Curcumin Analog L48H37 Induces Apoptosis in Human Oral Cancer Cells by Activating Caspase Cascades and Downregulating the Inhibitor of Apoptosis Proteins through JNK/p38 Signaling.

L48H37 is a synthetic curcumin analog that has anticancer potentials. Here, we further explored the anticancer effect of L48H37 on oral cancer cells and its mechanistic acts. Cell cycle distribution was assessed using flow cytometric analysis. Apoptosis was elucidated by staining with PI/Annexin V and activation of the caspase cascade. Cellular signaling was explored using apoptotic protein profiling, Western blotting, and specific inhibitors. Our findings showed that L48H37 significantly reduced the cell viability of SCC-9 and HSC-3 cells, resulting in sub-G1 phase accumulation and increased apoptotic cells. Apoptotic protein profiling revealed that L48H37 increased cleaved caspase-3, and downregulated cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) in SCC-9 cells, and the downregulated cIAP1 and XIAP in both oral cancer cells were also demonstrated by Western blotting. Meanwhile, L48H37 triggered the activation of caspases and mitogen-activated protein kinases (MAPKs). The involvement of c-Jun N-terminal kinase (JNK) and p38 MAPK (p38) in the L48H37-triggered apoptotic cascade in oral cancer cells was also elucidated by specific inhibitors. Collectively, these findings indicate that L48H37 has potent anticancer activity against oral cancer cells, which may be attributed to JNK/p38-mediated caspase activation and the resulting apoptosis. This suggests a potential benefit for L48H37 for the treatment of oral cancer.

Gambogic Acid Induces HO-1 Expression and Cell Apoptosis through p38 Signaling in Oral Squamous Cell Carcinoma.

Gambogic acid (GA), a natural and bioactive compound from the gamboge resin, has been reported to exhibit many oncostatic activities against several types of malignancies. However, its effects on the progression of oral squamous cell carcinoma (OSCC) remain largely unexplored. To fill this gap, we investigated the anticancer role of GA and molecular mechanisms underlying GA's actions in combating oral cancer. We found that GA negatively regulated the viability of OSCC cells, involving induction of the sub-G1 phase and cell apoptosis. In addition, a specific signature of apoptotic proteome, such as upregulation of heme oxygenase-1 (HO-1) and activation of caspase cascades, was identified in GA-treated OSCC. Moreover, such induction of HO-1 expression and caspase cleavage by GA was significantly diminished through the pharmacological inhibition of p38 kinase. In conclusion, these results demonstrate that GA promotes cell apoptosis in OSCC, accompanied with the activation of a p38-dependent apoptotic pathway. Our findings provide potential avenues for the use of GA with high safety and therapeutic implications in restraining oral cancer.

Magnolol Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells through JNK1/2 and p38 Pathways.

Magnolol is a natural compound extracted from Chinese herbal medicine and can induce apoptosis in numerous types of cancer cells. However, the molecular mechanisms of magnolol in oral cancer are still unclear. In this study, we investigated the anti-cancer effects and underlying mechanisms of magnolol in human oral cancer cell lines. Our results exhibited that magnolol inhibited the cell proliferation via inducing the sub-G1 phase and cell apoptosis of HSC-3 and SCC-9 cells. The human apoptosis array and Western blot assay showed that magnolol increased the expression of cleaved caspase-3 proteins and heme oxygenase-1 (HO-1). Moreover, we proved that magnolol induces apoptosis in oral cancer cell lines via the c-Jun N-terminal kinase (JNK)1/2 and p38 pathways. Overall, the current study supports the role for magnolol as a therapeutic approach for oral cancer through JNK1/2- and p38-mediated caspase activation.

Antimetastatic effects of Terminalia catappa leaf extracts on cervical cancer through the inhibition of matrix metalloprotein-9 and MAPK pathway.

The effects of Terminalia catappa leaf extracts (TCE) have been widely investigated, including its antioxidative, anti-inflammatory, and antidiabetic activity, as well as its antimetastatic effects on several types of human cancer. However, no study has examined the antimetastatic potential of TCE in cervical cancer cells. This study aimed to elucidate the potential antimetastatic properties of ethanol extracts of Terminalia catappa in 12-O-tetradecanoylphorbol-13-acetate treated human cervical cancer cells and investigate the signaling pathway of this process. We demonstrated that TCE elicited very low cytotoxicity and significantly inhibited cellular migration and invasion in human HeLa and SiHa cervical cancer cells. Moreover, the gelatin zymography, reverse transcription-polymerase chain reaction (RT-PCR), and real-time PCR analysis revealed that the activity and mRNA level of matrix metalloproteinase-9 (MMP-9) were inhibited by TCE in a concentration-dependent manner. The Western blot results demonstrated that the highest concentration of TCE (100 µg/ml) reduced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) by 46% in the HeLa cell lines. In conclusion, it was revealed that TCE exerted antimetastatic effects on cervical cancer cells by inhibiting the expression of MMP-9 through the ERK1/2 pathway.

Phyllanthus urinaria suppresses human osteosarcoma cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways.

Phyllanthus urinaria is widely used as anti-inflammatory, antiviral, antibacterial, and anti-hepatotoxic medicines in almost every tropical country. However, scientific evidence supporting its use in cancer metastasis is limited, particularly osteosarcoma. We investigated the effect of P. urinaria extract (PUE) on cell viability, invasion, and migration in the human osteosarcoma Saos-2 cell line, and looked at the impact of PUE on several relevant proteases and signaling pathways. This study demonstrates that PUE, at a range of concentrations (from 0 to 100 µg/ml), concentration-dependently inhibited the migration/invasion capacities of Saos-2 without cytotoxic effects. Zymographic and western blot analyses revealed that PUE inhibited the urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) enzyme activity, as well as protein expression. Western blot analysis also showed that PUE inhibits phosphorylation of ERK1/2 and Akt. Testing of mRNA level, quantitative real-time PCR, and promoter assays evaluated the inhibitory effects of PUE on u-PA expression in Saos-2 cells. The chromatin immunoprecipitation (ChIP) assay was reactive to the transcription protein SP-1, which was inhibited by PUE. In conclusion, PUE suppresses human osteosarcoma Saos-2 cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways. Therefore, PUE produces anti-metastatic activity in Saos-2 cells.