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Cervical cancer is the third most common cancer and the third leading cause of death among women. However, the standard treatment for cervical cancer includes cisplatin, which can cause side effects such as hematological damage or renal toxicity. New innovations in cervical cancer treatment focus on developing more effective and better-tolerated therapies such as Sp1-targeting drugs. Previous studies suggested that mithramycin A (Mith) inhibits the growth of various cancers by decreasing Sp1 protein. However, how Sp1 protein is decreased by Mith is not clear. Few studies have investigated the regulation of Sp1 protein by proteasome-dependent degradation as a possible control mechanism for the regulation of Sp1 in cancer cells. Here, we show that Mith decreased Sp1 protein by inducing proteasome-dependent degradation, thereby suppressing cervical cancer growth through a DR5/caspase-8/Bid signaling pathway. We found that prolonged Mith treatment was well tolerated after systemic administration to mice carrying cervical cancer cells. Reduction of body weight was minimal, indicating that Mith was a good therapeutic candidate for treatment of cancers in which Sp1 is involved in promoting and developing disease.

Background Variants in the Axis Inhibition Protein 2 (AXIN2) have been associated with tooth agenesis, a congenital condition characterized by missing teeth, and an increased risk of various cancers. Studies suggest that individuals with AXIN2 variants may exhibit both dental anomalies and a predisposition to malignancies, particularly colorectal cancer. This raises the possibility that tooth agenesis could serve as an early clinical marker for identifying individuals at higher cancer risk. Method A systematic review was conducted using data from 20 studies with 91 patients carrying 34 unique AXIN2 variants. The number and pattern of missing teeth, as well as the occurrence of cancer types, were evaluated. The genotypic location of AXIN2 variants was also assessed for clinical significance. Results Most AXIN2 variants were located within the SMAD3 domain. Patients with both tooth agenesis and cancer were more common than those with either condition alone. Among the mutation types, nonsense AXIN2 variants were associated with the most severe tooth agenesis phenotype, averaging 12.9 missing teeth. Second premolars were most frequently missing, and maxillary central incisors were least affected. Regarding cancer, colorectal cancer and polyps were the most common malignancies observed in both sexes, followed by breast and ovarian cancer in females and skin cancer in males. Conclusions Tooth agenesis, especially in individuals with AXIN2 variants affecting the SMAD3 domain, may serve as a clinical marker for identifying individuals at increased cancer risk. Recognizing congenital missing teeth in patients with AXIN2 mutations can aid in early cancer screening, improving early detection and outcomes through timely interventions and surveillance.

The rhizome of Zingiber officinale (Z. officinale), commonly known as ginger, has been characterized as a potential drug candidate due to its antitumor effects. However, the chemotherapeutic effect of ginger on human oral cancer remains poorly understood. In this study, we examined the effects of an ethanol extract of Z. officinale rhizomes (ZOE) on oral cancer and identified the components responsible for its pharmacological activity. ZOE exerts its inhibitory activity in oral cancer by inducing both autophagy and apoptosis simultaneously. Mechanistically, ZOE‐induced autophagy and apoptosis in oral cancer are attributed to the reactive oxygen species (ROS)‐mediated endoplasmic reticulum stress response. Additionally, we identified two active components of ZOE, 1‐dehydro‐6‐gingerdione and 8‐shogaol, which were sufficient to stimulate autophagy initiation and apoptosis induction by enhancing CHOP expression. These results suggest that ZOE and its two active components induce ROS generation, upregulate CHOP, initiate autophagy and apoptosis, and hold promising therapeutics against human oral cancer. ZOE targets CHOP, initiates autophagy and apoptosis, and may be useful therapeutics against human oral cancer.

Silymarin, a standardized extract from milk thistle fruits has been found to exhibit anti-cancer effects against various cancers. Here, we explored the anti-cancer activity of silymarin and its molecular target in human oral cancer in vitro and in vivo. Silymarin dose-dependently inhibited the proliferation of HSC-4 oral cancer cells and promoted caspase-dependent apoptosis. A human apoptosis protein array kit showed that death receptor 5 may be involved in silymarin-induced apoptosis, which was also shown through western blotting, immunocytochemistry, and reverse transcription-polymerase chain reaction. Silymarin increased cleaved caspase-8 and truncated Bid, leading to accumulation of cytochrome c. In addition, silymarin activated death receptor 5/caspase-8 to induce apoptotic cell death in two other oral cancer cell lines (YD15 and Ca9.22). Silymarin also suppressed tumor growth and volume without any hepatic or renal toxicity in vivo. Taken together, these results provide in vitro and in vivo evidence supporting the anti-cancer effect of silymarin and death receptor 5, and caspase-8 may be essential players in silymarin-mediated apoptosis in oral cancer.

Apigenin, an aromatic compound, exhibits antioxidant, anti-inflammatory and anti-viral effects. The present study aimed to investigate the effects of apigenin on cell proliferation and apoptosis of human melanoma cells A375P and A375SM. Therefore, melanoma cells were treated with apigenin to determine its anti-proliferative and survival effects, using wound healing and MTT assays. The results revealed that melanoma cell viability was decreased in a dose-dependent manner. Furthermore, chromatin condensation, indicating apoptosis, was significantly increased in a dose-dependent manner, as demonstrated by DAPI staining. In addition, increased apoptosis rate following treatment with apigenin was confirmed by Annexin V-propidium iodide staining. The changes in the expression levels of apoptosis-related proteins in A375P and A375SM melanoma cells were subsequently detected using western blot analysis. The results demonstrated that the protein expression levels of Bcl-2 were decreased, whereas those of Bax, cleaved poly ADP-ribose polymerase, cleaved caspase-9 and p53 were upregulated in a dose-dependent manner in apigenin-treated cells compared with those noted in untreated cells. In addition, in apigenin-treated A375P cells, phosphorylated (p)-p38 was upregulated and p-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK) and p-protein kinase B (Akt) were downregulated. However, in A375SM cells, apigenin treatment increased p-ERK and p-JNK and decreased p-p38 and p-Akt protein expression levels. Subsequently, the inhibitory effect of apigenin on tumor growth was investigated in vivo. Tumor volume was significantly reduced in the 25 and 50 mg/kg apigenin-treated groups compared with the control group. Additionally, a TUNEL assay was performed to detect apoptotic cells. Immunohistochemical staining also revealed elevated p-ERK expression in the apigenin-treated group compared with the control group. Overall, the findings of the present study indicated that apigenin attenuated the growth of A375SM melanoma cells by inducing apoptosis via regulating the Akt and mitogen-activated protein kinase signaling pathways.

Poly Adenylate Binding Protein Interacting protein 1 (PAIP1) plays a critical role in translation initiation and is associated with the several cancer types. However, its function and clinical significance have not yet been described in oral squamous cell carcinoma (OSCC) and its associated features like lymph node metastasis (LNM). Here, we used the data available from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) to analyze PAIP1 expression in oral cancer. The publicly available data suggests that PAIP1 mRNA and protein levels were increased in OSCC. The high PAIP1 expression was more evident in samples with advanced stage, LNM, and worse pattern of invasion. Moreover, the in vitro experiments revealed that PAIP1 knockdown attenuated colony forming, the aggressiveness of OSCC cell lines, decreasing MMP9 activity and SRC phosphorylation. Importantly, we found a correlation between PAIP1 and pSRC through the analysis of the IHC scores and CPTAC data in patient samples. Our findings suggest that PAIP1 could be an independent prognostic factor in OSCC with LNM and a suitable therapeutic target to improve OSCC patient outcomes.

Norcantharidin (NCTD), a demethylated analog of cantharidin isolated from blister beetles, has been used as a promising anticancer agent; however, the underlying function of NCTD against human oral squamous cell carcinoma (OSCC) has not been fully understood. Here, this study was aimed to investigate the apoptotic effect and molecular targets of NCTD in human OSCC in vitro and in vivo. The anticancer effects of NCTD and its related molecular mechanisms were evaluated by trypan blue exclusion assay, live/dead assay, western blotting, 4-6-Diamidino-2-Phenylindole (DAPI) staining, flow cytometric analysis, Terminal Deoxynucleotidyl Transferase dUTP Nick end Labeling (TUNEL) assay, and immunohistochemistry. NCTD significantly inhibited cell growth and increased the number of dead cells in HSC-3 and HN22 cell lines. It induced the following apoptotic phenomena: (1) the cleavages of poly (ADP-ribose) polymerase and casepase-3; (2) increase in apoptotic morphological changes (nuclear condensation and fragmentation); (3) increase in annexin V-positive cells or sub-G1 population of cells. NCTD significantly activated the p38 mitogen-activated protein kinase (MAPK) pathway but inactivated the signal transducer and activator of transcription (STAT)3 pathway. A p38 MAPK inhibitor (SB203580) partially attenuated NCTD-induced programmed cell death (apoptosis) in both cell lines, whereas ectopic overexpression of STAT3 did not affect it. NCTD strongly suppressed tumor growth in the tumor xenograft bearing HSC-3 cells, and the number of TUNEL-positive cells increased in NCTD-treated tumor tissues. In addition, NCTD did not cause any histopathological changes in the liver nor the kidney. NCTD induced programmed cell death via the activation of p38 MAPK in OSCC. Therefore, these results suggest that NCTD could be a potential anticancer drug candidate for the treatment of OSCC.

Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been reported to exhibit anticancer activities in several tumors. The aim of the present study was to investigate the anticancer effects and molecular mechanisms of oridonin in mucoepidermoid carcinoma (MEC). Treatment with oridonin induced the apoptosis of MC-3 and YD-15 cell and inhibited the expression of myeloid cell leukemia-1 (MCL-1) through the regulation of the protein level through post-translational regulation in these cell lines. Oridonin significantly increased the expression level of truncated Bid (t-Bid) as a downstream target of MCL-1 and subsequently decreased the mitochondrial membrane potential. The ectopic expression of MCL-1 protein was sufficient to reverse the induction of apoptosis and the increased t-Bid expression induced by oridonin in both cell lines. Taken together, these results suggest that oridonin exerts an apoptotic effect through the modulation of MCL-1 and t-Bid in human MEC cell lines and may thus be a potential anticancer drug candidate for the treatment of human MEC.

Norcantharidin (NCTD), a demethylated derivative of cantharidin, has been reported to exhibit activity against various types of cancers. However, the anti-invasive effects of NCTD and its molecular mechanism in human mucoepidermoid carcinoma (MEC) remain incompletely elucidated. Clonogenic, wound healing, invasion, zymography, western blotting and immunocytochemistry assays were performed in YD-15 cells to investigate the anti-invasive effect of NCTD and its molecular mechanism of action. The inhibitory effects of NCTD on invasiveness were compared with those of a novel focal adhesion kinase (FAK) kinase inhibitor, PF-562271. NCTD markedly suppressed the colony formation, migration, and invasion of YD-15 cells as well as the activities of MMP-2 and MMP-9. It disrupted F-actin reorganization through suppressing the FAK/Paxillin axis. Moreover, NCTD exhibited a powerful anti-invasive effect compared with that of PF-562271 in YD-15 cells. Collectively, these results suggest that NCTD has a potential anti-invasive activity against YD-15 cells. This study may clarify the impact of NCTD on migration and invasion of human MEC cells.

Tolfenamic acid (Tol) is a non‐steroidal anti‐inflammatory drug that was reported to exhibit anticancer activity in pancreatic and colorectal cancer models. This study examined the role of Tol in the death regulation of PC‐3 and DU145 human androgen‐independent prostate cancer cells. The results showed that Tol inhibited cell growth and induced apoptosis, as evidenced by nuclear fragmentation and cleaved caspase 3 and poly(ADP‐ribose) polymerase. Tol suppressed the specificity protein 1 (Sp1) protein in both PC‐3 and DU145 cells. Tol also attenuated Sp1 mRNA and its promoter activity in DU145 cells, but did not alter them in PC‐3 cells, indicating that Tol degrades Sp1 protein in these cells. Tol also downregulated protein levels, mRNA levels and promoter activities of survivin and myeloid cell leukemia‐1, which are downstream targets of Sp1. The expressions of survivin and Mcl‐1 and cancer cell growth were lower in the PC‐3 cells treated with Sp1 interfering RNA and mithramycin A. Moreover, an oral injection of Tol decreased tumor growth and downregulated the Sp1 protein in athymic nude mice bearing DU145 cell xenografts without hepatotoxicity. Overall, Tol downregulates the Sp1 protein to inhibit growth and induce apoptosis in androgen‐refractory prostate cancers, both in vitro and in vivo, that show resistance against many chemotherapeutic agents. (Cancer Sci 2011; 102: 742–748)