Gallic acid is one of the major flavonoids found in plants. It acts as an antioxidant, and seems to have anti-inflammatory, anti-viral, and anti-cancer properties. In this study, we investigated the effects of gallic acid on melanogenesis, including the activation of melanogenesis signaling pathways. Gallic acid significantly inhibited both melanin synthesis and tyrosinase activity in a dose- and time-dependent manner, and decreased the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and dopachrome tautomerase (Dct). In addition, gallic acid also acts by phosphorylating and activating melanogenesis inhibitory proteins such as Akt and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Using inhibitors against PI3K/Akt (LY294002) or MEK/ERK-specific (PD98059), the hypopigmentation effect was suppressed, and the gallic acid-initiated activation of MEK/ERK and PI3K/Akt was also revoked. Gallic acid also increased GSK3β and p-β-catenin expression but down-regulated p-GSK3β. Moreover, GSK3β-specific inhibitor (SB216763) restored gallic acid-induced melanin reduction. These results suggest that activation of the MEK/ERK, PI3K/Akt, and inhibition of Wnt/β-catenin signaling pathways is involved in the melanogenesis signaling cascade, and that activation by gallic acid reduces melanin synthesis via down-regulation of MITF and its downstream signaling pathway. In conclusion, gallic acid may be a potentially agent for the treatment of certain skin conditions.

Liquid biopsy has provided an efficient way for detection of gene alterations in advanced non‐small‐cell lung cancer (NSCLC). However, the correlation between systematic determination of somatic genomic alterations in liquid biopsy and tumor biopsy still remained unclear, and the concordance rate between cell‐free DNA (cfDNA) and matched tumor tissue DNA needs to be increased. A prospective study was performed to detect differences in genetic profiles of cfDNA in sputum, plasma, urine, and tumor tissue from 50 advanced NSCLC patients in parallel by the same next‐generation sequencing (NGS) platform. Driver genes alterations were identified in cfDNA sample and matched tumor sample, with an overall concordance rate of 86% in plasma cfDNA, 74% in sputum cfDNA, 70% in urine cfDNA, and 90% in cfDNA of combination of plasma, sputum, and urine. And the concordant rate of cfDNA in sputum in patients with smoking history was higher than that in patients without history of smoking (89% vs. 66%, P = 0.033) and equal to that in plasma cfDNA of the smoking patients (89% vs. 89%). In conclusion, sputum cfDNA can be considered as an alternative medium to liquid biopsy, while the complementarity of genomic profiles in cfDNA among plasma, sputum, and urine was beneficial to detect more diver genes alterations and improve the utility of liquid biopsy in advanced NSCLC (Liquid Biopsy for Detection of Driver Mutation in NSCLC; NCT02778854).

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Objective Lung cancer is the first leading cause of cancer-related deaths both worldwide and in China and threatens human health and quality of life. New drugs and therapeutic methods are urgently needed. Our study evaluated the roles of dihydroartemisinin (DHA) in lung cancer and further explored its underlying mechanisms. Methods CCK-8, colony formation and trypan blue exclusion assays were used to detect the cell viability, colony formation ability and cell death. qRT-PCR and Western blotting assays were applied to analyze the expressions of key molecules. Results DHA inhibited the proliferation and colony formation abilities and enhanced the cell death and induced ferroptosis of lung NCI-H23 and XWLC-05 cancer cells. DHA reduced PRIM2 expression and silencing PRIM2 mimicked the inhibitory roles on proliferation and colony formation and promotive roles on cell death and ferroptosis of DHA in lung NCI-H23 and XWLC-05 cancer cells. We further found that DHA treatment and loss of PRIM2 reduced the GSH level and increased the cellular lipid ROS and mitochondrial MDA levels, and further downregulated the expressions of SLC7A11 and β-catenin in lung cancer cells, respectively. Exogenetic overexpression of PRIM2 recovered the inhibitory effects of DHA on proliferation and colony formation in lung NCI-H23 cancer cells, meanwhile loss of PRIM2 sensitizes NCI-H23 cells to DHA therapy. In vivo experiment further showed that DHA treatment significantly suppressed the tumor growth and downregulated PRIM2 and SLC7A11. Conclusion Our study suggested that DHA inhibited the proliferation, colony formation and enhanced cell death and induced ferroptosis of lung cancer cells by inactivating PRIM2/SLC7A11 axis. Loss of PRIM2 induced ferroptosis might developed to be a novel therapeutic method in lung cancer therapy.

13-acetoxysarcocrassolide (13-AC), an active compound isolated from cultured Formosa soft coral Sarcophyton crassocaule, was found to possess anti-proliferative and apoptosis-inducing activities against AGS (human gastric adenocarcinoma cells) gastric carcinoma cells. The anti-tumor effects of 13-AC were determined by MTT assay, colony formation assessment, cell wound-healing assay, TUNEL/4,6-Diamidino-2-phenylindole (DAPI) staining, Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and flow cytometry. 13-AC inhibited the growth and migration of gastric carcinoma cells in a dose-dependent manner and induced both early and late apoptosis as assessed by flow cytometer analysis. 13-AC-induced apoptosis was confirmed through observation of a change in ΔΨm, up-regulated expression levels of Bax and Bad proteins, down-regulated expression levels of Bcl-2, Bcl-xl and Mcl-1 proteins, and the activation of caspase-3, caspase-9, p38 and JNK. Furthermore, inhibition of p38 and JNK activity by pretreatment with SB03580 (a p38-specific inhibitor) and SP600125 (a JNK-specific inhibitor) led to rescue of the cell cytotoxicity of 13-AC-treated AGS cells, indicating that the p38 and the JNK pathways are also involved in the 13-AC-induced cell apoptosis. Together, these results suggest that 13-AC induces cell apoptosis against gastric cancer cells through triggering of the mitochondrial-dependent apoptotic pathway as well as activation of the p38 and JNK pathways.

Lung cancer, a leading cause of cancer-related mortality, has a low rate of early diagnosis and a poor prognosis for advanced stages. Recent advances in further mastery of the biology of tumors promote the diagnosis and therapy, especially for non-small cell lung cancer (NSCLC). However, tumor tissue-based information is often not available in most cases due to the invasive and high risk nature of the tumor biopsy procedures. Liquid biopsy, based on the multiple liquid samples including circulating tumor cells (CTC), circulating tumor DNA (ctDNA), and tumor-derived exosome obtained from blood or urine as well as other body fluids, can also provide valuable tumor-related information, playing an important role in management of NSCLC in clinical practice. It is widely believed that concordance of detection for tumor by liquid samples in comparison with tissue biopsy for both early and advanced stage NSCLC patients is optimistic. We herein review the current and future clinical application of liquid biopsy, including early diagnosis and management of precise personalized treatment in lung cancer. The future directions of development for liquid biopsy are also discussed in this review.

Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigated the effects of sinulariolide on A375 melanoma cell growth and protein expression. Sinulariolide suppressed the proliferation and migration of melanoma cells in a concentration-dependent manner and was found to induce both early and late apoptosis by flow cytometric analysis. Comparative proteomic analysis was conducted to investigate the effects of sinulariolide at the molecular level by comparison between the protein profiles of melanoma cells treated with sinulariolide and those without treatment. Two-dimensional gel electrophoresis (2-DE) master maps of control and treated A375 cells were generated by analysis with PDQuest software. Comparison between these maps showed up- and downregulation of 21 proteins, seven of which were upregulated and 14 were downregulated. The proteomics studies described here identify some proteins that are involved in mitochondrial dysfunction and apoptosis-associated proteins, including heat shock protein 60, heat shock protein beta-1, ubiquinol cytochrome c reductase complex core protein 1, isocitrate dehydrogenase (NAD) subunit alpha (down-regulated), and prohibitin (up-regulated), in A375 melanoma cells exposed to sinulariolide. Sinulariolide-induced apoptosis is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome c, and activation of Bax, Bad and caspase-3/-9, as well as suppression of p-Bad, Bcl-xL and Bcl-2. Taken together, our results show that sinulariolide-induced apoptosis might be related to activation of the caspase cascade and mitochondria dysfunction pathways. Our results suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human melanoma.

Sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, has potent anti-microbial and anti-tumorigenesis effects towards melanoma and bladder cancer cells. In this study, we investigated the effects of sinulariolide on hepatocellular carcinoma (HCC) cell growth and protein expression. Sinulariolide suppressed the proliferation and colony formation of HCC HA22T cells in a dose-dependent manner and induced both early and late apoptosis according to flow cytometry, Annexin V/PI stain and TUNEL/DAPI stain analyses. A mechanistic analysis demonstrated that sinulariolide-induced apoptosis was activated through a mitochondria-related pathway, showing up-regulation of Bax, Bad and AIF, and downregulation of Bcl-2, Bcl-xL, MCl-1 and p-Bad. Sinulariolide treatment led to loss of the mitochondrial membrane potential, release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and caspase-3. Sinulariolide-induced apoptosis was significantly blocked by the caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK. The increased expression of cleaved PARP also suggested that caspase-independent apoptotic pathway was involved. In the western blotting; the elevation of ER chaperones GRP78; GRP94; and CALR; as well as up-regulations of PERK/eIF2α/ATF4/CHOP; and diminished cell death with pre-treatment of eIF2α phosphatase inhibitor; salubrinal; implicated the involvement of ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway following sinulariolide treatment in hepatoma cells. The current study suggested sinulariolide-induced hepatoma cell cytotoxicity involved multiple apoptotic signal pathways. This may implicate that sinulariolide is a potential compound for the treatment of hepatocellular carcinoma.