Wighteone, a prenylated flavonoid from licorice, inhibits growth of SW480 colorectal cancer cells by allosteric inhibition of Akt.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is a frequently used herbal medicine worldwide, and is used to treat cough, hepatitis, cancer and influenza in clinical practice of traditional Chinese medicine. Modern pharmacological studies indicate that prenylated flavonoids play an important role in the anti-tumor activity of licorice, especially the tumors in stomach, lung, colon and liver. Wighteone is one of the main prenylated flavonoids in licorice, and its possible effect and target against colorectal cancer have not been investigated. AIM OF THE STUDY: This study aimed to investigate the anti-colorectal cancer effect and underlying mechanism of wighteone. MATERIALS AND METHODS: SW480 human colorectal cancer cells were used to evaluate the in vitro anti-colorectal cancer activity and Akt regulation effect of wighteone by flow cytometry, phosphoproteomic and Western blot analysis. Surface plasmon resonance (SPR) assay, molecular docking and dynamics simulation, and kinase activity assay were used to investigate the direct interaction between wighteone and Akt. A nude mouse xenograft model with SW480 cells was used to verify the in vivo anti-colorectal cancer activity of wighteone. RESULTS: Wighteone inhibited phosphorylation of Akt and its downstream kinases in SW480 cells, which led to a reduction in cell viability. Wighteone had direct interaction with both PH and kinase domains of Akt, which locked Akt in a "closed" conformation with allosteric inhibition, and Gln79, Tyr272, Arg273 and Lys297 played the most critical role due to their hydrogen bond and hydrophobic interactions with wighteone. Based on Akt overexpression or activation in SW480 cells, further mechanistic studies suggested that wighteone-induced Akt inhibition led to cycle arrest, apoptosis and autophagic death of SW480 cells. Moreover, wighteone exerted in vivo anti-colorectal cancer effect and Akt inhibition activity in the nude mouse xenograft model. CONCLUSION: Wighteone could inhibit growth of SW480 cells through allosteric inhibition of Akt, which led to cell cycle arrest, apoptosis and autophagic death. The results contributed to understanding of the anti-tumor mechanism of licorice, and also provided a rationale to design novel Akt allosteric inhibitors for the treatment of colorectal cancer.

c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy.

BACKGROUND: c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS: The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS: The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.

Anticancer potential of Nymphaea nouchali Brum flowers against Ehrlich ascites carcinoma cell lines.

Background: Nymphaea nouchali Brum is exotic and medicinal plant in India. Aim of the Study: The main of this study is to evaluate the anticancer properties of Nymphaea nouchali Brum flowers against Ehrlich ascites carcinoma (EAC)-induced Swiss albino mice. Materials and Methods: The anticancer properties of Nymphaea nouchali Brum dry and fresh methanol extracts was investigated using EAC in Swiss albino mice. After inoculation of EAC cells into mice, treatment with NNDM flower extract (200 and 400 mg/kg) and standard drug 5-Fluorouracil (20 mg/kg) was continued for 9 days. The evaluation of the effect of drug response was made by the study of tumor growth response including increase in lifespan, the study of hematological parameters, biochemical estimations, and antioxidant assay of liver tissue compared to EAC control. The viability of cancer cell lines (such as HeLa, MCF-7, and MDA-MB 231 cells) was evaluated by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. Results: Therefore, from the results of the present study, it can be concluded that NNDM exhibited significant antitumor activity against EAC in Swiss albino mice. The effect of NNDM on viability of cancer cell lines (such as HeLa, MCF-7, and MDA-MB 231 cells) was evaluated by MTT assay, apoptosis in HeLa cell lines was evaluated by DNA laddering assay, HeLa cells treated with NNDM exhibited a characteristic "ladder" pattern after separation of the fragments by agarose gel electrophoresis and subsequent visualization, by ethidium bromide staining. NNDM exhibited a significant effect on cell viability. Conclusions: Based on results, it was concluded that NNDM exhibited cytotoxic effect on cancer cells and, from DNA laddering assay, it can be concluded that NNDM-induced apoptosis in EAC cells.

7-Geranyloxycinnamic Acid Isolated from Melicope lunu-ankenda Leaves Perturbs Colon Cancer and Breast Cancer Cell Lines' Growth via Induction of Apoptotic Pathway.

Globally, breast cancer is the most prevalent form of cancer in women and there is a need for alternative therapies such as plant-derived compounds with low systemic toxicity and selective toxicity to cancer cells. The aim of this study is to assess the cytotoxicity effects of 7-geranyloxycinnamic acid isolated from leaves of Melicope lunu-ankenda, a traditional medicinal plant, on the human breast cancer cell lines. Dried leaf powder was used for the preparation of different crude extracts using different solvents of increasing order of polarity. The structure of the isolated compound from the petroleum ether extract was elucidated by 1H and 13C NMR, LC-MS, and DIP-MS spectroscopy. The cytotoxic activity of the crude extract and 7-geranyloxycinnamic acid analyzed using MTT assay. Apoptotic analysis was evaluated using Annexin V-PI staining, AO/PI staining, intracellular ROS measurement, and measurement of activities of caspases 3/7, 8, and 9. Crude extracts and the isolated pure compound showed significant cytotoxicity against tested cancer cell lines. 7-geranyloxycinnamic acid was found to exert significant cytotoxic effects against breast cancer cell lines such as the MCF-7 and MDA-MB-231 cell lines. The cytotoxic effects are attributed to its ability to induce apoptosis via accumulation of ROS and activation of caspases in both breast cancer cell lines. The pure compound, 7-geranyloxycinnamic acid isolated from the leaves of M. lunu-ankenda, can exert significant cytotoxic effects against breast cancer cell lines without affecting the normal cells.

Green tea extract prevents CPT-11-induced diarrhea by regulating the gut microbiota.

Irinotecan (CPT-11) is an anticancer drug with indications for use in treating various cancers, but severe diarrhea develops as a side effect. We investigated the effects of green tea extract (GTE) on CPT-11-induced diarrhea, focusing on ß-glucuronidase and intestinal UGT1A1. When CPT-11 was administered to rats alone, the fecal water content was approximately 3.5-fold higher in this group than in the control group, and diarrhea developed. The fecal water content in the GTE-treated group was significantly higher than that in the control group, but the difference was smaller than that between the group treated with CPT-11 alone and the control group, and diarrhea improved. When CPT-11 was administered alone, the abundances of Bacteroides fragilis and Escherichia coli, which are ß-glucuronidase-producing bacteria, increased and interleukin-6 and interleukin-1ß mRNA levels in the colon increased, but GTE suppressed these increases. CPT-11 decreased colon UGT1A1 and short-chain fatty acid levels; however, this decrease was suppressed in the GTE-treated group. The findings that GTE decreases the abundance of ß-glucuronidase-producing bacteria and increases colon UGT1A1 levels, thereby decreasing the production of the active metabolite SN-38 in the intestinal tract, indicate that GTE ameliorates CPT-11-induced diarrhea.

Tongguanteng injection reverses paclitaxel resistance via upregulation of TAB1 expression in ovarian cancer in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongguanteng injection (TGT), the water extract from the stem of the Traditional Chinese hebal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as anticancer remedy for decades. TGT was not only used in the treatment of many malignant cancers extensively, but also an adjuvant anticancer drug with chemotherapeutics clinically. AIM OF THE STUDY: To evaluate the effects of TGT on reversing paclitaxel (PTX) resistance and investigate the potential mechanism related to TAB1 in ovarian cancer (OC) in vitro and in vivo. MATERIALS AND METHODS: The synergistic effect and reversal ratio were determined by CCK8 assay and median-effect principle after the combination of TGT and PTX in OC A2780 and its PTX-resistant (A2780/T) cells. The biological functions in cell apoptosis, migration and invasion of A2780/T cells treated by PTX 4 µM with TGT 20, 40, 80 mg⋅mL-1 for 24 h were evaluated by colony formation, flow cytometry, wound healing and transwell assays. Proteomics technique and bioinformatic analysis were used to indentify the change of TAB1 expression in A2780/T cells induced by TGT. The association between TAB1 expression and human OC was analyzed by gene expression databases. In A2780/T cells, western blotting and colony formation assays were used to investigate the relationship between TAB1 expression and PTX resistance after TAB1 overexpression by TAB1 plasmids. The mechanism of TGT and PTX regulating TAB1 and its related proteins were explored by western blotting and flow cytometry assays after TAB1 knock-down using siTAB1. Moreover, TUNEL staining, immunohistochemistry (IHC) and histopathology were used to observe the antitumor effects, TAB1 and p-p38 expression and the tissues impairments in nude mice xenograft model established by A2780/T cells after the co-treatment with TGT and PTX by in vivo. RESULTS: TGT combined with PTX showed the synergistic effect (CI<1), which could reverse the IC50 values of PTX in OC A2780 and A2780/T cells about 23.50 and 6.44 times, respectively. Besides, TGT combined with PTX could significantly inhibit the migration, invasion and promote apoptosis of A2780/T cells. We identified that TGT could induce TAB1 expression in A2780/T cells by proteomics analysis. TAB1 downregulation was significantly associated with tumorigenesis and poor prognosis in OC patients and PTX resistance in A2780/T cells. Furthermore, TGT could activate TAB1/TAK1/p38 MAPK signaling pathway targeting TAB1 and regulate the expression of Bax, Bcl-2 proteins to improve the sensitivity of A2780/T cells to PTX. TGT combined with PTX also showed a greater inhibition in tumor growth than PTX monotherapy in vivo. These promising results show the efficacy of TGT in reversing PTX resistance and provide a potential strategy that targeting TAB1/TAK1/p38 MAPK signaling pathway may improve the chemotherapy sensitivity in OC. CONCLUSIONS: Our results revealed that Tongguanteng injection could reverse paclitaxel resistance and the potential mechanism might be associated with the activation of TAB1/TAK1/p38 MAPK signaling pathway in OC in vitro and in vivo. TAB1 might be a pivotal target for reversing PTX resistance. This study will provide a theoretical basis for the combination of Tongguanteng injection and paclitaxel in clinic.

Extracts of Knoxia roxburghii (Spreng.) M. A. Rau Induce Apoptosis in Human MCF-7 Breast Cancer Cells via Mitochondrial Pathways.

Knoxia roxburghii (Spreng.) M. A. Rau (KR) is a plant clinically used in traditional Chinese medicine (TCM) for the treatment of cancer. The study objectives were to examine the effects of KR extracts, petroleum ether (PET), ethyl acetate (EtoAc), butanol (n-BuOH), and H2O-soluble fractions (HSF) of the 75% EtOH extraction on A549 (non-small cell lung cancer), HepG2 (liver cancer), HeLa (cervical cancer), MCF-7 (breast cancer), and L02 (normal hepatocyte) cells. It was found that HSF exhibited the strongest cytotoxic activity against MCF-7 cells, and was accompanied by reduced mitochondrial transmembrane potential, increased levels of intra-cellular reactive oxygen species (ROS) and activated caspases, and upregulated pro-apoptotic and downregulated anti-apoptotic proteins. LC-MS analysis further showed that HSF primarily consisted of calycosin, aloe emodin, rein, maackiain, asperuloside, orientin, vicenin-2, and kaempferide, which have been mostly reported for anti-tumor activity in previous studies. In summary, the current study illustrated the effect, mechanism, and the potential major active components of KR against breast cancer.

LC/MS analysis of Viscum cruciatum Sieber ex Boiss. extract with anti-proliferative activity against MCF-7 cell line via G0/G1 cell cycle arrest: An in-silico and in-vitro study.

ETHNOPHARMACOLOGICAL RELEVANCE: Viscum cruciatum Sieb is a well-known medicinal plant in Jordan containing various secondary metabolites. It has traditionally been used to treat many ailments, most notably cancer. However, there is a significant gap between scientific research and its value in traditional medicine. AIM OF THE WORK: To evaluate the antiproliferative activity of different V. cruciatum extracts against MCF-7 breast cancer cell lines and recognize the affected cell cycle phase. Besides, identifying the bioactive components present in the active extract using LC/MS technique. Also, to determine the possible mechanism of action by in silico and in-vitro study. MATERIALS AND METHODS: V. cruciatum was extracted using solvents with increasing polarity. The antiproliferative effects of the extracts against MCF-7 cell lines were evaluated using SRB assay. Further, flow cytometry was used to identify the inhibited phase of the cell cycle, while LC/MS-MS technique was used to analyze the chemical composition of the most active extract. After that, the putative mechanism of action was investigated through in-silico docking, molecular dynamic simulation for compounds with the highest docking scores, and Western blot analysis of cyclin-dependent kinases (CDK2/4/6). RESULTS: The chloroform/methanol 90/10 (ChMe) extract showed the most potent antiproliferative effect against MCF-7 cells (IC50 = 23.8 µg/mL), and cell cycle arrest at the G0/G1phase. Furthermore, LC-MS/MS analysis revealed the presence of several polyphenolics belonging to the flavonoids and phenolic acids classes. Additionally, quercetin-4'-glucoside, 3, 5, 7-trihydroxy-4'-methoxy flavone, and hesperetin-7-O-neohesperidoside demonstrated the highest docking binding scores and stable complexes against CDK2 and CDK4/6. Moreover, RMSD (root-mean-square deviation), RMSF (root-mean-square fluctuation), Rg (radius of gyration), and energy analysis during molecular dynamic simulation indicated the stable binding of the studied complexes. These results were supported by Western blot analysis, which revealed the downregulation of CDK2, CDK4, and CDK6 protein expression in MCF-7 cell lines. CONCLUSION: These findings emphasized the potential breast anticancer activity of the V. cruciatum ChMe extract by arresting the G0/G1 phase of the cell cycle, which could be related to its flavonoid content. Moreover, the results provided experimental support for the traditional anticancer activity of V. cruciatum, and its ChMe extract might be a source of chemoprotective or chemotherapeutic isolates.

Plants in Anticancer Drug Discovery: From Molecular Mechanism to Chemoprevention.

Cancer is one of the primary causes of mortality globally, and the discovery of new anticancer drugs is the most important need in recent times. Natural products have been recognized as effective in fight against various diseases including cancer for over 50 years. Plants and microbes are the primary and potential sources of natural compounds to fight against cancer. Moreover, researches in the field of plant-based natural compounds have moved towards advanced and molecular level understandings from the last few decades, leading to the development of potent anticancer agents. Also, plants have been accepted as abundant and prosperous sources for the development of novel therapeutic agents for the management and prevention of different cancer types. The high toxicity of some cancer chemotherapy drugs, as well as their unfavorable side effects and drugs resistance, drives up the demand for natural compounds as new anticancer drugs. In this detailed evidence-based mechanistic review, facts and information about various medicinal plants, their bioactive compounds with their potent anticancer activities against different cancers have been gathered, with further approach to represent the molecular mechanism behind the anticancer activity of these plants. This review will be beneficial for investigators/scientists globally involved in the development of natural, safe, effective, and economical therapeutic agents/drugs against various cancers. This might be an important contribution in the field of drug discovery, where drugs can be used alone or in combination to increase the efficacy of newly synthesized drugs.

Overview of the Biological Activity of Anthraquinons and Flavanoids of the Plant Rumex Species.

Rumex confertus belongs to the genus Rumex and is classified as an invasive parasitic plant in agriculture. Despite other Rumex species being widely used in herbal medicine due to their antimicrobial, antioxidant, antitumor, and anti-inflammatory effects, there are almost no information about the potential of Rumex confertus for the treatment of various diseases. In this review we analyzed scientific articles revealing properties of Rumex plant's substances against cancer, diabetes, pathogenic bacterial invasions, viruses, inflammation, and oxidative stress for the past 20 years. Compounds dominating in each composition of solvents for extraction were discussed, and common thin layer chromatography(TLC) and high performance liquid chromatography(HPLC) methods for efficient separation of the plant's extract are included. Physico-chemical properties such as solubility, hydrophobicity (Log P), pKa of flavonoids, anthraquinones, and other derivatives are very important for modeling of pharmacokinetic and pharmacodynamics. An overview of clinical studies for abounded selected substances of Rumex species is presented.

Anti-Cancer Properties of Stevia rebaudiana; More than a Sweetener.

Stevia rebaudiana Bertoni is a perennial shrub from Paraguay that is nowadays widely cultivated, since it is increasingly being utilized as a sugar substitute in various foodstuffs due to its sweetness and minimal caloric content. These properties of the plant's derivatives have spurred research on their biological activities revealing a multitude of benefits to human health, including antidiabetic, anticariogenic, antioxidant, hypotensive, antihypertensive, antimicrobial, anti-inflammatory and antitumor actions. To our knowledge, no recent reviews have surveyed and reported published work solely on the latter. Consequently, our main objective was to present a concise, literature-based review of the biological actions of stevia derivatives in various tumor types, as studied in in vitro and in vivo models of the disease. With global cancer estimates suggesting a 47% increase in cancer cases by 2040 compared to 2020, the data reviewed in this article should provide a better insight into Stevia rebaudiana and its products as a means of cancer prevention and therapy within the context of a healthy diet.

Experimental Research on the Antitumor Effect of Human Gastric Cancer Cells Transplanted in Nude Mice Based on Deep Learning Combined with Spleen-Invigorating Chinese Medicine.

Gastric cancer is still the fifth most common malignant tumor in the world and has the fourth highest mortality rate in the world. Gastric cancer is difficult to treat because of its unobvious onset, low resection rate, and rapid deterioration. Therefore, humans have been working hard to combat gastric cancer. At present, the most commonly used treatment method is radiotherapy. However, this method will damage the normal tissues of the irradiated area while treating malignant tumor cells. It not only has side effects of damage to the patient's skin and mucous membranes but also needs high-rate radiotherapy and has high cost for chemotherapy. In order to solve these problems, it is necessary to find new treatment methods. This article proposes the use of Chinese medicine to invigorate the spleen to inhibit human gastric cancer cells. This article combines modern machine learning technology with traditional Chinese medicine and combines traditional Chinese medicine physiotherapy with Western medicine nude mouse transplantation experiments. The treatment of tumors in Chinese medicine is based on the theory of Chinese medicine and has different characteristics. Western medicine has the advantage of permanently injuring patients. The process of the experiment is to transplant human-derived gastric cancer cells into nude mice. After grouping treatments and obtaining comparative data, deep learning techniques are used to analyze the properties of Chinese medicines for strengthening the spleen and to compare the properties of Chinese medicines for strengthening the spleen. The experimental results showed that the tumor inhibition rate of mice using fluorouracil was 18%, the tumor inhibition rate of mice using low-dose Chinese medicine was 16%, and the tumor inhibition rate of mice using high-dose Chinese medicine reached 52%. 80 days after the experiment, the survival rate of mice using high-dose Chinese medicine is 100% higher than that of mice without treatment.

Traditional Patchouli essential oil modulates the host's immune responses and gut microbiota and exhibits potent anti-cancer effects in ApcMin /+ mice.

Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the ApcMin /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of ApcMin /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcMmin /+ mice.

Novel molecules as the emerging trends in cancer treatment: an update.

As per World Health Organization cancer remains as a leading killer disease causing nearly 10 million deaths in 2020. Since the burden of cancer increases worldwide, warranting an urgent search for anti-cancer compounds from natural sources. Secondary metabolites from plants, marine organisms exhibit a novel chemical and structural diversity holding a great promise as therapeutics in cancer treatment. These natural metabolites target only the cancer cells and the normal healthy cells are left unharmed. In the emerging trends of cancer treatment, the natural bioactive compounds have long become a part of cancer chemotherapy. In this review, we have tried to compile about eight bioactive compounds from plant origin viz. combretastatin, ginsenoside, lycopene, quercetin, resveratrol, silymarin, sulforaphane and withaferin A, four marine-derived compounds viz. bryostatins, dolastatins, eribulin, plitidepsin and three microorganisms viz. Clostridium, Mycobacterium bovis and Streptococcus pyogenes with their well-established anticancer potential, mechanism of action and clinical establishments are presented.

In vitro anti-synovial sarcoma effect of diallyl trisulfide and mRNA profiling.

OBJECTIVE: Synovial sarcoma (SS) is a malignant soft tissue sarcoma and its natural history is a long, indolent clinical course followed by high rate of local recurrence and distant metastasis. Current therapies are still limited in increasing satisfactory of 5-year survival, especially for patients with recurrence and metastasis. Accordingly, finding new therapeutic drug for SS treatment is clinically urgent need. Diallyl trisulfide (DATS), a bioactive compound derived from garlic, is reported as a promising anti-cancer agent for various carcinomas. However, its effect on anti-SS remains unknown. This study investigated the anti-SS effect of DATS in human synovial sarcoma SW982 cells. METHODS: CCK-8 assay were used to examine the cell viability. High-content Imaging System was used to examine the apoptosis, intracellular ROS and autophagy. Flow cytometry was used to detect cell cycle. qPCR and Western blot were used to examine the expression of related mRNA and protein. High-throughput RNA-sequencing and bio-information analysis were used to investigate the mRNA profiling. RESULTS: The results showed a suppressive effect of DATS on tumor biology of SW982 cells including inducing apoptosis, triggering G2/M cell cycle arrest, elevating intracellular ROS and damaging mitochondria. Further high-throughput RNA-sequencing analysis clarified a comprehensive molecular portrait for DATS-induced transcriptional regulation. Besides, protein-protein interaction (PPI) analysis demonstrated that a network consisted of FOXM1, CCNA2, CCNB1, MYBL2, PLK1 and CDK1 might be response for DATS-induced G2/M cell cycle arrest and increased intracellular ROS. Notably, protein feature analysis revealed structure enrichment in microtubule network like kinesin motors domain, and tubulin domain. Molecular function analysis suggested that DATS-induced dysfunction of microtubule network might be the major cause for its effect on cell cycle arrest and successive apoptosis. Furthermore, 28 hub genes (including KIF2C, PLK1, CDK1, BIRC5, CCNB2, CENPF, TPX2, TOP2A and so on) were determined. Finally, pathway analysis showed that DATS-induced differentially expressed genes were mainly involved in cell cycle. CONCLUSION: Collectively, our findings for the first time provided the DATS-induced cellular response and transcriptional profiling of SW982 cells, which proposes that suppression of DATS on SS is multi-targeted and represent a therapeutic evidence for SS.

Peristrophe bicalyculata (Retz) Nees contains principles that are cytotoxic to cancer cells and induce caspase-mediated, intrinsic apoptotic death through oxidative stress, mitochondrial depolarisation and DNA damage.

The plant Peristrophe bicalyculata (Retz) Nees is used for the treatment of cancer. While its leaf extracts have been shown to inhibit the growth of some cancer cells, there is little information supporting the constituents' anti-tumour potential. This study, therefore, investigated the effects of the plant's leaf extracts on cancer cells and the associated cellular/molecular mechanisms. Extracts were prepared using hexane (PBH), chloroform (PBC), ethyl acetate (PBE) and methanol (PBM) and constituents were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Their cytotoxic effects on human cervical (HeLa) and lung cancer (MRC5-SV2) cells were assessed using the MTT and LDH release assays. Reactive oxygen species (ROS) production was assessed using 2',7'-dichlorofluorescein diacetate (DCFDA) and mitochondrial membrane potential by staining with JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide). Caspase activation was determined using a Caspase-Glo-3/7 assay, and DNA damage by the Comet assay. Changes to mRNA expression were assessed using Quantitative Real-Time PCR. PBC, PBE and PBM reduced cell viability and induced LDH release, with IC50 values (48 h, MTT, in µg/ml), respectively, of 6.21 ± 0.70, 23.39 ± 3.92, and 22.43 ± 3.58 (HeLa); and 1.98 ± 0.33, 8.57 ± 1.91 and 28.24 ± 5.57 (MRC5-SV2). PBC induced ROS, while PBC, PBE and PBM impaired mitochondrial membrane potential and induced caspase 3/7 activation. PBC and PBE induced DNA damage, and PBE induced caspase-3 mRNA expression. Constituents of the extracts included derivatives of gallic acid, dipeptides, diterpenoids and flavones. We conclude that P. bicalyculata contains cytotoxic principles that could be potential leads for developing novel anti-cancer agents.

Leaf extract of Osbeckia octandra induces apoptosis in oral squamous cell carcinoma cells.

BACKGROUND: Osbeckia octandra is a plant endemic to Sri Lanka and is used in ethnomedicine for treating various diseases. However, the anti-cancer properties of O. octandra are yet to be fully investigated. In the present study, we evaluated the anti-cancer effects of O. octandra on oral cancer cells. METHODS: Human oral cancer cell lines (HSC2, YD10B, YD38, YD9, and YD32) were used in this study. BrdU incorporation, cell cycle and annexin-V/PI staining were all evaluated using flow cytometry to determine the extent to which O. octandra leaf extract inhibits cell proliferation and induces apoptosis. Cell viability and reactive oxygen species (ROS) were also measured in order to investigate the anti-cancer effects of O. octandra extracts. Western blotting was performed to detect cell cycle related protein such as cyclin d1 and cdk4, and to detect apoptosis-related proteins such as Bcl-2, Bcl-XL, Bax, Caspase-9, Cleaved caspase-3, Fas, Caspase-8, and Bid. RESULTS: Leaf extract of O. octandra reduced oral squamous cell carcinoma (OSCC) cell viability in a dose-dependent manner. Leaf extract of O. octandra has non-toxic in normal keratinocytes. Also, O. octandra extract interrupted the DNA replication via G1 phase arrests, and this effect was independent of ROS generation. In the apoptosis-related experiments, the population of annexin V-positive cells increased upon treatment with O. octandra extract. Furthermore, the expression of anti-apoptotic protein (Bcl-2 and Bcl-xL) was decreased, whereas the expression of cleaved caspase-3 protein was increased in O. octandra-treated OSCC cells. CONCLUSIONS: The results suggest that a leaf extract of O. octandra inhibited the proliferation of OSCC cells through G1 phase arrest and interrupting DNA replication. The leaf extract of O. octandra could trigger the apoptotic response via caspase 3 activation in OSCC cells. These results suggest that O. octandra has the potential to be developed as an alternative medicine for treating OSCC.

Coptis chinensis and dried ginger herb combination inhibits gastric tumor growth by interfering with glucose metabolism via LDHA and SLC2A1.

ETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis Franch (CC) and Zingiber officinale Roscoe (dried ginger; DG) are traditional Chinese medicines. CC can dry dampness, relieve fire and detoxify, and is used to treat gastritis, gastric ulcer, colitis. DG can warm spleen and stomach for dispelling cold, used for the treatment of spleen and stomach deficiency. Both CC and DG are widely used to treat gastrointestinal diseases. CC-DG herb medicine combination originates from Huanglian decoction and Pinellia xiexin decoction in "Shanghan Lun" to comfort the stomach and intestines. CC and DG are used for the treatment of nausea and choking diaphragm which highly associated with gastric cancer clinically in ancient time. AIM OF THE STUDY: This study aimed to investigate the effects and underlying molecular mechanisms of CC-DG combination on gastric cancer. MATERIALS AND METHODS: The CC-DG extract was subjected to HPLC analysis. Viability (MTT) and cytotoxicity (CCK8) assays were performed using the SGC7901 and MFC cells. Cell cycle and apoptosis were measured by flow cytometry. The mRNA expression levels were measured by RT-PCR. In vivo anti-tumor activity of CC-DG was assessed in a tumor xenograft model. RESULTS: Twelve different proportions of CC-DG were tested for inhibitory effects on gastric cancer cells; CC-DG ratio 1:1 was found most effective. CC-DG administration significantly reduced the cell proliferation, migration, and colony formation, while increased cell apoptosis compared with the control group. CC-DG regulated differentially expressed genes in SGC7901 cells were subjected to pathway enrichment analysis. CC-DG significantly inhibited the cell glucose metabolism, downregulated the expression of LDHA and SLC2A1 genes, and changed the expression of other related genes including ME2, LDHD, LDHB, HIF1A, PKM, Pcx, and Got1. In addition, CC-DG suppressed tumorigenesis and inhibited MKI67 expression in the tumor xenograft model. CONCLUSIONS: CC-DG inhibited the proliferation, migration, invasion of SGC7901/MFC gastric cells, and in turn, suppressed tumorigenesis by regulating glucose metabolism through regulation of LDHA and SLC2A1 genes.

Brazilin: Biological activities and therapeutic potential in chronic degenerative diseases and cancer.

Caesalpinia sappan and Haematoxylum brasiletto belong to the Fabaceae family, predominantly distributed in Southeast Asia and America. The isoflavonoid brazilin has been identified from the bark and heartwood of these plants. This review summarizes the studies describing the biological activities of these plants and brazilin. Mainly, brazilin protects cells from oxidative stress, shows anti-inflammatory and antibacterial properties, and hypoglycemic effect. In addition, it has a biological impact on various pathologies such as Alzheimer's disease, Parkinson's disease, fibrillogenesis, and osteoarthritis. Interestingly, most of the antecedents are related to the anticancer effect of brazilin. In several cancers such as osteosarcoma, neuroblastoma, multiple myeloma, glioblastoma, bladder, melanoma, breast, tongue, colon, cervical, head, and neck squamous cell carcinoma, brazilin induces autophagy by increasing the levels of the LC3-II protein. Furthermore, it inhibits cell proliferation and induces apoptosis through increased expression of Bcl-2, Bcl-XL, p21, p27, activation of caspase-3 and -7, and the cleavage of PARP and inhibiting the expression of Bax. In addition, it blocks the expression of JNK and regulates the nuclear translocation of Nrf2. Together, these data positions brazilin as a compound of natural origin with multiple bioactivities and therapeutic potential in various chronic degenerative diseases and cancer.

A novel strategy to reveal clinical advantages and molecular mechanism of aidi injection in the treatment of pancreatic cancer based on network meta-analysis and network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Pancreatic cancer is a common malignancy worldwide due to its poor prognosis and high mortality rate. It is clinically proven that the combination of chemotherapeutic drugs and Traditional Chinese Medicine injections (TCMIs) significantly improves the therapeutic effect. AIM OF THE STUDY: To evaluate the efficacy and clinical benefits of TCMIs in combination with chemotherapy in the treatment of pancreatic cancer and to explore the mechanism of clinical advantage of Aidi injection. METHODS: Randomized controlled trials (RCTs) were searched in databases by NMA before December 29, 2020. WinBUGS 1.4, Stata 14.0, and R 4.0.4 software were used for calculations. All results were expressed as odds ratios and 95% credible intervals. Through the network pharmacology method, the chemical components and their targets, as well as the disease targets were further analyzed. And then, biological experiments were integrated to verify the results of network pharmacology analysis. (PROSPERO ID: CRD42021283559). RESULTS: A total of 33 RCTs with 8 TCMIs and 2011 patients were included. The results of NMA showed that Aidi injection can significantly improve the clinical efficacy (OR = 0.34, 95%CI: 0.16-0.74), and the clinical advantage was that it can significantly alleviate the leukopenia and thrombocytopenia caused by chemotherapy (OR = 5.65, 95%CI: 1.18-28.13). A total of 23 chemical compounds and 280 potential targets for Aidi injection were obtained from the online databases. Among them, there were 22 compounds, 50 targets and 211 signaling pathways closely related to leukopenia. Five genes were predicted to be core targets of ADI in alleviating leukopenia, and 2 of them (TP53 and VEGFA) were confirmed by biological experiments as regulatory targets of ADI in the treatment of PC. CONCLUSIONS: In conclusion, TCMIs in combination with chemotherapy, can improve clinical efficacy and safety in the treatment of pancreatic cancer. However, the overall evidence base is low, and large samples with multi-center RCTs are still needed to support further research findings. Aidi injection can alleviate leukopenia mainly by intervening in oxidative stress, regulating cell proliferation and apoptosis, and regulating the inflammatory response. The combined application of NMA, network pharmacology, and biological experiments provides a reference for clinical evaluation and mechanism of action exploration of other drugs.