Arenobufagin induces cell apoptosis by modulating the cell cycle regulator claspin and the JNK pathway in nasopharyngeal carcinoma cells.

BACKGROUND: The high recurrence rate and incidence of distant metastasis of nasopharyngeal carcinoma (NPC) result in poor prognosis. It is necessary to identify natural compounds that can complement combination radiation therapy. Arenobufagin is commonly used for heart diseases and liver cancer, but its effectiveness in NPC is unclear. STUDY DESIGN AND METHODS: The effect of arenobufagin-induced apoptosis was measured by a cell viability assay, tumorigenic assay, fluorescence assay, and Western blot assay through NPC-039 and NPC-BM cell lines. The protease array, Western blot assay, and transient transfection were used to investigate the underlying mechanism of arenobufagin-induced apoptosis. An NPC xenograft model was established to explore the antitumor activity of arenobufagin in vivo. RESULTS: Our findings indicated that arenobufagin exerted cytotoxic effects on NPC cells, inhibiting proliferation through apoptosis activation. Downregulation of claspin was confirmed in arenobufagin-induced apoptosis. Combined treatment with arenobufagin and mitogen-activated protein kinase inhibitors demonstrated that arenobufagin induced NPC apoptosis through the c-Jun N-terminal kinases (JNK) pathway inhibition. Furthermore, arenobufagin suppressed NPC tumor proliferation in vivo. CONCLUSION: Our results revealed the antitumor effect of arenobufagin in vitro and in vivo. Arenobufagin may have clinical utility in treating NPC due to its suppression of claspin and inhibition of the JNK pathway.

LDL Receptor-Related Protein 1B Polymorphisms Associated with Increased Risk of Lymph Node Metastasis in Oral Cancer Group with Diabetes Mellitus.

Oral cancer ranks fourth among malignancies among Taiwanese men and is the eighth most common cancer among men worldwide in terms of general diagnosis. The purpose of the current study was to investigate how low-density lipoprotein receptor-related protein 1B (LDL receptor related protein 1B; LRP1B) gene polymorphisms affect oral squamous cell carcinoma (OSCC) risk and progression in individuals with diabetes mellitus (DM). Three LRP1B single-nucleotide polymorphisms (SNPs), including rs10496915, rs431809, and rs6742944, were evaluated in 311 OSCC cases and 300 controls. Between the case and control groups, we found no evidence of a significant correlation between the risk of OSCC and any of the three specific SNPs. Nevertheless, in evaluating the clinicopathological criteria, individuals with DM who possess a minimum of one minor allele of rs10496915 (AC + CC; p = 0.046) were significantly associated with tumor size compared with those with homozygous major alleles (AA). Similarly, compared to genotypes homologous for the main allele (GG), rs6742944 genotypes (GA + AA; p = 0.010) were more likely to develop lymph node metastases. The tongue and the rs6742944 genotypes (GA + AA) exhibited higher rates of advanced clinical stages (p = 0.024) and lymph node metastases (p = 0.007) when compared to homozygous alleles (GG). LRP1B genetic polymorphisms appear to be prognostic and diagnostic markers for OSCC and DM, as well as contributing to genetic profiling research for personalized medicine.

The Interaction between CLSPN Gene Polymorphisms and Alcohol Consumption Contributes to Oral Cancer Progression.

Most disease single nucleotide polymorphisms (SNPs) are regulatory and approximately half of heritability is occupied by the top 1% of genes, with the gene-level structure varying with the number of variants associated with the most common alleles. Cancer occurrence and progression are significantly affected by Claspin (CLSPN) gene polymorphism present in the population, which alters the expression, function, and regulation of the gene. CLSPN genotypes are associated with oral cancer, but the literature on this association is limited. As a result, the goal of this study is to investigate the correlation between CLSPN genotypes and oral cancers' development. This study will explore the presence of four CLSPN SNPs including rs12058760, rs16822339, rs535638 and rs7520495 gene polymorphisms, and analyze the expression of these genes in 304 cancer-free controls and 402 oral squamous cell carcinoma (OSCC) cases. Attempts have been made to obtain insight into the role of CLSPN gene polymorphisms in oral cancer through the analysis of this study. We demonstrated that the OSCC risk of individuals with four CLSPN SNPs relative to the wild type did not differ significantly from that of the wild type when the polymorphisms are analyzed according to individual habits. We further studied the mechanism by which CLSPN polymorphisms affect the progression of clinicopathological features in OSCC patients. The results of the degree of cell differentiation showed that compared with patients of rs7520495 SNP carrying the CC genotype, the incidence of poor cell differentiation in patients carrying the CC + GG genotype was higher (AOR: 1.998-fold; 95% CI, 1.127-3.545; p = 0.018). In particular, patients with the G genotype of rs7520495 had increased poor cell differentiation compared with patients with the C genotype (AOR: 4.736-fold; 95% CI, 1.306-17.178; p = 0.018), especially in the drinking group. On the basis of our analysis of the Cancer Genome Atlas dataset, we found that higher CLSPN levels were associated with poorer cell differentiation in oral cancers. In this study, we provide the first evidence showing that CLSPN SNPs contribute to oral cancer. Whether or not rs7520495 can be used as a confirmatory factor in the future is uncertain, but it seems likely that it can be used as an important factor in predicting recurrence, response to treatment and medication toxicity to patients with oral cancer.

Semilicoisoflavone B induces oral cancer cell apoptosis by targeting claspin and ATR-Chk1 signaling pathways.

The prevalence of oral squamous cell carcinoma (OSCC) is increasing worldwide mainly due to poor oral hygiene and unrestricted lifestyle. Advanced-stage OSCC is associated with poor prognosis and a 5-year survival rate of only 30%-50%. The present study was designed to investigate the anticancer effect and mode of action of Glycyrrhiza-derived semilicoisoflavone B (SFB) in 5-fluorourasil (5FU)-resistant human OSCC cell lines. The study findings revealed that SFB significantly reduces OSCC cell viability and colony formation ability by arresting cell cycle at the G2/M and S phases and reducing the expressions of key cell cycle regulators including cyclin A, cyclin B, CDC2, and CDK2. The compound caused a significant induction in the percentage of nuclear condensation and apoptotic cells in OSCC. Regarding pro-apoptotic mode of action, SFB was found to increase Fas-associated death domain and death receptor 5 expressions and reduce decoy receptor 2 expression, indicating involvement of extrinsic pathway. Moreover, SFB was found to increase pro-apoptotic Bim expression and reduce anti-apoptotic Bcl-2 and Bcl-xL expressions, indicating involvement of intrinsic pathway. Moreover, SFB-mediated induction in cleaved caspases 3, 8, and 9 and cleaved poly(ADP-ribose) polymerase confirmed the induction of caspase-mediated apoptotic pathways. Regarding upstream signaling pathway, SFB was found to reduce extracellular signal regulated kinase 1/2 (ERK) phosphorylation to execute its pro-apoptotic activity. The Human Apoptotic Array findings revealed that SFB suppresses claspin expression, which in turn caused reduced phosphorylation of ATR, checkpoint kinase 1 (Chk1), Wee1, and CDC25C, indicating disruption of ATR-Chk1 signaling pathway by SFB. Taken together, these findings indicate that SFB acts as a potent anticancer compound against 5FU-resistant OSCC by modulating mitogen-activated protein kinase (MAPK) and ATR-Chk1 signaling pathways.

Hellebrigenin induces oral cancer cell apoptosis by modulating MAPK signalling and XIAP expression.

Oral squamous cell carcinoma (OSCC), which accounts for 90% of all oral cancers, has become a public health crisis worldwide. despite advances in therapeutic interventions, the prognosis remains poor for advanced-stage OSCC. In this study, we investigate the anticancer activity and the mode of action of hellebrigenin in human OSCC. The findings demonstrated that hellebrigenin exerted cytotoxic effects in OSCC cells through cell cycle arrest at the G2/M phase and downregulation of cell cycle-related proteins (cyclins A2, B1 and D3, Cdc2, CDK4 and CDK6). Moreover, hellebrigenin caused activation of PARP and caspase 3, 8 and 9, followed by downregulation of antiapoptotic proteins (Bcl-2 and Bcl-xL) and upregulation of pro-apoptotic proteins (Bax and Bak). The hellebrigenin treatment also increased Fas, DR5, DcR2 and DcR3 expressions in oral cancer cells, indicating the compound causes oral cancer cell apoptosis through both intrinsic and extrinsic pathways. Regarding upstream signalling, hellebrigenin was found to reduce the phosphorylation of ERK, p38, and JNK, indicating that hellebrigenin triggers caspase-mediated apoptosis by downregulating MAPK signalling pathway. Finally, the human apoptosis array findings revealed that hellebrigenin specifically suppressed the expression of XIAP to execute its pro-apoptotic activities. Taken together, the study suggests that hellebrigenin can act as a potent anticancer compound in human OSCC.

Picrasidine J, a Dimeric ß-Carboline-Type Alkaloid from Picrasma quassioides, Inhibits Metastasis of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) are associated with recurrence, distant metastasis, and poor overall survival. This highlights the need for identifying potential therapeutics with minimal side-effects. The present study was designed to investigate the anticancer effects of picrasidine J, a dimeric ß-carboline-type alkaloid isolated from the southern Asian plant Picrasma quassioides. The results showed that picrasidine J significantly inhibits HNSCC cell motility, migration, and invasion. Specifically, picrasidine J inhibited the EMT process by upregulating E-cadherin and ZO-1 and downregulating beta-catenin and Snail. Moreover, picrasidine J reduced the expression of the serine protease KLK-10. At the signaling level, the compound reduced the phosphorylation of ERK. All these factors collectively facilitated the inhibition of HNSCC metastasis with picrasidine J. Taken together, the study identifies picrasidine J as a potential anticancer compound of plant origin that might be used clinically to prevent the distant metastasis and progression of HNSCC.

Epiberberine suppresses the metastasis of head and neck squamous cell carcinoma cells by regulating the MMP-13 and JNK pathway.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common histological types of head and neck cancer. Epiberberine is a potent antitumour agent for several types of cancer. This study is aimed at investigating the regulatory and molecular mechanism of epiberberine on HNSSC cell metastasis. The results showed that epiberberine inhibited the motility of Ca9-22 and FaDu cell lines at nontoxicity doses. Moreover, the epithelial-mesenchymal transition (EMT)-related proteins, vimentin, snail and slug, were found suppressing after epiberberine treatments. In addition, the JNK signalling cascade and the metalloproteinase 13 (MMP-13) expression were also found downregulated by epiberberine. In conclusion, the present study demonstrates that epiberberine suppresses cell migration and invasion by regulating the JNK pathway and MMP-13. These results suggest that epiberberine could be a potential antimetastatic agent in HNSCC cells.

Limocitrin increases cytotoxicity of KHYG-1 cells against K562 cells by modulating MAPK pathway.

Natural killer (NK) cells are gaining popularity in the field of cancer immunotherapy. The present study was designed to investigate the effect of a natural flavonol compound limocitrin in increasing cytotoxicity of a permanent NK leukemia cell line KHYG-1 against an aggressive leukemia cell line K562. The findings revealed that limocitrin increased the expressions of cytolytic molecules perforin, granzymes A and B, and granulysin in KHYG-1 cells by inducing phosphorylation of transcription factor CREB, leading to increased lysis of K562 cells. Mechanistically, limocitrin was found to increase the expressions of t-Bid, cleaved caspase 3, and cleaved PARP to induce K562 cell apoptosis. Moreover, limocitrin reduced the expressions of SET and Ape1 to inhibit DNA repair mechanism, leading to caspase-independent K562 cell death. At the molecular level, limocitrin was found to increase the phosphorylation of ERK, p38, and JNK to increase granzyme B expression in KHYG-1 cells. Taken together, the study indicates that limocitrin increases cytotoxicity of NK cells against a range of cancer cells.

FAM13A polymorphisms are associated with a specific susceptibility to clinical progression of oral cancer in alcohol drinkers.

BACKGROUND: Single nucleotide polymorphism (SNP) is a genetic variation that occurs when a single nucleotide base in the DNA sequence varies between individuals and is present in at least 1% of the population. Genetic variants in FAM13A are associated with different types of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and lung cancer. However, there is little literature on the association of FAM13A genotypes with oral cancer. Therefore, this project will explore the correlation between the FAM13A genotype and the formation of oral cancer. METHODS: In this project, we will examine the presence of gene polymorphisms gene polymorphisms of rs1059122, rs3017895, rs3756050, and rs7657817 in the FAM13A gene exon, and combine the expression of these genes to try to clarify the impact of the FAM13A gene polymorphism on oral cancer. First, four loci (rs1059122, rs3017895, rs3756050, and rs7657817) of the FAM13A SNP were genotyped using TaqMan allelic discrimination. RESULTS: By estimating OR and AOR, FAM13A exhibited different genotypic variables in four SNPs that were not statistically significant between controls and patients with oral cancer. The results of the general analysis showed that different distributions of allelic types did not affect clinical stage, tumour size, lymph node invasion, distant metastasis, and pathological differentiation status. However, in the alcohol drinking group specifically, patients with the rs3017895 SNP G genotype had a 3.17-fold (95% CI, 1.102-9.116; p = 0.032) increase in the well differentiated state of cells compared to patients with the A allele. CONCLUSIONS: Our results suggested that the SNP rs3017895 FAM13A could contribute to oral cancer. More sample studies are needed in the future to confirm our results and more functional studies are needed to investigate their relevant roles in the development of oral cancer.

Semilicoisoflavone B Induces Apoptosis of Oral Cancer Cells by Inducing ROS Production and Downregulating MAPK and Ras/Raf/MEK Signaling.

Oral squamous cell carcinoma (OSCC) is the sixth most common type of cancer worldwide. Despite advancement in treatment, advanced-stage OSCC is associated with poor prognosis and high mortality. The present study aimed to investigate the anticancer activities of semilicoisoflavone B (SFB), which is a natural phenolic compound isolated from Glycyrrhiza species. The results revealed that SFB reduces OSCC cell viability by targeting cell cycle and apoptosis. The compound caused cell cycle arrest at the G2/M phase and downregulated the expressions of cell cycle regulators including cyclin A and cyclin-dependent kinase (CDK) 2, 6, and 4. Moreover, SFB induced apoptosis by activating poly-ADP-ribose polymerase (PARP) and caspases 3, 8, and 9. It increased the expressions of pro-apoptotic proteins Bax and Bak, reduced the expressions of anti-apoptotic proteins Bcl-2 and Bcl-xL, and increased the expressions of the death receptor pathway protein Fas cell surface death receptor (FAS), Fas-associated death domain protein (FADD), and TNFR1-associated death domain protein (TRADD). SFB was found to mediate oral cancer cell apoptosis by increasing reactive oxygen species (ROS) production. The treatment of the cells with N-acetyl cysteine (NAC) caused a reduction in pro-apoptotic potential of SFB. Regarding upstream signaling, SFB reduced the phosphorylation of AKT, ERK1/2, p38, and JNK1/2 and suppressed the activation of Ras, Raf, and MEK. The human apoptosis array conducted in the study identified that SFB downregulated survivin expression to induce oral cancer cell apoptosis. Taken together, the study identifies SFB as a potent anticancer agent that might be used clinically to manage human OSCC.

Narciclasine suppresses oral cancer metastasis by modulating cathepsin B and extracellular signal-related kinase pathways.

Oral cancer is a malignancy with unfavorable prognosis due to its high rates of recurrence and lymph node metastasis. Narciclasine is extracted from Narcissus species (Amaryllidaceae), which have antitumor and anti-inflammatory properties. However, the antitumor properties of narciclasine toward oral cancer remain unclear. The present study explored the antimetastatic effects of narciclasine in oral cancer as well as the underlying molecular mechanisms. We treated three oral cancer cell lines with noncytotoxic concentrations of narciclasine and discovered a dose-dependent antimetastatic effect. Mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), were regulated by narciclasine. We further discovered the ERK pathway to directly affect narciclasine-induced metastasis inhibition by combining treatment with narciclasine and ERK inhibitor. Furthermore, downregulation of cathepsin B (CTSB) in the SAS and SCC-47 cell lines revealed the critical role of CTSB in the antimetastatic effect of narciclasine. Our findings indicate that narciclasine inhibits oral cancer metastasis by regulating the ERK pathway and CTSB. This study provides evidence of the mechanism of narciclasine-induced inhibition oral cancer metastasis and suggests potential targets for use in oral cancer treatment.

Shuterin Enhances the Cytotoxicity of the Natural Killer Leukemia Cell Line KHYG-1 by Increasing the Expression Levels of Granzyme B and IFN-γ through the MAPK and Ras/Raf Signaling Pathways.

Natural killer (NK) cell therapy is an emerging tool for cancer immunotherapy. NK cells are isolated from peripheral blood, and their number and activity are limited. Therefore, primary NK cells should be expanded substantially, and their proliferation and cytotoxicity must be enhanced. Shuterin is a phytochemical isolated from Ficus thonningii. In this study, we explored the possible capacity of shuterin to enhance the proliferation and activity of KHYG-1 cells (an NK leukemia cell line). Shuterin enhanced the proliferation of KHYG-1 cells and their cytotoxicity to K562 cells. Moreover, this phytochemical induced the expression of granzyme B by promoting the phosphorylated cyclic adenosine monophosphate response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, the secretion of interferon (IFN)-γ increased with increasing levels of shuterin in KHYG-1 cells and NK cells obtained from adults with head and neck squamous cell carcinoma. Shuterin appeared to induce IFN-γ secretion by increasing the expression of lectin-like transcript 1 and the phosphorylation of proteins involved in the Ras/Raf pathway. Thus, shuterin represents a promising agent for promoting the proliferation and cytotoxicity of NK cells.

7-Epitaxol induces apoptosis in cisplatin-resistant head and neck squamous cell carcinoma via suppression of AKT and MAPK signalling.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although cisplatin-based chemotherapy is commonly used in HNSCC, frequent development of cisplatin resistance is a potential cause of poor HNSCC prognosis. In the present study, we investigated the anticancer efficacy of a major paclitaxel metabolite namely 7-Epitaxol in cisplatin-resistant HNSCC. The findings revealed that 7-Epitaxol exerts cytotoxic effects in cisplatin-resistant HNSCC cell lines by inducing cell cycle arrest and intrinsic and extrinsic apoptotic pathways. Specifically, 7-Epitaxol increased Fas, TNF-R1, DR5, DcR3 and DcR2 expressions, reduced Bcl-2 and Bcl-XL (anti-apoptotic proteins) expressions, and increased Bid and Bim L/S (pre-apoptotic proteins) expressions, leading to activation of caspase-mediated cancer cell apoptosis. At the upstream cell signalling level, 7-Epitaxol reduced the phosphorylation of AKT, ERK1/2 and p38 to trigger apoptosis. In vivo results showed that animals treated with 7-Epitaxol show antitumor growth compared to control animals. Taken together, the study demonstrates the potential anticancer efficacy of 7-Epitaxol in inducing apoptosis of cisplatin-resistant HNSCC cells through the suppression of AKT and MAPK signalling pathways.

Picrasidine I Triggers Heme Oxygenase-1-Induced Apoptosis in Nasopharyngeal Carcinoma Cells via ERK and Akt Signaling Pathways.

Nasopharyngeal carcinoma (NPC) has a higher incidence in Taiwan than worldwide. Although it is a radiosensitive malignancy, cancer recurrence is still high in the advanced stages because of its ability to induce lymph node metastasis. Picrasidine I from Picrasma quassioides has been reported as a potential drug for targeting multiple signaling pathways. The present study aimed to explore the role of picrasidine I in the apoptosis of NPC cells. Our results show that picrasidine I induced cytotoxic effects in NPC cells and caused cell cycle arrest in the sub-G1, S, and G2/M phases. Western blot analysis further demonstrated that the modulation of apoptosis through the extrinsic and intrinsic pathways was involved in picrasidine I-induced cell death. Downregulation of the ERK1/2 and Akt signaling pathways was also found in picrasidine I-induced apoptosis. Additionally, the apoptosis array showed that picrasidine I significantly increased heme oxygenase-1 (HO-1) expression, which could act as a critical molecule in picrasidine I-induced apoptosis in NPC cells. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets also revealed that the HMOX1 mRNA level (HO-1) is lower in patients with head and neck squamous carcinoma (HNSCC) and NPC than in patients without cancer. Our study indicated that picrasidine I exerts anticancer effects in NPC by modulating HO-1 via the ERK and Akt signaling pathways.

Association of KMT2C Genetic Variants with the Clinicopathologic Development of Oral Cancer.

Lysine methyltransferase 2C (KMT2C) is a tumor-suppressor gene in several myeloid cells and epithelia and is linked with blood and solid tumor cancers. KMT2C single-nucleotide polymorphisms (SNPs) are also connected with several cancer types. Our study aimed to explore the potential genetic polymorphisms of KMT2C in oral cancer. Five KMT2C SNPs, including rs201834857, rs4725443, rs6464221, rs74483926, and rs6943984, were evaluated in 284 cancer-free controls and 284 oral squamous cell carcinoma (OSCC) cases. We found that individuals with the TC genotype or TC + CC genotype of rs4725443 had a higher risk of oral cancer incidence than those with the TT genotype. Further analysis of KMT2C SNP rs4725443 revealed that the TC + CC genotype of rs4725443 was associated with a significantly advanced tumor stage in the non-alcohol-drinking population. Moreover, the TC + CC genotype of rs4725443 was connected with poor cell differentiation in the alcohol-drinking population. Through analyzing a dataset from The Cancer Genome Atlas (TCGA), we found that reduced KMT2C levels were associated with advanced tumor stage, lymph node invasion, and poor cell differentiation in head and neck squamous cell carcinomas. Our data suggest that KMT2C SNP rs4725443 is a potential genetic marker for oral cancer patients in both non-alcohol-drinking and alcohol-drinking populations.

Xanthohumol targets the JNK1/2 signaling pathway in apoptosis of human nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is one of the most aggressive malignant tumors of the head and neck. Xanthohumol (Xn) is a compound extracted in a high concentration from the hard resin of hops (Humulus lupulus L.), the basic raw material of beer. This study investigated the apoptotic effect and anticancer properties of Xn in human NPC cell lines. Our study demonstrated that at the concentration 40 µM, Xn significantly reduced cell viability and promoted cell cycle arrest in the G2/M phase in two cell lines. The results indicated that Xn induced apoptosis in NPC cell lines through annexin V/propidium iodide staining, chromatin condensation, and apoptosis-related pathways. Xn upregulated the expression of apoptosis-related proteins, namely DR5, cleaved RIP, caspase-3, caspase-8, caspase-9, PARP, Bim, and Bak, and it downregulated the expression of Bcl-2. Xn upregulated the c-Jun N-terminal kinase (JNK) in the mitogen-activated protein kinase (MAPK), and the inhibition of JNK clearly resulted in decreasing expression of Xn-activated cleaved caspase-3 and PARP. Our research provides sufficient evidence to confirm that Xn induces the MAPK JNK pathway to promote apoptosis of NPC and is expected to become a safe and acceptable treatment option for human NPC.

Anticancer effects of picrasidine I on oral squamous cell carcinoma.

Picrasidine I is a dimeric alkaloid derived from a Southern Asian plant Picrasma quassioides and demonstrated to possess pharmacological activities, such as anti-inflammatory and anti-osteoclastogenic effects. However, its potential anticancer effect remains unclear. In the present study, anticancer activity of picrasidine I was assessed by treating oral squamous cell carcinoma cells with different concentrations of picrasidine I (20, 30, and 40 µM) for 24, 48, and 72 h. The findings revealed that picrasidine I reduced the cell viability in a dose-dependent manner. Picrasidine I exerted its cytotoxic effect through arresting cell cycle at G2/M phase by downregulating cyclin A, cyclin B, CDK4, and CDK6, and inducing apoptosis in oral cancer cells. The induction of apoptosis was evidenced by increasing expression of death receptors, disruption of mitochondrial membrane potential, increased activation of PARP and caspases 3, 8, and 9, enhanced expression of proapoptotic mediators (Bak and Bim L/S), and reduced expression of antiapoptotic mediators (Bcl-2 and Bcl-xL). Moreover, analysis of MAPK signaling pathway revealed that picrasidine I-mediated proapoptotic activities by downregulating JNK phosphorylation. Taken together, the study identifies picrasidine I as a potent anticancer agent that can be used as a therapeutic intervention against oral squamous cell carcinoma.

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway.

As the main derivative of paclitaxel, 7-Epitaxol is known to a have higher stability and cytotoxicity. However, the anticancer effect of 7-Epitaxol is still unclear. The purpose of this study was to explore the anticancer effects of 7-Epitaxol in squamous cell carcinoma of the head and neck (HNSCC). Our study findings revealed that 7-Epitaxol potently suppressed cell viability in SCC-9 and SCC-47 cells by inducing cell cycle arrest. Flow cytometry and DAPI staining demonstrated that 7-Epitaxol treatment induced cell death, mitochondrial membrane potential and chromatin condensation in OSCC cell lines. The compound regulated the proteins of extrinsic and intrinsic pathways at the highest concentration, and also increased the activation of caspases 3, 8, 9, and PARP in OSCC cell lines. Interestingly, a 7-Epitaxol-mediated induction of LC3-I/II expression and suppression of p62 expression were observed in OSCC cells lines. Furthermore, the MAPK inhibitors indicated that 7-Epitaxol induces apoptosis and autophagy marker proteins (cleaved-PARP and LC3-I/II) by reducing the phosphorylation of ERK1/2. In conclusion, these findings indicate the involvement of 7-Epitaxol in inducing apoptosis and autophagy through ERK1/2 signaling pathway, which identify 7-Epitaxol as a potent cytotoxic agent in HNSCC.

Chrysosplenol D Triggers Apoptosis through Heme Oxygenase-1 and Mitogen-Activated Protein Kinase Signaling in Oral Squamous Cell Carcinoma.

Chrysosplenol D, a flavonol isolated from Artemisia annua L., can exert anticancer effects. This study investigated the anticancer property of chrysosplenol D and its underlying mechanism in oral squamous cell carcinoma (OSCC). We observed that chrysosplenol D reduced cell viability and caused cell cycle arrest in the G2/M phase. The findings of annexin V/propidium iodide staining, chromatin condensation, and apoptotic-related protein expression revealed that chrysosplenol D regulated apoptosis in OSCC. Furthermore, chrysosplenol D altered the expression of the autophagy marker LC3 and other autophagy-related proteins. Phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase (MAPK) were downregulated by chrysosplenol D, and the inhibition of these pathways significantly enhanced chrysosplenol D-induced cleaved poly (ADP-ribose) polymerase activation. Moreover, the upregulation of heme oxygenase-1 (HO-1) was found to be critical for chrysosplenol D-induced apoptotic cell death. The analysis of clinical data from The Cancer Genome Atlas and Gene Expression Omnibus datasets revealed that patients with head and neck cancer had lower HO-1 expression than did those with no head and neck cancer. The findings of the present study indicated that chrysosplenol D exerts anticancer effects on OSCC by suppressing the MAPK pathway and activating HO-1 expression.

PlatyphyllenoneExerts Anti-Metastatic Effects on Human Oral Cancer Cells by Modulating Cathepsin L Expression, MAPK Pathway and Epithelial-Mesenchymal Transition.

Advanced-stage oral cancers with lymph node metastasis are associated with poor prognosis and a high mortality rate. Although recent advancement in cancer treatment has effectively improved the oral cancer prognosis, the majority of therapeutic interventions are highly expensive and are associated with severe sideeffects. In the present study, we studied the efficacy of a diarylheptanoid derivative, platyphyllenone, in modulating the metastatic potential of human oral cancer cells. Specifically, we treated the human oral cancer cells (FaDu, Ca9-22, and HSC3) with different concentrations of platyphyllenone and measured the cell proliferation, migration, and invasion. The study findings revealed that platyphyllenonesignificantly inhibited the motility, migration, and invasion of human oral cancer cells. Mechanistically, platyphyllenone reduced p38 phosphorylation, decreased ß-catenin and Slug, increased E-cadherin expression, and reduced cathepsin L expression, which collectively led to a reduction in cancer cell migration and invasion. Taken together, our study indicates that platyphyllenone exerts significant anti-metastatic effects on oral cancer cells by modulating cathepsin L expression, the MAPK signaling pathway, and the epithelial-mesenchymal transition process.