• APR3
• Apoptosis
• Autophagy
• Cancer
• Cell cycle
• Cell death

• Humans
• Apoptosis/genetics
• Apoptosis Regulatory Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/therapy
• Oxidative Stress
• Autophagy/genetics
• NF-kappa B/metabolism

• ER stress
• IRE1α
• Neurodegenerative diseases
• XBP1

Marine microalgae can be used as sustainable protein sources in many fields with positive effects on human and animal health. DAPTMGY is a heptapeptide isolated from Isochrysis zhanjiangensis which is a microalga. In this study, we evaluated its anti-photoaging properties and mechanism of action in human immortalized keratinocytes cells (HaCaT). The results showed that DAPTMGY scavenged reactive oxygen species (ROS) and increase the level of endogenous antioxidants. In addition, through the exploration of its mechanism, it was determined that DAPIMGY exerted anti-photoaging effects. Specifically, the heptapeptide inhibits UVB-induced apoptosis through down-regulation of p53, caspase-8, caspase-3 and Bax and up-regulation of Bcl-2. Thus, DAPTMGY, isolated from I. zhanjiangensis, exhibits protective effects against UVB-induced damage.

• MMPs
• UVB
• apoptosis
• heptapeptide
• photoaging

• Akt/FoxO1/p27(kip1) signaling
• Conditionally reprogrammed hepatocellular carcinoma cells
• Endoplasmic reticulum stress
• Pristimerin
• Sorafenib resistance

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Survival/drug effects
• Cyclin-Dependent Kinase Inhibitor p27/metabolism
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress/drug effects
• Forkhead Box Protein O1/metabolism
• Human Umbilical Vein Endothelial Cells
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Middle Aged
• Pentacyclic Triterpenes/administration & dosage
• Proto-Oncogene Proteins c-akt/metabolism
• Reactive Oxygen Species/metabolism
• Signal Transduction/drug effects
• Sorafenib/administration & dosage
• Tumor Cells, Cultured

Pulmonary fibrosis is the primary reason for mortality in patients with paraquat (PQ) poisoning. Our previous study demonstrated that epithelial-mesenchymal transition (EMT) had a role in PQ-induced pulmonary fibrosis. However, the role of endoplasmic reticulum (ER) stress in PQ-induced EMT remains clear. The present study aimed to determine the role of ER stress in EMT in PQ-induced pulmonary fibrosis. A549 and RLE-6TN cells were incubated with LY294002 (a PI3K inhibitor) or transfected with protein kinase RNA-like ER kinase (PERK) small interfering RNA (si) for 24 h prior to being exposed to PQ. Next, the expression levels of ER stress-related proteins, PI3K/AKT/GSK-3β signaling pathway-related proteins and EMT-related markers were analyzed by performing western blotting, reverse transcription-quantitative PCR and immunofluorescence assays. The results of the present study revealed that the protein expression levels of PERK, phosphorylated (p)-PERK, p-eukaryotic initiation factor 2 (eIF2)α were significantly upregulated in the PQ group, whereas p-PI3K, p-AKT and p-GSK-3β were significantly upregulated in the sicontrol + PQ group compared with the sicontrol group. In vitro, following transfection with siPERK or treatment with the PI3K inhibitor, the protein expression levels of E-cadherin (an epithelial marker) were upregulated, whereas the protein expression levels of α-SMA (a mesenchymal marker) were downregulated. Immunofluorescence analysis revealed that the levels of E-cadherin were markedly upregulated, whereas the levels of α-SMA were notably downregulated following transfection with siPERK compared with the sicontrol group. The results of wound healing assay demonstrated that cell migration in the siPERK + PQ group was markedly decreased compared with the sicontrol + PQ group. These indicated that PQ-induced EMT was suppressed after silencing PERK. The expression levels of p-GSK-3β, p-AKT and p-PI3K were also markedly downregulated in the siPERK + PQ group compared with the sicontrol + PQ group. In conclusion, the findings of the present study suggested that ER stress may promote EMT through the PERK signaling pathway in PQ-induced pulmonary fibrosis. Thus, ER stress may represent a potential therapeutic target for PQ-induced pulmonary fibrosis.

• endoplasmic reticulum stress
• epithelial‑mesenchymal transition
• paraquat
• pulmonary fibrosis

• Autophagy
• Chemoresistance
• Endoplasmic reticulum (ER) stress
• Melanoma
• Unfolding protein response

• Apoptosis
• Autophagy
• Drug Resistance, Neoplasm
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress
• Humans
• Melanoma/drug therapy
• Melanoma/genetics
• Proto-Oncogene Proteins B-raf/genetics
• Signal Transduction
• Skin Neoplasms/drug therapy
• Skin Neoplasms/genetics
• Unfolded Protein Response
• Melanoma, Cutaneous Malignant

• Apoptosis resistance
• Autophagy
• Endoplasmic reticulum stress
• Hepatocellular carcinoma
• Melatonin
• Sorafenib

• calpain (CAPN)
• cancer
• metastasis
• signaling pathway

• Apoptosis
• Atomic force microscopy (AFM)
• Cardiomyopathies
• Cardiotoxicity
• Fluoride toxicity
• Inflammation
• Interleukin-17
• MMP-9
• SEM-EDX
• Ultrastructure

• BRAFV600E
• Bortezomib
• NF-κB
• Vemurafenib
• thyroid cancer

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Bortezomib/pharmacology
• Bortezomib/therapeutic use
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins B-raf/antagonists & inhibitors
• Proto-Oncogene Proteins B-raf/metabolism
• Thyroid Neoplasms/drug therapy
• Vemurafenib/pharmacology
• Vemurafenib/therapeutic use

• P30 GM114732 NIGMS NIH HHS
• R01 HL072889 NHLBI NIH HHS
• U54 GM104940 NIGMS NIH HHS

• Apoptosis
• Cardiovascular toxicity
• Fluoride
• Fluorosis
• H9c2 cardiomyocytes

• Animals
• Apoptosis/drug effects
• Caspase 3/metabolism
• Caspase 9/metabolism
• Cell Line
• Cell Proliferation/drug effects
• Fluorides/metabolism
• Fluorides/toxicity
• Humans
• Membrane Potential, Mitochondrial/drug effects
• Mitochondria/metabolism
• Myocytes, Cardiac/drug effects
• Sodium Fluoride/pharmacology

Oral cancer is a subtype of head and neck cancer which represents 2.65% of all human malignancies. Most of oral cancer is histopathologically diagnosed as oral squamous cell carcinoma (OSCC). OSCC is characterized by a high degree of local invasion and a high rate of metastasis to the cervical lymph nodes. How to prevention and treatment of OSCC is important and imperative. Here, we investigated the therapeutic effect and molecular mechanism of cantharidin, an active compound isolated from blister beetles, on OSCC in vitro. Results showed that cantharidin significantly decreased cell viability in human tongue squamous carcinoma-derived SAS, CAL-27, and SCC-4 cell lines. The further mechanistic studies were carried out in SAS cells. Cantharidin also significantly increased apoptosis-related signals, including caspase-9, caspase-7 and caspase-3 proteins. Besides, cantharidin decreased mitochondrial transmembrane potential (MMP) and induced cytochrome c and apoptosis inducing factor (AIF) release. Cantharidin also increased Bax, Bid, and Bak protein expressions and decreased Bcl-2 protein expression. Cantharidin could also increase the endoplasmic reticulum (ER) stress signals, including the expressions of phosphorylated eIF-2α and CHOP, but not Grp78 and Grp94. Furthermore, cantharidin reduced pro-caspase-12 protein expression. In signals of mitogen-activated protein kinases, cantharidin increased the phosphorylation of JNK, but not ERK and p38. Transfection of shRNA-JNK to OSCC cells effectively reversed the cantharidin-induced cell apoptotic signals, including the mitochondrial and ER stress-related signaling molecules. Taken together, these findings suggest that cantharidin induces apoptosis in OSCC cells via the JNK-regulated mitochondria and ER stress-related signaling pathways.

Goniothalamin, a natural occurring styryl-lactone isolated from Goniothalamus macrophyllus (Blume) Hook. f. & Thomson var. macrophyllus, can trigger cancer cell death in various types of cancer cell. The present study focused on elucidation of the mitochondria-mediated apoptosis associated with endoplasmic reticulum (ER) stress-induced activation of c-Jun NH₂-terminal kinase (JNK) by goniothalamin in HeLa cervical cancer cells. Cell viability was determined using an MTT assay, and DNA condensation and loss of mitochondrial membrane potential were determined using Hoechst 33342 and JC-1 staining, respectively. Flow cytometry was used for cell cycle and phosphatidyl-serine exposure analyses. Apoptotic-associated ER stress signaling pathways were determined using immunoblotting, reverse transcription-polymerase chain reaction (RT-PCR) and RT-quantitative PCR analyses. The results suggested that goniothalamin suppressed cell proliferation in a time- and dose-dependent manner. The induction of apoptosis was confirmed by increased DNA condensation, loss of mitochondrial membrane potential and cell surface phosphatidyl-serine presentation. The cell cycle analysis demonstrated that the goniothalamin-treated HeLa cells were in G2/M arrest. Determination of the caspase cascade and apoptotic proteins indicated the induction of apoptosis through the intrinsic pathway. In addition, the levels of phosphorylated JNK and the transcription factor, C/EBP homologous protein (CHOP), an ER stress-associated apoptotic molecule, were increased in the goniothalamin-treated cells. These data indicated that goniothalamin exerted a cytotoxic effect against HeLa cells via the induction of mitochondria-mediated apoptosis, associated with ER stress-induced activation of JNK.

• apoptosis
• c-Jun NH2-terminal kinase
• cervical cancer
• endoplasmic reticulum stress
• goniothalamin
• transcription factor C/EBP homologous protein

Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail.

IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δψm) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress.

In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.

• FN-γ
• HNSCC
• HO-1
• IDO
• JAK
• STAT1

Flavokawain C (FKC) is a naturally occurring chalcone which can be found in Kava (Piper methysticum Forst) root. The present study evaluated the effect of FKC on the growth of various human cancer cell lines and the underlying associated mechanisms. FKC showed higher cytotoxic activity against HCT 116 cells in a time- and dose-dependent manner in comparison to other cell lines (MCF-7, HT-29, A549 and CaSki), with minimal toxicity on normal human colon cells. The apoptosis-inducing capability of FKC on HCT 116 cells was evidenced by cell shrinkage, chromatin condensation, DNA fragmentation and increased phosphatidylserine externalization. FKC was found to disrupt mitochondrial membrane potential, resulting in the release of Smac/DIABLO, AIF and cytochrome c into the cytoplasm. Our results also revealed that FKC induced intrinsic and extrinsic apoptosis via upregulation of the levels of pro-apoptotic proteins (Bak) and death receptors (DR5), while downregulation of the levels of anti-apoptotic proteins (XIAP, cIAP-1, c-Flip_L, Bcl-xL and survivin), resulting in the activation of caspase-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase (PARP). FKC was also found to cause endoplasmic reticulum (ER) stress, as suggested by the elevation of GADD153 protein after FKC treatment. After the cells were exposed to FKC (60μM) over 18hrs, there was a substantial increase in the phosphorylation of ERK 1/2. The expression of phosphorylated Akt was also reduced. FKC also caused cell cycle arrest in the S phase in HCT 116 cells in a time- and dose-dependent manner and with accumulation of cells in the sub-G1 phase. This was accompanied by the downregulation of cyclin-dependent kinases (CDK2 and CDK4), consistent with the upregulation of CDK inhibitors (p21^Cip1 and p27^Kip1), and hypophosphorylation of Rb.

• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Apoptosis/drug effects
• Caspases/metabolism
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Chalcones/chemistry
• Chalcones/pharmacology
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• DNA Fragmentation/drug effects
• Endoplasmic Reticulum Stress/drug effects
• Enzyme Activation/drug effects
• HCT116 Cells
• HT29 Cells
• Humans
• MAP Kinase Signaling System/drug effects
• MCF-7 Cells
• Membrane Potential, Mitochondrial/drug effects
• Phosphatidylserines/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Receptors, Death Domain/metabolism
• Signal Transduction/drug effects

Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanoma's extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment.

• Melanoma
• Endoplasmic reticulum
• Apoptosis
• Autophagy
• Signaling pathways
• Chemotherapy

A phosphine copper(I) complex [Cu(thp)₄][PF₆] (CP) was recently identified as an efficient in vitro antitumor agent. In this study, we evaluated the antiproliferative activity of CP in leukemia cell lines finding a significant efficacy, especially against SEM and RS4;11 cells. Immunoblot analysis showed the activation of caspase-12 and caspase-9 and of the two effector caspase-3 and -7, suggesting that cell death occurred in a caspase-dependent manner. Interestingly we did not observe mitochondrial involvement in the process of cell death. Measures on semipurified proteasome from RS4;11 and SEM cell extracts demonstrated that chymotrypsin-, trypsin- and caspase-like activity decreased in the presence of CP. Moreover, we found an accumulation of ubiquitinated proteins and a remarkable increase of ER stress markers: GRP78, CHOP, and the spliced form of XBP1. Accordingly, the protein synthesis inhibitor cycloheximide significantly protected cancer cells from CP-induced cell death, suggesting that protein synthesis machinery was involved. In well agreement with results obtained on stabilized cell lines, CP induced ER-stress and apoptosis also in primary cells from B-acute lymphoblastic leukemia patients. Importantly, we showed that the combination of CP with some chemotherapeutic drugs displayed a good synergy that strongly affected the survival of both RS4;11 and SEM cells.

Melanoma is characterized by dysregulated intracellular signalling pathways including an impairment of the cell death machinery, ultimately resulting in melanoma resistance, survival and progression. This explains the tumour's extraordinary resistance to the standard treatment. Imiquimod is a topical immune response modifier (imidazoquinoline) with both antiviral and antitumour activities. The mechanism by which imiquimod triggers the apoptosis of melanoma cells has now been carefully elucidated. Imiquimod‐induced apoptosis is associated with the activation of apoptosis signalling regulating kinase1/c‐Jun‐N‐terminal kinase/p38 pathways and the induction of endoplasmic stress characterized by the activation of the protein kinase RNA‐like endoplasmic reticulum kinase signalling pathway, increase in intracellular Ca²⁺ release, degradation of calpain and subsequent cleavage of caspase‐4. Moreover, imiquimod triggers the activation of NF‐κB and the expression of the inhibitor of apoptosis proteins (IAPs) such as, X‐linked IAP (XIAP) together with the accumulation of reactive oxygen species (ROS). Also, imiquimod triggers mitochondrial dysregulation characterized by the loss of mitochondrial membrane potential (Δψm), the increase in cytochrome c release, and cleavage of caspase‐9, caspase‐3 and poly(ADP‐ribose) polymerase (PARP). Inhibitors of specific pathways, permit the elucidation of possible mechanisms of imiquimod‐induced apoptosis. They demonstrate that inhibition of NF‐kB by the inhibitor of nuclear factor kappa‐B kinase (IKK) inhibitor Bay 11‐782 or knockdown of XIAP induces melanoma apoptosis in cells exposed to imiquimod. These findings support the use of either IKK inhibitors or IAP antagonists as adjuvant therapies to improve the effectiveness topical imiquimod in the treatment of melanoma.

• ER stress
• NF-κB
• apoptosis
• imiquimod
• melanoma

• Breast cancer
• CXCL10
• CXCR3
• CXCR4
• Circulating tumor cells (CTCs)
• MMP-1
• Metastasis
• Survivin

Gambogic acid (GA) was extracted from the dried yellow resin of gamboge (Garcinia hanburyi) which is traditionally used as a coloring material for painting and cloth dying. Gamboge has been also used as a folk medicine for an internal purgative and externally infected wound. We focused on the mechanisms of apoptosis induction by GA through the unfold protein response (ER stress) in HeLa cells.

The cytotoxic effect of GA against HeLa cells was determined by trypan blue exclusion assay. Markers of ER stress such as XBP-1, GRP78, CHOP, GADD34 and ERdj4 were analyzed by RT-PCR and Real-time RT-PCR. Cell morphological changes and apoptotic proteins were performed by Hoechst33342 staining and Western blotting technique.

Our results indicated a time- and dose-dependent decrease of cell viability by GA. The ER stress induction is determined by the up-regulation of spliced XBP1 mRNA and activated GRP78, CHOP, GADD34 and ERdj4 expression. GA also induced cell morphological changes such as nuclear condensation, membrane blebbing and apoptotic body in Hela cells. Apoptosis cell death detected by increased DR5, caspase-8, −9, and −3 expression as well as increased cleaved-PARP, while decreased Bcl-2 upon GA treatment. In addition, phosphorylated JNK was up-regulated but phosphorylated ERK was down-regulated after exposure to GA.

These results suggest that GA induce apoptosis associated with the ER stress response through up-regulation of p-JNK and down-regulation of p-ERK in HeLa cells.

• CAPE
• CD133
• CSC
• E2F1
• MAP kinase
• Melanoma

• Aging-related disease
• ER stress
• Epithelial–mesenchymal transition
• Free radicals
• Mitochondria
• Oxidative stress

• Aging
• Animals
• Cell Survival/drug effects
• Endoplasmic Reticulum/metabolism
• Endoplasmic Reticulum/pathology
• Endoplasmic Reticulum Stress/genetics
• Epithelial-Mesenchymal Transition
• Free Radicals/toxicity
• Hydrogen Peroxide/pharmacology
• Macular Degeneration/metabolism
• Macular Degeneration/pathology
• Mice
• Mitochondria/metabolism
• Mitochondria/pathology
• Oxidative Stress/genetics
• Retinal Pigment Epithelium/metabolism
• Retinal Pigment Epithelium/pathology
• Tobacco Products/toxicity
• Unfolded Protein Response/genetics

• R01 EY019904 NEI NIH HHS
• P30 EY001765 NEI NIH HHS
• R01 EY014005 NEI NIH HHS
• P30EY001765 NEI NIH HHS
• EY019904 NEI NIH HHS

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacokinetics
• Antineoplastic Agents/pharmacology
• Curcumin/chemistry
• Curcumin/pharmacokinetics
• Curcumin/pharmacology
• Humans
• Neoplasms/metabolism

• Aldosterone/adverse effects
• Animals
• Annexin A5/genetics
• Annexin A5/metabolism
• Apoptosis/drug effects
• Apoptosis Inducing Factor/genetics
• Apoptosis Inducing Factor/metabolism
• Calpain/genetics
• Calpain/metabolism
• Caspase 3/genetics
• Caspase 3/metabolism
• Cell Survival
• Cells, Cultured
• In Situ Nick-End Labeling
• L-Lactate Dehydrogenase/metabolism
• Mitochondria/drug effects
• Mitochondria/metabolism
• Myocytes, Cardiac/drug effects
• Myocytes, Cardiac/metabolism
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Spironolactone/pharmacology
• Up-Regulation

Ischemia/reperfusion injury plays a crucial role in renal transplantation, and represents a significant risk factor for acute renal failure and delayed graft function. The pathophysiological contribution of endoplasmic reticulum and mitochondria stress to ischemia/reperfusion injury has also been highlighted. Berberine (BBR) has been showed to attenuate ischemia/reperfusion injury by inhibiting oxidative stress. The study was carried out to investigate whether the pretreatment of BBR could reduce hypoxia/reoxygenation (H/R)-induced injury by inhibiting mitochondria stress and endoplasmic reticulum stress pathways.

The cultured human renal proximal tubular cell line HK-2 cells were exposed to 24 h hypoxia (5% CO₂, 1% O₂, 94% N₂) followed by 3 h reoxygenation (5% CO₂, 21% O₂, 74% N₂). And BBR was added to the culture medium 2h prior to the treatment. Then the cell viability, oxidative stress level, morphological change of apoptosis and apoptotic rate were determined. In addition, Western blot analysis was performed to identify the expression of apoptotic pathway parameters, including Bcl-2, Bax and cytochrome C involved in mitochondrial-dependent pathway and ER stress hallmarks such as glucose-regulated protein 78 and CCAAT/enhancer binding protein homologous protein.

H/R produced dramatic injuries in HK-2 cells. The cell viability and the oxidative stress level in group H/R was significantly decreased. The classical morphological change of apoptosis was found, while the apoptotic rate and the expression of proteins involved in mitochondrial stress and endoplasmic reticulum stress pathways increased (p<0.05). Administration of BBR significantly inhibited these H/R induced changes (p<0.05).

This study revealed that BBR pretreatment serves a protective role against H/R induced apoptosis of human renal proximal tubular cells, and the mechanism is related to suppression of mitochondrial stress and endoplasmic reticulum stress pathways.

Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy.

• Apoptosis/drug effects
• Cell Line, Tumor
• Dichloroacetic Acid/pharmacology
• Humans
• MAP Kinase Signaling System/drug effects
• Oxidation-Reduction/drug effects
• Reactive Oxygen Species/metabolism
• Sulindac/pharmacology

• K01 CA095620 NCI NIH HHS
• R15 CA122001 NCI NIH HHS
• 5K01CA95620 NCI NIH HHS

Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies.

• Hepatitis C virus
• Hepatocellular carcinoma
• Extrahepatic
• Signalling
• Therapy