salubrinal and Liver-Neoplasms

We investigated the antitumor activity and mechanism of an extract from

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Proliferation; Cinnamates; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Ganoderma; Hep G2 Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms; Spores, Fungal; Thiourea; Up-Regulation

Hepatocellular carcinoma (HCC) is the one of the most common cancers worldwide. Because the side effects of current treatments are severe, new effective therapeutic strategies are urgently required. Pterostilbene (PT), a natural analogue of resveratrol, has diverse pharmacologic activities, including antioxidative, anti-inflammatory and antiproliferative activities. Here we demonstrated that PT inhibits HCC cell growth without the induction of apoptosis in an endoplasmic reticulum (ER) stress- and autophagy-dependent manner. Mechanistic studies indicated that the combination of salubrinal and PT modulates ER stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. An in vivo xenograft analysis revealed that PT significantly reduced tumour growth in mice with a SK-Hep-1 tumour xenograft. Taken together, our results yield novel insights into the pivotal roles of PT in ER stress- and autophagy-dependent cell death in HCC cells.

Topics: Activating Transcription Factor 4; Animals; Antineoplastic Agents; Apoptosis; Autophagosomes; Autophagy; Carcinoma, Hepatocellular; Cinnamates; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Female; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Signal Transduction; Stilbenes; Thiourea; Transplantation, Heterologous

Hepatocellular carcinoma (HCC) responds poorly to conventional systemic therapies. The first-in-class proteasome inhibitor bortezomib has been approved in clinical use for hematologic malignancies and has shown modest activity in solid tumors, including HCC. However, a considerable proportion of patients fail to respond and experience important adverse events. Recently, the next-generation orally bioavailable irreversible proteasome inhibitor oprozomib was developed. Here, we assessed the efficacy of oprozomib and its effects on the unfolded protein response (UPR), a signaling cascade activated through the ATF6, PERK and IRE1 pathways by accumulation of unfolded proteins in the endoplasmic reticulum, in HCC. The effects of oprozomib and the role of the UPR were evaluated in HCC cell lines and in diethylnitrosamine-induced and xenograft mouse models for HCC. Oprozomib dose-dependently reduced the viability and proliferation of human HCC cells. Unexpectedly, oprozomib-treated cells displayed diminished cytoprotective ATF6-mediated signal transduction as well as unaltered PERK and IRE1 signaling. However, oprozomib increased pro-apoptotic UPR-mediated protein levels by prolonging their half-life, implying that the proteasome acts as a negative UPR regulator. Supplementary boosting of UPR activity synergistically improved the sensitivity to oprozomib via the PERK pathway. Oral oprozomib displayed significant antitumor effects in the orthotopic and xenograft models for HCC, and importantly, combining oprozomib with different UPR activators enhanced the antitumor efficacy by stimulating UPR-induced apoptosis without cumulative toxicity. In conclusion, next-generation proteasome inhibition by oprozomib results in dysregulated UPR activation in HCC. This finding can be exploited to enhance the antitumor efficacy by combining oprozomib with clinically applicable UPR activators.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Cinnamates; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Liver Neoplasms; Mice; Nelfinavir; Oligopeptides; Proteasome Inhibitors; Thiourea; Tunicamycin; Unfolded Protein Response; Xenograft Model Antitumor Assays

Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-

Topics: Animals; Anthozoa; Anthracenes; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Cinnamates; Diterpenes; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; Mitochondria; Signal Transduction; Thiourea; Transcription Factor CHOP; Unfolded Protein Response

6-Shogaol is an active compound isolated from Ginger (Zingiber officinale Rosc). In this work, we demonstrated that 6-shogaol induces apoptosis in human hepatocellular carcinoma cells in relation to caspase activation and endoplasmic reticulum (ER) stress signaling. Proteomic analysis revealed that ER stress was accompanied by 6-shogaol-induced apoptosis in hepatocellular carcinoma cells. 6-shogaol affected the ER stress signaling by regulating unfolded protein response (UPR) sensor PERK and its downstream target eIF2α. However, the effect on the other two UPR sensors IRE1 and ATF6 was not obvious. In prolonged ER stress, 6-shogaol inhibited the phosphorylation of eIF2α and triggered apoptosis in SMMC-7721 cells. Salubrinal, an activator of the PERK/eIF2α pathway, strikingly enhanced the phosphorylation of eIF2α in SMMC-7721 cells with no toxicity. However, combined treatment with 6-shogaol and salubrinal resulted in significantly increase of apoptosis and dephosphorylation of eIF2α. Overexpression of eIF2α prevented 6-shogaol-mediated apoptosis in SMMC-7721 cells, whereas inhibition of eIF2α by small interfering RNA markedly enhanced 6-shogaol-mediated cell death. Furthermore, 6-shogaol-mediated inhibition of tumor growth of mouse SMMC-7721 xenograft was associated with induction of apoptosis, activation of caspase-3, and inactivation of eIF2α. Altogether our results indicate that the PERK/eIF2α pathway plays an important role in 6-shogaol-mediated ER stress and apoptosis in SMMC-7721 cells in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Catechols; Cell Line, Tumor; Cell Survival; Cinnamates; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; eIF-2 Kinase; Electrophoresis, Gel, Two-Dimensional; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Humans; Liver Neoplasms; Mice; Neoplasm Proteins; Phosphorylation; RNA, Small Interfering; Thiourea; Time Factors; Transcription Factor CHOP; Unfolded Protein Response; Up-Regulation; Xenograft Model Antitumor Assays