Search

Abstract Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.

Small molecule-driven JNK activation has been found to induce apoptosis and paraptosis in cancer cells. Herein pharmacological effects of synthetic oxazine (4aS, 7aS)-3-((4-(4‑chloro-2-fluorophenyl)piperazin-1-yl)methyl)-4-phenyl-4, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[e] [1,2]oxazine (FPPO; BSO-07) on JNK-driven apoptosis and paraptosis has been demonstrated in human breast cancer (BC) MDA-MB231 and MCF-7 cells respectively. BSO-07 imparted significant cytotoxicity in BC cells, induced activation of JNK, and increased intracellular reactive oxygen species (ROS) levels. It also enhanced the expression of apoptosis-associated proteins like PARP, Bax, and phosphorylated p53, while decreasing the levels of Bcl-2, Bcl-xL, and Survivin. Furthermore, the drug altered the expression of proteins linked to paraptosis, such as ATF4 and CHOP. Treatment with N-acetyl-cysteine (antioxidant) or SP600125 (JNK inhibitor) partly reversed the effects of BSO-07 on apoptosis and paraptosis. Advanced in silico bioinformatics, cheminformatics, density Fourier transform and molecular electrostatic potential analysis further demonstrated that BSO-07 induced apoptosis and paraptosis via the ROS/JNK pathway in human BC cells.

Abstract Cancer cachexia is a multifactorial condition that contributes to the death of about 20% of cancer patients. It has the potential to cause weight loss, reduction in muscle mass, and loss of fat tissue, significantly lowering the quality of life. Currently, there are no approved drugs for cancer cachexia. Here, we have explored the possible impact of brassinin (BSN) on cancer cachexia under in vitro and in vivo settings. After differentiation, C2C12 and 3T3‐L1 cells were incubated with colorectal carcinoma cells conditioned media or BSN. For preclinical studies, mice were injected with HT‐29 cells followed by intraperitoneal administration of BSN, and muscle and adipose tissues were evaluated by Western blotting and hematoxylin and eosin staining. BSN effectively suppressed muscle atrophy by down‐regulating the levels of Muscle RING‐finger protein‐1 and Atrogin‐1, while also increasing the expression of myosin heavy chain in cachexia‐induced‐C2C12 myotubes. The induction of adipogenesis by BSN prevented adipocyte atrophy in cachexia‐induced 3T3‐L1 adipocytes. We also noted that BSN disrupted the interaction between COX‐2 and signaling transducer and activator of transcription 3 (STAT3) promoter, leading to down‐regulation of STAT3 activation. Moreover, it was found that BSN inhibited weight loss in mice and demonstrated anti‐cachexic effects. Overall, our observations indicate that BSN can attenuate cancer cachexia through diverse mechanisms.

Cancer is a major global health concern. To address this, the combination of traditional medicine and newly appreciated therapeutic modalities has been gaining considerable attention. This study explores the combined effects of Aucklandiae Radix (AR) and 43 °C hyperthermia (HT) on human gastric adenocarcinoma (AGS) cell proliferation and apoptosis. We investigated the synergistic effects of AR and HT on cell viability, apoptosis, cell cycle progression, and reactive oxygen species (ROS)-dependent mechanisms. Our findings suggest that the combined treatment led to a notable decrease in AGS cell viability and increased apoptosis. Furthermore, cell cycle arrest at the G2/M phase contributed to the inhibition of cancer cell proliferation. Notably, the roles of heat shock proteins (HSPs) were highlighted, particularly in the context of ROS regulation and the induction of apoptosis. Overexpression of HSPs was observed in cells subjected to HT, whereas their levels were markedly reduced following AR treatment. The suppression of HSPs and the subsequent increase in ROS levels appeared to contribute to the activation of apoptosis, suggesting a potential role for HSPs in the combined therapy’s anti-cancer mechanisms. These findings provide valuable insights into the potential of integrating AR and HT in cancer and HSPs.

Abstracts Benign prostate hyperplasia (BPH) is an age-related disease in men characterized by the growth of prostate cells and hyperproliferation of prostate tissue. This condition is closely related to chronic inflammation. In this study, we highlight the therapeutic efficacy of ellagic acid (EA) for BPH by focusing on the AR signaling axis and STAT3. To investigate the effect of EA on BPH, we used EA, a phytochemical abundant in fruits and vegetables, to treat testosterone propionate (TP)-induced BPH rats and RWPE-1 human prostate epithelial cells. The EA treatment reduced prostate weight, prostate epithelial thickness, and serum DHT levels in the TP-induced BPH rat model. In addition, EA improved testicular injury by increasing antioxidant enzymes in testis of the BPH rats. EA reduced the protein levels of AR, 5AR2, and PSA. It also induced apoptosis by regulating Bax, Bcl_xL, cytochrome c, caspase 9, and caspase 3 with increasing mitochondrial dynamics. Furthermore, EA reduced the expression of IL-6, TNF-α, and NF-κB, as well as phosphorylation of STAT3 and IκBα. These findings were also confirmed in TP-treated RWPE-1 cells. Overall, our data provide evidence of the role of EA in improving BPH through inhibition of AR and the STAT3 pathway.

Nuclear factor kappa B (NF–κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine– and piperazine–linked pyrimidines was developed as inhibitors of NF–κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine–pyrimidine and piperazine–pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF–7) viability with an IC50 value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4–methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF–κB, with the binding energies −9.32 and −7.32 kcal mol−1. Furthermore, compounds 3a and 5b inhibited NF–κB in MCF–7 breast cancer cells. In conclusion, we herein report newer structures that target NF–κB in BC cells.

Euphorbiasteroid (EPBS) has gained attention for its activity against human lung cancer and sarcoma; however, its impact on hepatocellular carcinoma has not yet been elucidated. Here, we investigated the cytotoxic effect of EPBS on human hepatocellular carcinoma (HCC) cells. We found that EPBS induced both apoptosis and autophagy in HCC cells. Additionally, we observed that EPBS treatment suppressed the constitutive as well as the inducible activation of a signal transducer and activator of transcription 3 (STAT3) protein expression. Moreover, EPBS promoted the expression of SHP-1 protein and the production of reactive oxidative stress (ROS). Furthermore, the knockdown of SHP-1 by siRNA transfection reversed the effects of EPBS, which have inductive effects related to apoptosis and autophagy. Therefore, EPBS can potentially function as an anti-cancer agent by inducing apoptosis and autophagy when targeting the SHP-1/STAT3 pathway.

Introduction: The development of cancer generally occurs as a result of various deregulated molecular mechanisms affecting the genes that can control normal cellular growth. Signal transducer and activator of transcription 3 (STAT3) pathway, once aberrantly activated can promote carcinogenesis by regulating the transcription of a number of oncogenic genes. Objectives: Here, we evaluated the impact of fangchinoline (FCN) to attenuate tumor growth and survival through modulation of oncogenic STAT3 signaling pathway using diverse tumor cell lines and a xenograft mouse model. Methods: To evaluate the action of FCN on STAT3 cascade, protein levels were analyzed by Western blot analysis and electrophoretic mobility shift assay (EMSA). Translocation of STAT3 was detected by immunocytochemistry. Thereafter, FCN-induced ROS was measured by GSH/GSSG assay and H2DCF-DA. FCN-induced apoptosis was analyzed using Western blot analysis and flow cytometry for various assays. Finally, anti-cancer effects of FCN in vivo was evaluated in a myeloma model. Results: We noted that FCN abrogated protein expression levels of STAT3 and upstream signals (JAK1/2 and Src). In addition, FCN also attenuated DNA binding ability of STAT3 and its translocation into the nucleus. It altered the levels of upstream signaling proteins, increased SHP-1 levels, and induced substantial apoptosis in U266 cells. FCN also promoted an increased production of reactive oxygen species (ROS) and altered GSSG/GSH ratio in tumor cells. Moreover, FCN effectively abrogated tumor progression and STAT3 activation in a preclinical myeloma model. Conclusion: Overall, this study suggests that FCN may have a tremendous potential to alter abnormal STAT3 activation and induce cell death in malignant cells along with causing the suppression of pathogenesis and growth of cancer through a pro-oxidant dependent molecular mechanism.

Panax ginseng C.A. Meyer, a widely used traditional medicine in East Asia, shows many beneficial effects on immune function, male erectile dysfunction, cancer, excessive oxidants, and aging issues. However, its effect on benign prostatic hyperplasia (BPH) and its potential in the treatment of side effects related to finasteride (Fi), an FDA-approved drug for BPH, are less known. This study aimed to verify the therapeutic effects of a water extract of P. ginseng (PGWE) on BPH in testosterone propionate (TP)-induced BPH rats and TP-treated RWPE-1 human epithelial cells, and the inhibitory potential on the Fi-induced side effects is also explored. In the TP-induced BPH rat model, PGWE alleviated the pathological markers of BPH such as weight and epithelial thickness of the prostate, and the serum level of dihydrotestosterone. PGWE downregulated androgen-related BPH factors such as 5α-reductase 2 and androgen receptor. PGWE also showed prostatic cell apoptosis accompanied by increased expression of Bax and decreased expression of Bcl-xL and cleaved-caspase 3, respectively, in addition to increasing mitochondrial dynamics in both in vivo and in vitro BPH models. Notably, reduced sperm count, one of the serious side effects of Fi, in the epididymis of BPH rats was recovered with PGWE treatment, suggesting less toxicity to sperm development by PGWE. PGWE also protected against Fi-induced sperm loss when PGWE was administered in combination with Fi without compromising the therapeutic effects of Fi on BPH. Based on these findings, we propose that PGWE could be an alternative therapeutic agent for BPH.

Nuclear factor kappa beta (NF-κB) is a transcriptional factor that plays a crucial role in regulating cancer cell proliferation. Therefore, the inhibition of NF-κB activity by small molecules may be beneficial in cancer therapy. In this report, methyl-thiol-bridged oxadiazole and triazole heterocycles were synthesized via click chemistry and it was observed that the lead structure, 2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(4-methoxybenzyl)-1,3,4-oxadiazole (4c), reduced the viability of MCF-7 cells with an IC50 value of 7.4 µM. Compound 4c also caused concentration-dependent loss of cell viability in chronic myelogenous leukemia (CML) cells. Furthermore, compound 4c inhibited the activation of NF-κB in human CML cells as observed by nuclear translocation and DNA binding assays. Functionally, compound 4c produced PARP cleavage and also suppressed expression of Bcl-2/xl, MMP-9, COX-2, survivin, as well as VEGF, resulting in apoptosis of CML cells. Moreover, ChIP assay showed that compound 4c decreased the binding of COX-2 to the p65 gene promoter. Detailed in silico analysis also indicated that compound 4c targeted NF-κB in CML cells. In conclusion, a novel structure bearing both triazole and oxadiazole moieties has been identified that can target NF-κB in CML cells and may constitute a potential novel drug candidate.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells.

Introduction: Epithelial-mesenchymal transition (EMT) is a process of transdifferentiation where epithelial cells attain mesenchymal phenotype to gain invasive properties and thus, can contribute to metastasis of tumor cells. Objectives: The antimetastatic and antitumor efficacy of brusatol (BT) was investigated in a hepatocellular carcinoma (HCC) model. Methods: We evaluated the action of BT on EMT process using various biological assays in HCC cell lines and its effect on tumorigenesis in an orthotopic mouse model. Results: We found that BT treatment restored the expression of Occludin, E-cadherin (epithelial markers) while suppressing the levels of different mesenchymal markers in HCC cells and tumor tissues. Moreover, we observed a decline in the expression of transcription factors (Snail, Twist). Since the expression of these two factors can be regulated by STAT3 signaling, we deciphered the influence of BT on modulation of this pathway. BT suppressed the phosphorylation of STAT3Y705 and STAT3 depletion using siRNA resulted in the restoration of epithelial markers. Importantly, BT (1mg/kg) reduced the tumor burden in orthotopic mouse model with a concurrent decline in lung metastasis. Conclusions: Overall, our results demonstrate that BT interferes with STAT3 induced metastasis by altering the expression of EMT-related proteins in HCC model.

Tanshinone is a herbal medicinal compound described in Chinese medicine, extracted from the roots of Salvia miltiorrhiza (Danshen). This family of compounds, including Tanshinone IIA and Tanshinone I, have shown remarkable potential as anti-cancer molecules, especially against breast, cervical, colorectal, gastric, lung, and prostate cancer cell lines, as well as leukaemia, melanoma, and hepatocellular carcinoma among others. Recent data has indicated that Tanshinones can modulate multiple molecular pathways such as PI3K/Akt, MAPK and JAK/STAT3, and exert their pharmacological effects against different malignancies. In addition, preclinical and clinical data, together with the safety profile of Tanshinones, encourage further applications of these compounds in cancer therapeutics. In this review article, the effect of Tanshinones on different cancers, challenges in their pharmacological development, and opportunities to harness their clinical potential have been documented.

Brassinin (BSN), a potent phytoalexin found in cruciferous vegetables, has been found to exhibit diverse anti-neoplastic effects on different cancers. However, the impact of BSN on chronic myelogenous leukemia (CML) cells and the possible mode of its actions have not been described earlier. We investigated the anti-cytotoxic effects of BSN on the KBM5, KCL22, K562, and LAMA84 CML cells and its underlying mechanisms of action in inducing programmed cell death. We noted that BSN could induce apoptosis, autophagy, and paraptosis in CML cells. BSN induced PARP cleavage, subG1 peak increase, and early apoptosis. The potential action of BSN on autophagy activation was confirmed by an LC3 expression and acridine orange assay. In addition, BSN induced paraptosis through increasing the reactive oxygen species (ROS) production, mitochondria damage, and endoplasmic reticulum (ER) stress. Moreover, BSN promoted the activation of the MAPK signaling pathway, and pharmacological inhibitors of this signaling pathway could alleviate all three forms of cell death induced by BSN. Our data indicated that BSN could initiate the activation of apoptosis, autophagy, and paraptosis through modulating the MAPK signaling pathway.

In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC50 value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC.

Gastric cancer has been associated with a high incidence and mortality, accompanied by a poor prognosis. Given the limited therapeutic options to treat gastric cancer, alternative treatments need to be urgently developed. Hyperthermia therapy is a potentially effective and safe treatment option for cancer; however, certain limitations need to be addressed. We applied 43 °C hyperthermia to AGS gastric cancer cells combined with Ponciri Fructus Immaturus (PF) to establish their synergistic effects. Co-treatment with PF and hyperthermia synergistically suppressed AGS cell proliferation by inducing extrinsic and intrinsic apoptotic pathways. Additionally, PF and hyperthermia suppressed factors related to metastasis. Cell cycle arrest was determined by flow cytometry, revealing that co-treatment induced arrest at the G2/M phase. As reactive oxygen species (ROS) are critical in hyperthermia therapy, we next examined changes in ROS generation. Co-treatment with PF and hyperthermia increased ROS levels, and apoptotic induction mediated by this combination was partially dependent on ROS generation. Furthermore, heat shock factor 1 and heat shock proteins (HSPs) were notably suppressed following co-treatment with PF and hyperthermia. The HSP-regulating effect was also dependent on ROS generation. Overall, these findings suggest that co-treatment with PF and hyperthermia could afford a promising anticancer therapy for gastric cancer.

Small molecules are being used to inhibit cyclin dependent kinase (CDK) enzymes in cancer treatment. There is evidence that CDK is a drug-target for cancer therapy across many tumor types because it catalyzes the transfer of the terminal phosphate of ATP to a protein that acts as a substrate. Herein, the identification of pyranopyrazoles that were CDK inhibitors was attempted, whose synthesis was catalyzed by nano-zirconium dioxide via multicomponent reaction. Additionally, we performed an in-situ analysis of the intermediates of multicomponent reactions, for the first-time, which revealed that nano-zirconium dioxide stimulated the reaction, as estimated by Gibbs free energy calculations of spontaneity. Functionally, the novel pyranopyrazoles were tested for a loss of cell viability using human breast cancer cells (MCF-7). It was observed that compounds 5b and 5f effectively produced loss of viability of MCF-7 cells with IC50 values of 17.83 and 23.79 µM, respectively. In vitro and in silico mode-of-action studies showed that pyranopyrazoles target CDK1 in human breast cancer cells, with lead compounds 5b and 5f having potent IC50 values of 960 nM and 7.16 μM, respectively. Hence, the newly synthesized bioactive pyranopyrazoles could serve as better structures to develop CDK1 inhibitors against human breast cancer cells.

Yuja (Citrus junos) has been cultivated and used for food and medicinal purposes in China and Korea. Its antioxidant, anti-wrinkle, moisturizing, and whitening effects were evaluated in HaCaT, HDF, and B16F10 cells. UVB has been known to cause cellular stress and the production of reactive oxygen species (ROS). Ambivalence of oxidative stress has been reported; however, excessive levels of ROS contribute to skin aging through the loss of elasticity and collagen fibers of connective tissue in the dermis. Skin aging is one of the biological processes that is affected by various factors, including UVB. Pro-Collagen I and hyaluronic acid contents were measured in UVB-irradiated HaCaT and HDF cells to evaluate the anti-wrinkle and moisturizing effects of Yuja-peel (YJP) fractions in -EA (ethyl acetate), -Hex (hexane), and -BuOH (butanol). The expression of matrix metalloproteinases (MMPs) involved in collagen degradation was confirmed to be inhibited by YJP fractions at both the protein and mRNA levels. Filaggrin and serine palmitoyltransferase (SPT), which are moisturizing factors, were induced by YJP fractions. B16F10 cells were treated with α-MSH to induce hyperpigmentation, and then the whitening efficacy of YJP fractions was verified by observing a decrease in melanin content. Overall, our results contribute to the development of various novel skin-improving cosmetics and pharmaceuticals with YJP fractions as active ingredients.

Colorectal cancer (CRC) is an inflammation-associated common cancer worldwide. Paejang-san and Mori Cortex Radicis have been traditionally used for treating intestinal inflammatory diseases in Korea and China. In the present study, we developed a new herbal formula as an alternative to CRC treatments, which is composed of two main components of Paejangsan (Patriniae Radix (Paejang in Korean) and Coix Seed (Yiyiin in Korean)), and Mori Cortex Radicis (Sangbekpi in Korean) based on the addition and subtraction theory in traditional medicine, hence the name PSY, and explored the potential therapeutic effects of the new formula PSY in human CRC cells by analyzing viability, cell cycle and apoptosis. We found that PSY ethanol extract (EtOH-Ex), but not water extract, significantly suppressed the viability of human CRC cells, and synergistically decreased the cell proliferation compared to each treatment of Patriniae Radix and Coix Seed extract (PY) or Mori Cortex Radicis extract (S), suggesting the combination of PY and S in a 10-to-3 ratio for the formula PSY. PSY EtOH-Ex in the combination ratio reduced cell viability but induced cell cycle arrest at the G2/M and sub-G1 phases as well as apoptosis in CRC cells. In addition, the experimental results of Western blotting, immunofluorescence staining and reporter assays showed that PSY also inhibited STAT3 by reducing its phosphorylation and nuclear localization, which resulted in lowering STAT3-mediated transcriptional activation. In addition, PSY regulated upstream signaling molecules of STAT3 by inactivating JAK2 and Src and increasing SHP1. Moreover, the chemical profiles of PSY from UPLC-ESI-QTOF MS/MS analysis revealed 38 phytochemicals, including seven organic acids, eight iridoids, two lignans, twelve prenylflavonoids, eight fatty acids, and one carbohydrate. Furthermore, 21 potentially bioactive compounds were highly enriched in the PSY EtOH-Ex compared to the water extract. Together, these results indicate that PSY suppresses the proliferation of CRC cells by inhibiting the STAT3 signaling pathway, suggesting PSY as a potential therapeutic agent for treating CRC and 21 EtOH-Ex-enriched phytochemicals as anti-cancer drug candidates which may act by inhibiting STAT3.

This Biomedicines Special Issue was designed to attract articles that focused on the pleiotropic role of the signal transducer and activator of transcription 3 (STAT3) transcription factor in different facets of tumorigenesis [...]

Context: Citrus unshiu Markovich (Rutaceae) peel is known to contain high concentrations of flavonoids and exerts pharmacological effects on antioxidant, anti-inflammation, allergies, diabetes and viral infections. Objective: Very little is known about potential activity of fermented dried Citrus unshiu peel extracts (FCU) using Bacillus subtilis, as well as its mechanism of action. We investigated the effects of FCU on the anti-inflammatory activities in murine macrophages and moisturizing effects in human keratinocytes. Materials and methods: We isolated the Bacillus subtilis from Cheonggukjang and FCU using these Bacillus subtilis to prepare samples. The cells were pre-treated with various extracts for 2 h and then induced with LPS for 22 h. We determined the NO assay, TNF-α, IL-6 and PGE2 in RAW 264.7 ells. The expression of SPT and Filaggrin by FCU treatment was measured in HaCaT cells. Result: We found that two types of FCU highly suppressed LPS-induced nitric oxide (NO) without exerting cytotoxic effects on RAW 264.7 cells (21.9 and 15.4% reduction). FCU inhibited the expression of LPS-induced iNOS and COX-2 proteins and their mRNAs in a concentration-dependent manner. TNF-α (59 and 30.9% reduction), IL-6 (39.1 and 65.6% reduction), and PGE2 secretion (78.6 and 82.5% reduction) were suppressed by FCU in LPS-stimulated macrophages. Furthermore, FCU can induce the production of hyaluronic acid (38 and 38.9% induction) and expression of Filaggrin and SPT in HaCaT keratinocyte cells. Discussion and conclusion: FCU potentially inhibits inflammation, improves skin moisturizing efficacy, and it may be a therapeutic candidate for the treatment of inflammation and dry skin.

CXCR7 and CXCR4 are G protein-coupled receptors (GPCRs) that can be stimulated by CXCL12 in various human cancers. CXCR7/4–CXCL12 binding can initiate activation of multiple pathways including JAK/STAT and manganese superoxide dismutase (MnSOD) signaling, and initiate epithelial–mesenchymal transition (EMT) process. It is established that cancer cell invasion and migration are caused because of these events. In particular, the EMT process is an important process that can determine the prognosis for cancer. Since the antitumor effect of leelamine (LEE) has been reported in various previous studies, here, we have evaluated the influence of LEE on the CXCR7/4 signaling axis and EMT processes. We first found that LEE suppressed expression of CXCR7 and CXCR4 both at the protein and mRNA levels, and showed inhibitory effects on these chemokines even after stimulation by CXCL12 ligand. In addition, LEE also reduced the level of MnSOD and inhibited the EMT process to attenuate the invasion and migration of breast cancer cells. In addition, phosphorylation of the JAK/STAT pathway, which acts down-stream of these chemokines, was also abrogated by LEE. It was also confirmed that LEE can induce an imbalance of GSH/GSSG and increases ROS, thereby resulting in antitumor activity. Thus, we establish that targeting CXCR7/4 in breast cancer cells can not only inhibit the invasion and migration of cancer cells but also can affect JAK/STAT, EMT process, and production of ROS. Overall, the findings suggest that LEE can function as a novel agent affecting the breast cancer.

Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.

EGFR and Wnt/β-catenin signaling pathways play a prominent role in tumor progression in various human cancers including non-small-cell lung carcinoma (NSCLC). Transactivation and crosstalk between the EGFR and Wnt/β-catenin pathways may contribute to the aggressiveness of cancers. Targeting these oncogenic pathways with small molecules is an attractive approach to counteract various types of cancers. In this study, we demonstrate the effect of euphorbiasteroid (EPBS) on the EGFR and Wnt/β-catenin pathways in NSCLC cells. EPBS induced preferential cytotoxicity toward A549 (wildtype EGFR-expressing) cells over PC-9 (mutant EGFR-expressing) cells. EPBS suppressed the expression of EGFR, Wnt3a, β-catenin, and FZD-1, and the reduction in β-catenin levels was found to be mediated through the activation of GSK-3β. EPBS reduced the phosphorylation of GSK-3βS9 with a parallel increase in β-TrCP and phosphorylation of GSK-3βY216. Lithium chloride treatment increased the phosphorylation of GSK-3βS9 and nuclear localization of β-catenin, whereas EPBS reverted these effects. Forced expression or depletion of EGFR in NSCLC cells increased or decreased the levels of Wnt3a, β-catenin, and FZD-1, respectively. Overall, EPBS abrogates EGFR and Wnt/β-catenin pathways to impart its anticancer activity in NSCLC cells.

Osteoarthritis (OA) causes persistent pain, joint dysfunction, and physical disability. It is the most prevalent type of degenerative arthritis, affecting millions of people worldwide. OA is currently treated with a focus on pain relief, inflammation control, and artificial joint surgery. Hence, a therapeutic agent capable of preventing or delaying the progression of OA is needed. OA is strongly associated with the degeneration of the articular cartilage and changes in the ECM, which are primarily associated with a decrease in proteoglycan and collagen. In the progress of articular cartilage degradation, catabolic enzymes, such as matrix metalloproteinases (MMPs), are activated by IL-1β stimulation. Given the tight relationship between IL-1β and ECM (extra-cellular matrix) degradation, this study examined the effects of Chaenomeles Fructus (CF) on IL-1β-induced OA in rat chondrocytes. The CF treatment reduced IL-1β-induced MMP3/13 and ADAMTS-5 production at the mRNA and protein levels. Similarly, CF enhanced col2a and aggrecan accumulation and chondrocyte proliferation. CF inhibited NF-κB (nuclear factor kappa B) activation, nuclear translocation induced by IL-1β, reactive oxygen species (ROS) production, and ERK phosphorylation. CF demonstrated anti-OA and articular regeneration effects on rat chondrocytes, thus, suggesting that CF is a viable and fundamental therapeutic option for OA.

A number of uracil amides cleave poly (ADP-ribose) polymerase and therefore novel thiouracil amide compounds were synthesized and screened for the loss of cell viability in a human-estrogen-receptor-positive breast cancer cell line. The synthesized compounds exhibited moderate to significant efficacy against human breast cancer cells, where the compound 5e IC50 value was found to be 18 μM. Thouracil amide compounds 5a and 5e inhibited the catalytical activity of PARP1, enhanced cleavage of PARP1, enhanced phosphorylation of H2AX, and increased CASPASE 3/7 activity. Finally, in silico analysis demonstrated that compound 5e interacted with PARP1. Hence, specific thiouracil amides may serve as new drug-seeds for the development of PARP inhibitors for use in oncology.

Leelamine (LEE) has recently attracted significant attention for its growth inhibitory effects against melanoma, breast cancer, and prostate cancer cells; however, its impact on hematological malignancies remains unclear. Here, we first investigate the cytotoxic effects of LEE on several human chronic myeloid leukemia (CML) cells. We noted that LEE stimulated both apoptosis and autophagy in CML cells. In addition, the constitutive activation of signal transducer and activator of transcription 5 (STAT5) was suppressed substantially upon LEE treatment. Moreover, STAT5 knockdown with small interfering RNA (siRNA) increased LEE-induced apoptosis as well as autophagy and affected the levels of various oncogenic proteins. Thus, the targeted mitigation of STAT5 activation by LEE can contribute to its diverse anticancer effects by enhancing two distinct cell death pathways.

Atopic dermatitis (AD) is an inflammatory disease of the skin, resulting from an immune dysfunction, that often occurs as a comorbidity of obesity. This investigation evaluated the capacity of Taeumjowi-tang (TJT), a Korean herbal formulation from the Sasang medical tradition to influence prognostic features of AD and obesity in a mouse model. Here, obesity and AD were induced by a high-fat diet (HFD) and 1-fluoro-2,4-dinitrobenzene (DNFB). Following an 8-week HFD regimen and 4 weeks of DNFB administration, the comorbid (CO) group manifested increased body weight and AD-like lesions, as compared to normal control (NC) mice, while TJT administration diminished these symptoms of obesity and AD. Specifically, TJT treatment reduced epidermal thickness and eosinophil/mast cell infiltration, along with reduction in immunoglobulin E, interleukin (IL)-4, IL-6, and tumor necrosis factor-alpha (TNF-α). It was additionally demonstrated that TJT suppresses HFD/DNFB-associated increase of the inflammation-related nuclear factor-kappa beta (NF-κB) and mitogen activated protein kinase. Moreover, significantly increased levels of hypoxia inducible factor-1 alpha (HIF-1α) protein was observed in CO group versus controls, an increase significantly down-regulated by TJT-treatment. These outcomes suggest that TJT may prove useful in clinical management of obesity-AD comorbidity treatment, an effect that may be due to regulation of HIF-1α expression.

Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

The extract of the Gardenia jasminoides fruit (GJFE) can been consumed as an herbal tea or used as a yellow dye. Recently, studies report that GFJE exerts inhibitory effects on lipid accumulation and adipogenesis in white adipocytes. We evaluated the thermogenic actions of GJFE by focusing on mitochondrial activation and studying the underlying mechanisms. To investigate the role of GJFE on thermogenesis in mice, we used an acute cold exposure model. After 2 weeks of feeding, the cold tolerance of GJFE-fed mice was notably increased compared to PBS-fed mice. This was due to an increase in thermogenic proteins in the inguinal white adipose tissue of the cold-exposed mice. Moreover, GJFE significantly increased thermogenic factors such as peroxisome proliferator-activated receptor gamma (PPARγ), uncoupling protein 1 (UCP1), and PPARγ coactivator 1 alpha (PGC1α) in vitro as well. Factors related to mitochondrial abundance and functions were also induced by GJFE in white and beige adipocytes. However, the treatment of PPARγ inhibitor abolished the GJFE-induced changes, indicating that activation of PPARγ is critical for the thermogenic effect of GJFE. In conclusion, GJFE induces thermogenic action by activating mitochondrial function via PPARγ activation. Through these findings, we suggest GJFE as a potential anti-obesity agent with a novel mechanism involving thermogenic action in white adipocytes.

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s).

Background: The prevalence of allergic inflammatory diseases such as atopic dermatitis (AD), asthma, and allergic rhinitis worldwide has increased and complete recovery is difficult. Korean Red Ginseng, which is the heat-processed root of Panax ginseng Meyer, is widely and frequently used as a traditional medicine in East Asia. In this study, we investigated whether Korean Red Ginseng water extract (RGE) regulates the expression of proinflammatory cytokines and chemokines via the mitogen-activated protein kinases (MAPKs)/nuclear factor kappa B (NF-κB) pathway in allergic inflammation. Methods: Compound 48/80-induced anaphylactic shock and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced AD-like skin lesion mice models were used to investigate the antiallergic effects of RGE. Human keratinocytes (HaCaT cells) and human mast cells (HMC-1) were also used to clarify the effects of RGE on the expression of proinflammatory cytokines and chemokines. Results: Anaphylactic shock and DNFB-induced AD-like skin lesions were attenuated by RGE administration through reduction of serum immunoglobulin E (IgE) and interleukin (IL)-6 levels in mouse models. RGE also reduced the production of proinflammatory cytokines including IL-1β, IL-6, and IL-8, and expression of chemokines such as IL-8, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) in HaCaT cells. Additionally, RGE decreased the release of tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-8 as well as expressions of chemokines including macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, and IL-8 in HMC-1 cells. Furthermore, our data demonstrated that these inhibitory effects occurred through blockage of the MAPK and NF-κB pathway. Conclusion: RGE may be a useful therapeutic agent for the treatment of allergic inflammatory diseases such as AD-like dermatitis.

Overexpression of chemokine receptor type 4 (CXCR4) has been found to be associated with increased cell proliferation, metastasis and also act as an indicator of poor prognosis in patients with breast cancer. Therefore, new agents that can abrogate CXCR4 expression have potential against breast cancer metastasis. In this study, we examined the potential effect of thymoquinone (TQ), derived from the seeds of Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. TQ was found to inhibit the expression of CXCR4 in MDA-MB-231 triple negative breast cancer (TNBC) cells in a dose- and time-dependent manner. It was noted that suppression of CXCR4 by TQ was possibly transcriptionally regulated, as treatment with this drug caused down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and suppression of NF-κB binding to the CXCR4 promoter. Pretreatment with a proteasome inhibitor and/or lysosomal stabilization did not affect TQ induced suppression of CXCR4. Down-regulation of CXCR4 was further correlated with the inhibition of CXCL12-mediated migration and invasion of MDA-MB-231 cells. Interestingly, it was observed that the deletion of p65 could reverse the observed anti-invasive/anti-migratory effects of TQ in breast cancer cells. TQ also dose-dependently inhibited MDA-MB-231 tumor growth and tumor vascularity in a chick chorioallantoic membrane assay model. We also observed TQ (2 and 4 mg/kg) treatment significantly suppressed multiple lung, brain, and bone metastases in a dose-dependent manner in a metastasis breast cancer mouse model. Interestingly, H&E and immunohistochemical analysis of bone isolated from TQ treated mice indicated a reduction in number of osteolytic lesions and the expression of metastatic biomarkers. In conclusion, the results indicate that TQ primarily exerts its anti-metastatic effects by down-regulation of NF-κB regulated CXCR4 expression and thus has potential for the treatment of breast cancer.

Albendazole (ABZ) has been reported to display anti-tumoral actions against various maliganncies, but possible impact of ABZ on gastric cancer has not been deciphered. As aberrant phosphorylation of STAT3 and STAT5 proteins can regulate the growth and progression of gastric cancer, we postulated that ABZ may interrupt the activation of these oncogenic transcription factors. We found that ABZ exposure abrogated STAT3/5 activation, inhibited phosphorylation of Janus-activated kinases 1/2 and Src and enhanced the levels of SHP-1 protein. Silencing of SHP-1 gene by small interfering RNA (siRNA) reversed the ABZ-promoted attenuation of STAT3 as well as STAT5 activation and cellular apoptosis. In addition, these effects were noted to be driven by an augmented levels of reactive oxygen species caused by drug-induced GSH/GSSG imbalance. Thus, the data indicates that ABZ can modulate the activation of STAT3 and STAT5 by pleiotropic mechanisms in gastric cancer cells.

Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate tumor growth and metastasis in hepatocellular carcinoma (HCC) cells. This study aimed to evaluate the anti-neoplastic effect of GGC against HCC cells and we observed that GGC inhibited HGF-induced c-Met and c-Met downstream oncogenic pathways, such as PI3K/Akt/mTOR and MEK/ERK. In addition, GGC also suppressed the proliferation of expression of diverse tumorigenic proteins (Bcl-2, Bcl-xL, Survivin, IAP-1, IAP-2, Cyclin D1, and COX-2) and induced apoptosis. Interestingly, the silencing of c-Met by small interfering RNA (siRNA) mitigated c-Met expression and enhanced GGC-induced apoptosis. Moreover, it was noted that GGC also significantly reduced the invasion and migration of HCC cells. Overall, the data clearly demonstrate that GGC exerts its anti-neoplastic activity through modulating c-Met phosphorylation and may be used as an effective therapy against HCC.

Corilagin (CLG), a major component of several medicinal plants, can exhibit diverse pharmacological properties including those of anti-cancer, anti-inflammatory, and hepatoprotective qualities. However, there are no prior studies on its potential impact on the epithelial-to-mesenchymal transition (EMT) process. EMT can lead to dissemination of tumor cells into other organs and promote cancer progression. Hence, we aimed to investigate the effect of CLG on EMT and its mechanism(s) of action in tumor cells. We noted that CLG reduced the expression of various epithelial markers and up-regulated the expression of Occludin and E-cadherin in both basal and TGFβ-stimulated tumor cells. CLG treatment also abrogated cellular invasion and migration in colon and prostate carcinoma cells. In addition, CLG effectively attenuated the Wnt/β-catenin signaling cascade in TGFβ-stimulated cells. Overall, our study suggests that CLG may function as and effective modulator of EMT and metastasis in neoplastic cells.

Renal cell carcinoma (RCC) represents the most common form of kidney cancer, which accounts for 3–5% newly diagnosed cancer cases. Since limited therapies are available for RCC, a search for new options is required. Therefore, in this study, we evaluated the combination effect of cinnamaldehyde (CNM) and hyperthermia treatment. CNM treatment combined with 43 °C hyperthermia synergistically increased cytotoxicity in RCC cell line ACHN cells. Through Western blot assays, we observed increased apoptosis signaling and decreased proliferation/metastasis signaling, along with a repressed heat shock protein 70 level. In flow cytometry analyses, CNM and hyperthermia combination clearly induced apoptosis and mitochondrial potential of ACHN cells, while arresting the cell cycle. Investigation of reactive oxygen species (ROS) suggested a significant increase of ROS generation by CNM and 43 °C hyperthermia co-treatment. We could verify that ROS is crucial in the apoptotic action of combination treatment with CNM and hyperthermia through further experiments regarding an ROS scavenger. Overall, we suggest CNM and hyperthermia combination treatment as an alternative option of anticancer strategies for RCC.

Resveratrol (Res) is a well-known natural product that can exhibit important pharmacological activities such as antioxidant, anti-diabetes, anti-tumor, and anti-inflammatory. An evaluation of its therapeutic effects demonstrates that this naturally occurring bioactive compound can target different molecular pathways to exert its pharmacological actions. Transforming growth factor-beta (TGF-β) is an important molecular pathway that is capable of regulating different cellular mechanisms such as proliferation, migration, and angiogenesis. TGF-β has been reported to be involved in the development of disorders such as diabetes, cancer, inflammatory disorders, fibrosis, cardiovascular disorders, etc. In the present review, the relationship between Res and TGF-β has been investigated. It was noticed that Res can inhibit TGF-β to suppress the proliferation and migration of cancer cells. In addition, Res can improve fibrosis by reducing inflammation via promoting TGF-β down-regulation. Res has been reported to be also beneficial in the amelioration of diabetic complications via targeting the TGF-β signaling pathway. These topics are discussed in detail in this review to shed light on the protective effects of Res mediated via the modulation of TGF-β signaling.

Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. The effects of matrine on CXCR4, MMP-9/2, and nuclear factor κB (NF-κB) activation in lung (A549), prostate (DU145), and pancreas (MIA PaCa-2) cells were investigated by diverse techniques. The expression level of CXCR4 and MMP-9/2 was analyzed by western blot analysis and reverse transcription polymerase chain reaction. NF-κB activation was also evaluated by western blot analysis, electrophoretic mobility shift assay as well as immunocytochemical experiments. Furthermore, we monitored cell invasion and metastasis activities by wound healing and Boyden chamber assays. We noted that matrine induced a down-regulation of CXCR4 and MMP-9/2 at both protein and mRNA levels. In addition, matrine negatively regulated human epidermal growth factor receptor 2 (HER2) and C-X-C Motif Chemokine Ligand 12 (CXCL12)-induced CXCR4 expression. Moreover, NF-κB suppression by matrine led to inhibition of metastatic potential of tumor cells. Our results suggest that matrine can block the cancer metastasis through the negative regulation of CXCR4 and MMP-9/2 and consequently it can be considered as a potential candidate for cancer therapy.

According to the World Health Organization (WHO), cancer is the second-highest cause of mortality in the world, and it kills nearly 9.6 million people annually. Besides the fatality of the disease, poor prognosis, cost of conventional therapies, and associated side-effects add more burden to patients, post-diagnosis. Therefore, the search for alternatives for the treatment of cancer that are safe, multi-targeted, effective, and cost-effective has compelled us to go back to ancient systems of medicine. Natural herbs and plant formulations are laden with a variety of phytochemicals. One such compound is rhein, which is an anthraquinone derived from the roots of Rheum spp. and Polygonum multiflorum. In ethnomedicine, these plants are used for the treatment of inflammation, osteoarthritis, diabetes, and bacterial and helminthic infections. Increasing evidence suggests that this compound can suppress breast cancer, cervical cancer, colon cancer, lung cancer, ovarian cancer, etc. in both in vitro and in vivo settings. Recent studies have reported that this compound modulates different signaling cascades in cancer cells and can prevent angiogenesis and progression of different types of cancers. The present review highlights the cancer-preventing and therapeutic properties of rhein based on the available literature, which will help to extend further research to establish the chemoprotective and therapeutic roles of rhein compared to other conventional drugs. Future pharmacokinetic and toxicological studies could support this compound as an effective anticancer agent.

Cancer is one of the greatest causes of mortality worldwide. The prevalence rates of different types of cancer is increasing around the world as well. Limitations in chemotherapy and radiotherapy, owing to multiple side effects including cytotoxic effects of antitumor compounds on normal cells as well as the development of resistance to these treatment options in patients, create a serious threat to successful treatment of cancer. The use of natural compounds to prevent and treat cancers has been found to be quite effective, with fewer adverse effects found in patients. Umbelliprenin (UMB) is a naturally occurring sesquiterpene compound found in Ferula species and recently in Artemisia absinthium. Many studies have highlighted the antitumor potential of UMB in different cancer cell lines as well as in animal models. UMB exerts its anticancer actions by regulating extrinsic and intrinsic apoptotic pathways; causing inhibition of the cell cycle at the G0/G1 phase; and attenuating migration and invasion by modulating the Wnt signaling, NF-ĸB, TGFβ, and Fox3 signaling pathways. UMB also affects the key hallmarks of tumor cells by attenuating tumor growth, angiogenesis, and metastasis. This review provides an insight into the role of UMB as a potential antitumor drug for different malignancies and highlights the signaling cascades affected by UMB treatment in diverse tumor cell lines and preclinical models.

Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of Garcinia indica (G. indica) and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes.

Cancer persists as one of the leading causes of deaths worldwide, contributing to approximately 9.6 million deaths per annum in recent years. Despite the numerous advancements in cancer treatment, there is still abundant scope to mitigate recurrence, adverse side effects and toxicities caused by existing pharmaceutical drugs. To achieve this, many phytochemicals from plants and natural products have been tested against cancer cell lines in vivo and in vitro. Likewise, casticin, a flavonoid extracted from the Vitex species, has been isolated from the leaves and seeds of V. trifolia and V. agnus-castus. Casticin possesses a wide range of therapeutic properties, including analgesic, anti-inflammatory, antiangiogenic, antiasthmatic and antineoplastic activities. Several studies have been conducted on the anticancer effects of casticin against cancers, including breast, bladder, oral, lung, leukemia and hepatocellular carcinomas. The compound inhibits invasion, migration and proliferation and induces apoptosis (casticin-induced, ROS-mediated and mitochondrial-dependent) and cell cycle arrest (G0/G1, G2/M, etc.) through different signaling pathways, namely the PI3K/Akt, NF-κB, STAT3 and FOXO3a/FoxM1 pathways. This review summarizes the chemo-preventive ability of casticin as an antineoplastic agent against several malignancies.

Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis.

Natural compounds extracted from plants have gained immense importance in the fight against cancer cells due to their lesser toxicity and potential therapeutic effects. Raddeanin A (RA), an oleanane type triterpenoid is a major compound isolated from Anemone raddeana Regel. As an anticancer agent, RA induces apoptosis, cell cycle arrest, inhibits invasion, migration and angiogenesis in malignant cell lines as well as in preclinical models. In this systemic review, the pharmacological effects of RA and its underlying molecular mechanisms were carefully analyzed and potential molecular targets have been highlighted. The apoptotic potential of RA can be mediated through the modulation of Bcl-2, Bax, caspase-3, caspase-8, caspase-9, cytochrome c and poly-ADP ribose polymerase (PARP) cleavage. PI3K/Akt signaling pathway serves as the major molecular target affected by RA. Furthermore, RA can block cell proliferation through inhibition of canonical Wnt/β-catenin signaling pathway in colorectal cancer cells. RA can also alter the activation of NF-κB and STAT3 signaling pathways to suppress invasion and metastasis. RA has also exhibited promising anticancer potential against drug resistant cancer cells and can enhance the anticancer effects of several chemotherapeutic agents. Overall, RA may function as a promising compound in combating cancer, although further in-depth study is required under clinical settings to validate its efficacy in cancer patients.

The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20 Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1β, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.

Daidzin (DDZ) extracted from Pueraria lobate (Fabaceae) is a widely known phytoestrogen. DDZ can display anti-cancer activities against breast and prostate cancers, but its anti-oncogenic actions in multiple myeloma (MM) cells have not been studied. The signal transducer and activator of transcription 3 (STAT3) can control key processes including proliferation, differentiation, and survival in MM cells. Here, we noted that DDZ abrogated STAT3 activation (both constitutive as well as inducible) at Tyr705 and Ser727 in MM cells. Additionally, DDZ mitigated the phosphorylation of STAT3 upstream Janus-activated kinases (JAK1/2) and c-Src kinases. Pervanadate (tyrosine phosphatase blocker) exposure altered the DDZ-induced inhibition of STAT3 activation, thus affecting the action of this phytoestrogen on apoptosis. Moreover, DDZ impeded proliferation and augmented the apoptotic effects of bortezomib (Bor) in MM cells. Overall, the data indicate that DDZ may act as a potent suppressor of STAT3 signaling cascade, and the co-treatment of DDZ and Bor could be a promising therapeutic strategy, specifically in MM.

Because of the essential role of signal transducer and activator of transcription 3 (STAT3) in proliferation, anti-apoptosis, and chemoresistance of multiple myeloma (MM), we investigated whether icariin, a prenylated flavonol glycoside, inhibits both constitutive and inducible STAT3 activation in human myeloma cell lines. We noted that icariin could block constitutive STAT3 phosphorylation as well as its nuclear translocation and DNA binding ability in U266 cells. Icariin also suppressed IL-6-induced STAT3 activation through the inhibition of upstream kinases (Janus activated kinase-1 and -2, and c-Src). We found that icariin downregulated the protein expression of STAT3 downstream target gene products such as Bcl-2, Bcl-xl, survivin, IAP-1/2, COX-2, VEGF, and matrix metallopeptidase 9 (MMP-9) in a concentration-dependent manner. Moreover, this flavonoid also exhibited the capacity to significantly induce apoptosis and suppress proliferation of MM cells. Interestingly, this agent also significantly potentiated the apoptotic effects of bortezomib through the suppression of STAT3 activation in MM cells. Altogether, our data indicates that the potential application of icariin as a STAT3 blocker in myeloma therapy.

Background: β-Lapachone is a quinone-containing compound found in red lapacho ( Tabebuia impetiginosa , syn. T avellanedae ) trees. Lapacho has been used in traditional medicine by several South and Central American indigenous people to treat various types of cancer. The purpose of this study was to investigate the antimetastatic properties of β-lapachone and the underlying mechanisms using colon cancer cells. Methods: This research used metastatic murine colon cancer cell lines, colon 26 (CT26) and colon 38 (MC38). A WST assay, annexin V assay, cell cycle analysis, wound healing assay, invasion assay, western blot analysis, and real-time reverse transcription–polymerase chain reaction were performed to examine the effects of β-lapachone on metastatic phenotypes and molecular mechanisms. The effect of β-lapachone on lung metastasis was assessed in a mouse experimental metastasis model. Results: We found that the inhibition of proliferation of the colon cancer cell lines by β-lapachone was due to the induction of apoptosis and cell cycle arrest. β-Lapachone induced the apoptosis of CT26 cells through caspase-3, -8, and -9 activation; poly(ADP-ribose) polymerase cleavage; and downregulation of the Bcl-2 family in a dose- and time-dependent manner. In addition, a low concentration of β-lapachone decreased the cell migration and invasion by decreasing the expression of matrix metalloproteinases-2 and -9, and increased the expression of tissue inhibitors of metalloproteinases-1 and -2. Moreover, β-lapachone treatment regulated the expression of epithelial-mesenchymal transition markers such as E- and N-cadherin, vimentin, β-catenin, and Snail in CT26 cells. In the mouse experimental metastasis model, β-lapachone significantly inhibited the lung metastasis of CT26 cells. Conclusions: Our results demonstrated the inhibitory effect of β-lapachone on colorectal lung metastasis. This compound may be useful for developing therapeutic agents to treat metastatic cancer.

Brown adipocytes dissipate energy as heat and hence have an important therapeutic capacity for obesity. Development of brown-like adipocytes (also called beige) is also another attractive target for obesity treatment. Here, we investigated the effect of farnesol, an isoprenoid, on adipogenesis in adipocytes and on the browning of white adipose tissue (WAT) as well as on the weight gain of high-fat diet (HFD)-induced obese mice. Farnesol inhibited adipogenesis and the related key regulators including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α through the up-regulation of AMP-activated protein kinase in 3T3-L1 murine adipocytes and human adipose tissue-derived mesenchymal stem cells (hAMSCs). Farnesol markedly increased the expression of uncoupling protein 1 and PPARγ coactivator 1 α in differentiated hAMSCs. In addition, farnesol limited the weight gain in HFD obese mice and induced the development of beige adipocytes in both inguinal and epididymal WAT. These results suggest that farnesol could be a potential therapeutic agent for obesity treatment.