecules are carried by EVs, and the two major types of biomolecules, noncoding RNAs (ncRNAs) and proteins, are transported between cells and regulate physiological and pathological functions in recipient cells. Understanding the regulation of EVs and their cargoes in tumor angiogenesis has become increasingly important. In this review, we summarize the effects of tumor-derived EVs and their cargoes, especially ncRNAs and proteins, on tumor angiogenesis and their mechanisms, and we highlight the clinical implications of EVs in bodily fluids as biomarkers and as diagnostic, prognostic, and therapeutic targets in cancer patients.

Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential.

Depression is the second most common disease burden worldwide that threatens human health; however, mechanisms underlying the development of depression remain unclear. A family of non-coding RNAs, circular RNAs (circRNAs), has been shown to play a critical role in the development of depression by competitively binding to certain microRNAs (miRNA) and regulating the expression of target genes. Behavioral symptoms of depression may be ameliorated by knockdown or overexpression of depression-associated circRNAs. In this review, we summarized important functions of circRNAs and analyzed the most recent findings regarding the expression and biological function of circRNAs in depression. We discussed novel circRNA-based strategies to illuminate potential therapeutic targets that may aid in the development of new treatments for depression.

Bioinformatics and Network Pharmacology-Based Approaches to Explore the Potential Mechanism of the Antidepressant Effect of Cyperi Rhizoma through Soothing the Liver.

Major depressive disorder (MDD) has become the second most common disease worldwide, making it a threat to human health. Cyperi Rhizoma (CR) is a traditional herbal medicine with antidepressant properties. Traditional Chinese medicine theory states that CR relieves MDD by dispersing stagnated liver qi to soothe the liver, but the material basis and underlying mechanism have not been elucidated. In this study, we identified the active compounds and potential anti-MDD targets of CR by network pharmacology-based approaches. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we hypothesized that the anti-MDD effect of CR may be mediated by an altered response of the liver to lipopolysaccharide (LPS) and glucose metabolism. Through bioinformatics analysis, comparing normal and MDD liver tissue in rats with spontaneous diabetes, we identified differentially expressed genes (DEGs) and selected PAI-1 (SERPINE1) as a target of CR in combating MDD. Molecular docking and molecular dynamics analysis also verified the binding of the active compound quercetin to PAI-1. It can be concluded that quercetin is the active compound of CR that acts against MDD by targeting PAI-1 to enhance the liver response to LPS and glucose metabolism. This study not only reveals the material basis and underlying mechanism of CR against MDD through soothing the liver but also provides evidence for PAI-1 as a potential target and quercetin as a potential agent for MDD treatment.

1ß-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chansu, dried secretions from Bufonidae, has long been used for cancer treatment as a traditional Chinese medicine. In searching for effective anti-hepatoma agents from Chansu, our preliminary drug screening found that a bufadienolide, namely 1ß-hydroxyl-arenobufagin (1ß-OH-ABF), displays anti-hepatoma activities. However, the anti-hepatoma effects and molecular mechanisms of 1ß-OH-ABF have not been defined. AIM OF THE STUDY: To evaluate the anti-hepatoma activity of 1ß-OH-ABF against liver cancer Hep3B and HepG2 cells in vitro and in vivo, as well as explore the underlying mechanisms. MATERIALS AND METHODS: The anti-proliferative effects of 1ß-OH-ABF on liver cancer Hep3B, HepG2, HuH7, SK-HEP-1 and normal hepatocyte LO2 cells were examined by MTT assay and colony formation assay. Hoechst 33258 staining and Annexin V-FITC/PI staining assay were used to analyze apoptosis induced by 1ß-OH-ABF. The collapse of the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining assay. Western blotting was used to examine the expression levels of targeted proteins. The role of mTOR in 1ß-OH-ABF-induced apoptosis was investigated using small interfering RNA (siRNA) transfection. Zebrafish xenograft model was established to evaluate the anti-hepatoma effects of 1ß-OH-ABF in vivo. RESULTS: We found that 1ß-OH-ABF inhibits the proliferation of Hep3B, HepG2, HuH7, SK-HEP-1 cells but has little cytotoxicity towards LO2 cells. 1ß-OH-ABF induces mitochondria dysfunction and triggers mitochondria apoptotic pathway, which is accompanied by the loss of ΔΨm, upregulation and translocation of Bax, as well as cleavages of caspase-9, caspase-3 and PARP. Mechanistically, 1ß-OH-ABF markedly decreases the expression level of p-AKT/AKT and p-mTOR (Ser2248 and Ser2481)/mTOR in a time-dependent manner. Inhibition of mTOR by siRNA strengthens 1ß-OH-ABF-mediated apoptosis. Critically, 1ß-OH-ABF shows a marked in vivo anti-hepatoma effect on human Hep3B cell xenografts in zebrafish model. CONCLUSION: 1ß-OH-ABF induces mitochondrial apoptosis through the suppression of mTOR signaling in vitro and in vivo, indicating that 1ß-OH-ABF may serve as a potential agent for the treatment of liver cancer.

Digitoxin inhibits proliferation of multidrug-resistant HepG2 cells through G2/M cell cycle arrest and apoptosis.

Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed multidrug resistance. Therefore, the identification of efficient chemotherapeutic drugs for multidrug resistant HCC has become an urgent issue. Natural products have always been of significance in drug discovery. In the present study, a cell-based method was used to screen a natural compound library, which consisted of 78 compounds, and the doxorubicin-resistant cancer cell line, HepG2/ADM, as screening tools. The findings of the present study led to the shortlisting of one of the compounds, digitoxin, which displayed an inhibitory effect on HepG2/ADM cells, with 50% inhibitory concentration values of 132.65±3.83, 52.29±6.26, and 9.13±3.67 nM for 24, 48, and 72 h, respectively. Immunofluorescence, western blotting and cell cycle analyses revealed that digitoxin induced G2/M cell cycle arrest via the serine/threonine-protein kinase ATR (ATR)-serine/threonine-protein kinase Chk2 (CHK2)-M-phase inducer phosphatase 3 (CDC25C) signaling pathway in HepG2/ADM cells, which may have resulted from a DNA double-stranded break. Digitoxin also induced mitochondrial apoptosis, which was characterized by changes in the interaction between Bcl-2 and Bax, the release of cytochrome c, as well as the activation of the caspase-3 and -9. To the best of our knowledge, the present study is the first report that digitoxin displays an anti-HCC effect on HepG2/ADM cells through G2/M cell cycle arrest, which was mediated by the ATR-CHK2-CDC25C signaling pathway and mitochondrial apoptosis. Therefore, digitoxin could be a promising chemotherapeutic agent for the treatment of patients with HCC.

Molecular mechanisms of bufadienolides and their novel strategies for cancer treatment.

Bufadienolides are cardioactive C24 steroids with an α-pyrone ring at position C17. In the last ten years, accumulating studies have revealed the anticancer activities of bufadienolides and their underlying mechanisms, such as induction of autophagy and apoptosis, cell cycle disruption, inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and stemness, and multidrug resistance reversal. As Na+/K+-ATPase inhibitors, bufadienolides have inevitable cardiotoxicity. Short half-lives, poor stability, low plasma concentration and oral bioavailability in vivo are obstacles for their applications as drugs. To improve the drug potency of bufadienolides and reduce their side effects, prodrug strategies and drug delivery systems such as liposomes and nanoparticles have been applied. Therefore, systematic and recapitulated information about the antitumor activity of bufadienolides, with special emphasis on the molecular or cellular mechanisms, prodrug strategies and drug delivery systems, is of high interest. Here, we systematically review the anticancer effects of bufadienolides and the molecular or cellular mechanisms of action. Research advancements regarding bufadienolide prodrugs and their tumor-targeting delivery strategies are critically summarized. This work highlights recent scientific advances regarding bufadienolides as effective anticancer agents from 2011 to 2019, which will help researchers to understand the molecular pathways involving bufadienolides, resulting in a selective and safe new lead compound or therapeutic strategy with improved therapeutic applications of bufadienolides for cancer therapy.

MicroRNAs target the Wnt/ß­catenin signaling pathway to regulate epithelial­mesenchymal transition in cancer (Review).

Epithelial­mesenchymal transition (EMT), during which cancer cells lose the epithelial phenotype and gain the mesenchymal phenotype, has been verified to result in tumor migration and invasion. Numerous studies have shown that dysregulation of the Wnt/ß­catenin signaling pathway gives rise to EMT, which is characterized by nuclear translocation of ß­catenin and E­cadherin suppression. Wnt/ß­catenin signaling was confirmed to be affected by microRNAs (miRNAs), several of which are down­ or upregulated in metastatic cancer cells, indicating their complex roles in Wnt/ß­catenin signaling. In this review, we demonstrated the targets of various miRNAs in altering Wnt/ß­catenin signaling to promote or inhibit EMT, which may elucidate the underlying mechanism of EMT regulation by miRNAs and provide evidence for potential therapeutic targets in the treatment of invasive tumors.

Natural products and their derivatives: Promising modulators of tumor immunotherapy.

A wealth of evidence supports the role of tumor immunotherapy as a vital therapeutic option in cancer. In recent decades, accumulated studies have revealed the anticancer activities of natural products and their derivatives. Increasing interest has been driven toward finding novel potential modulators of tumor immunotherapy from natural products, a hot research topic worldwide. These works of research mainly focused on natural products, including polyphenols (e.g., curcumin, resveratrol), cardiotonic steroids (e.g., bufalin and digoxin), terpenoids (e.g., paclitaxel and artemisinins), and polysaccharide extracts (e.g., lentinan). Compelling data highlight that natural products have a promising future in tumor immunotherapy. Considering the importance and significance of this topic, we initially discussed the integrated research progress of natural products and their derivatives, including target T cells, macrophages, B cells, NKs, regulatory T cells, myeloid-derived suppressor cells, inflammatory cytokines and chemokines, immunogenic cell death, and immune checkpoints. Furthermore, these natural compounds inactivate several key pathways, including NF-κB, PI3K/Akt, MAPK, and JAK/STAT pathways. Here, we performed a deep generalization, analysis, and summarization of the previous achievements, recent progress, and the bottlenecks in the development of natural products as tumor immunotherapy. We expect this review to provide some insight for guiding future research.

Digitoxin inhibits HeLa cell growth through the induction of G2/M cell cycle arrest and apoptosis in vitro and in vivo.

Cervical cancer is the fourth most common gynecological malignancy affecting the health of women worldwide and the second most common cause of cancer­related mortality among women in developing regions. Thus, the development of effective chemotherapeutic drugs for the treatment of cervical cancer has become an important issue in the medical field. The application of natural products for the prevention and treatment of various diseases, particularly cancer, has always attracted widespread attention. In the present study, a library of natural products composed of 78 single compounds was screened and it was found that digitoxin exhibited the highest cytotoxicity against HeLa cervical cancer cells with an IC50 value of 28 nM at 48 h. Furthermore, digitoxin exhibited extensive antitumor activities in a variety of malignant cell lines, including the lung cancer cell line, A549, the hepatoma cell line, MHCC97H, and the colon cancer cell line, HCT116. Mechanistically, digitoxin caused DNA double­stranded breaks (DSBs), inhibited the cell cycle at the G2/M phase via the ataxia telangiectasia mutated serine/threonine kinase (ATM)/ATM and Rad3­related serine/threonine kinase (ATR)­checkpoint kinase (CHK1)/checkpoint kinase 2 (CHK2)­Cdc25C pathway and ultimately triggered mitochondrial apoptosis, which was characterized by the disruption of Bax/Bcl­2, the release of cytochrome c and the sequential activation of caspases and poly(ADP­ribose) polymerase (PARP). In addition, the in vivo anticancer effect of digitoxin was confirmed in HeLa cell xenotransplantation models. On the whole, the findings of the present study demonstrate the efficacy of digitoxin against cervical cancer in vivo and elucidate its molecular mechanisms, including DSBs, cell cycle arrest and mitochondrial apoptosis. These results will contribute to the development of digitoxin as a chemotherapeutic agent in the treatment of cervical cancer.

Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog.

Betulinic acid (BA) and its derivatives are a class of high-profile drug candidates, but their anticancer effects on resistant cancer have rarely been reported. Although a few studies indicated mitophagy is related with drug resistance, its role in different cancer types and anticancer agents treatment remains largely unclear. Here, we find that B5G1, a new derivative of BA, induces cell death in multidrug resistant cancer cells HepG2/ADM and MCF-7/ADR through mitochondrial-apoptosis pathway. B5G1 also triggers mitophagy independent on Atg5/Beclin 1. Further mechanistic study indicates that B5G1 upregulates PTEN-induced putative kinase 1 (PINK1) to recruit Parkin to mitochondria followed by ubiquitination of Mfn2 to initiate mitophagy. Inhibition of mitophagy by PINK1 siRNA, mdivi-1, or bafilomycin A1 (Baf A1) promotes B5G1-induced cell death. In addition, ROS production and mitochondrial damage in B5G1-treated HepG2/ADM cells cause mitochondrial apoptosis and mitophagy. In vivo study shown that B5G1 dramatically inhibits HepG2/ADM xenograft growth accompanied by apoptosis and mitophagy induction. Together, our results provide the first demonstration that B5G1, as a novel mitophagy inducer, has the potential to be developed into a drug candidate for treating multidrug resistant cancer.