Cancer formation is a highly regulated and complex process, largely dependent on its microenvironment. This complexity highlights the need for developing novel target-based therapies depending on cancer phenotype and genotype. Autophagy, a catabolic process, removes damaged and defective cellular materials through lysosomes. It is activated in response to stress conditions such as nutrient deprivation, hypoxia, and oxidative stress. Oxidative stress is induced by excess reactive oxygen species (ROS) that are multifaceted molecules that drive several pathophysiological conditions, including cancer. Moreover, autophagy also plays a dual role, initially inhibiting tumor formation but promoting tumor progression during advanced stages. Mounting evidence has suggested an intricate crosstalk between autophagy and ROS where they can either suppress cancer formation or promote disease etiology. This review highlights the regulatory roles of autophagy and ROS from tumor induction to metastasis. We also discuss the therapeutic strategies that have been devised so far to combat cancer. Based on the review, we finally present some gap areas that could be targeted and may provide a basis for cancer suppression.

• ROS
• anticancer therapy resistance
• autophagy
• epithelial–mesenchymal transition
• metastasis
• tumor microenvironment

• Combined therapy
• Histone deacetylases
• Histone deacetylases inhibitors
• Pancreatic cancer
• Precision medicine

• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/pathology
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/therapeutic use
• Histone Deacetylases/genetics
• Histone Deacetylases/therapeutic use
• Humans
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology

• Autophagy
• Cancer
• Liver disease

• Autophagy
• Endoplasmic reticulum (ER) stress
• HDAC inhibitor
• Neratinib
• Sorafenib
• Vorinostat

• AMPK
• Apoptosis
• Autophagy
• Mitochondria
• Reactive oxygen species

• AMP-Activated Protein Kinases/metabolism
• Animals
• Antineoplastic Agents/pharmacology
• Autophagy/drug effects
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Caspase 9/metabolism
• Cell Death/drug effects
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm/drug effects
• Hep G2 Cells
• Humans
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Mitochondria, Liver/drug effects
• Mitochondria, Liver/metabolism
• Nitric Oxide/metabolism
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
• Rats, Wistar
• Signal Transduction/drug effects
• Sorafenib/pharmacology

Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate therapeutic efficiency of GX 15–070, a pan-Bcl-2 family inhibitor, used alone and in combination with conventional drugs or with hydroxychloroquine (HCQ), an autophagy inhibitor.

Five neuroblastoma cell lines were tested for the cytotoxic activity of GX 15–070 alone or in combination with cisplatin, doxorubicin, HCQ or Z-VAD-FMK a broad-spectrum caspase inhibitor. Apoptosis and autophagy levels were studied by western-blot and FACS. Orthotopic injections were performed on NOD/LtSz-scid/IL-2Rgamma null mice that were treated with either GX 15–070 alone or in combination with HCQ.

Synergistic cytotoxicity was observed for the drug combination in all of the 5 neuroblastoma cell lines tested, including MYCN amplified lines and in cancer stem cells. GX 15–070 significantly increased apoptosis and autophagy in neuroblastoma cells as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by HCQ, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agent plays a cytoprotective role. In vivo, GX 15–070 combined with HCQ significantly decreased the growth of the tumor and the number of distant metastases.

Based on the synergistic effect of HCQ and GX 15–070 observed in this study, the combination of these two drugs may be utilized as a new therapeutic approach for neuroblastoma.

• Apoptosis
• Autophagy
• Bcl-2
• GX15–070
• Neuroblastoma

Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. In order to assist the cancer cell in defeating the imbalance between cell growth and cell death, histone deacetylase inhibitors (HDACi) have been employed to reverse epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase- and deacetylase-mediated acetylation of both histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy, which are either mutually exclusive or activated in combination. Here, we compile known molecular signals and pathways involved in the HDACi-triggered induction of apoptosis and autophagy. Currently, the factors that determine the mode of HDACi-elicited cell death are mostly unclear. Correspondingly, we also summarized as yet established intertwined mechanisms, in particular with respect to the oncogenic tumor suppressor protein p53, that drive the interplay between apoptosis and autophagy in response to HDACi. In this context, we also note the significance to determine the presence of functional p53 protein levels in the cancer cell. The confirmation of the context-dependent function of autophagy will pave the way to improve the benefit from HDACi-mediated cancer treatment.

• HDAC
• HDACi
• SAHA
• apoptosis
• autophagy
• cancer
• cell death
• p53
• tumor

Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells. However, it remains an ongoing issue how tumor cells determine to respond to HDACi treatment by preferentially undergoing apoptosis or autophagy. In this review, we summarize HDACi-mediated mechanisms of action, particularly with respect to the induction of cell death. There is a keen interest in assessing suitable molecular factors allowing a prognosis of HDACi-mediated treatment. Addressing the results of our recent study, we highlight the role of p53 as a molecular switch driving HDACi-mediated cellular responses towards one of both types of cell death. These findings underline the importance to determine the mutational status of p53 for an effective outcome in HDACi-mediated tumor therapy.

• HDAC
• HDACi
• SAHA
• apoptosis
• autophagy
• p53
• tumor

Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading unnecessary or dysfunctional cellular organelles and proteins in all living cells. In addition to its vital homeostatic role, this degradation pathway also involves in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. Therefore, the comprehensive understanding of autophagy process, autophagy-related modulators and corresponding pathway and disease information will be of great help for identifying the new autophagy modulators, potential drug candidates, new diagnostic and therapeutic targets. In recent years, some autophagy databases providing structural and functional information were developed, but the specific databases covering autophagy modulator (proteins, chemicals and microRNAs)-related target, pathway and disease information do not exist. Hence, we developed an online resource, Human Autophagy Modulator Database (HAMdb, http://hamdb.scbdd.com), to provide researchers related pathway and disease information as many as possible. HAMdb contains 796 proteins, 841 chemicals and 132 microRNAs. Their specific effects on autophagy, physicochemical information, biological information and disease information were manually collected and compiled. Additionally, lots of external links were available for more information covering extensive biomedical knowledge. HAMdb provides a user-friendly interface to query, search, browse autophagy modulators and their comprehensive related information. HAMdb will help researchers understand the whole autophagy process and provide detailed information about related diseases. Furthermore, it can give hints for the identification of new diagnostic and therapeutic targets and the discovery of new autophagy modulators. In a word, we hope that HAMdb has the potential to promote the autophagy research in pharmacological and pathophysiological area.

• Autophagy
• Autophagy modulator
• Database
• Disease
• Pathophysiological
• Pathway

• Apoptosis
• JNK signaling pathway
• Mcl-1
• RASSF6
• Sorafenib
• Targeted therapy

• Autophagy
• Autophagy inducers
• Cancer

To determine if combination treatment with pemetrexed and sorafenib is safe and tolerable in patients with advanced solid tumors.

Thirty-seven patients were enrolled and 36 patients were treated (24 in cohort A; 12 in cohort B). The cohort A dose schedule resulted in problematic cumulative toxicity, while the cohort B dose schedule was found to be more tolerable. The maximum tolerated dose (MTD) was pemetrexed 750 mg/m² every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m² every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Thirty-three patients were evaluated for antitumor activity. One complete response and 4 partial responses were observed (15% overall response rate). Stable disease was seen in 15 patients (45%). Four patients had a continued response at 6 months, including 2 of 5 patients with triple-negative breast cancer.

A phase I trial employing a standard 3 + 3 design was conducted in patients with advanced solid tumors. Cohort A involved a novel dose escalation schema exploring doses of pemetrexed every 14 days with continuous sorafenib. Cohort B involved a modified schedule of sorafenib dosing on days 1–5 of each 14-day pemetrexed cycle. Radiographic assessments were conducted every 8 weeks.

Pemetrexed and intermittent sorafenib therapy is a safe and tolerable combination for patients, with promising activity seen in patients with breast cancer.

• clinical trial
• pemetrexed
• solid tumors
• sorafenib

• activators
• autophagy
• cancer
• immunity

• Adaptive Immunity/immunology
• Animals
• Autoimmune Diseases/immunology
• Autophagy/drug effects
• Autophagy/immunology
• Autophagy/physiology
• Benzylisoquinolines/pharmacology
• Cholecalciferol/pharmacology
• Humans
• Immune System Diseases/immunology
• Immunity, Innate/immunology
• Indoles
• Infections/immunology
• Isoquinolines/pharmacology
• Lysosomes/metabolism
• Maprotiline/pharmacology
• Metformin/pharmacology
• Neoplasms/immunology
• Phenols/pharmacology
• Pyrroles/pharmacology
• Resveratrol
• Sirolimus/pharmacology
• Spermidine/pharmacology
• Stilbenes/pharmacology
• Tetrahydroisoquinolines/pharmacology
• Trehalose/pharmacology

The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5′ AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance.

• autophagy
• cancer therapeutic
• dug resistance
• hepatocellular carcinoma
• sorafenib

• Acquired resistance
• Autophagy
• Sorafenib
• Targeting kinase inhibitor

Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi‐kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug‐treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, and cyclophilin A. Prolonged ‘rafenib/sildenafil treatment killed tumor cells and also rapidly decreased the expression of: the drug efflux pumps ABCB1 and ABCG2; and NPC1 and NTCP, receptors for Ebola/Hepatitis A and B viruses, respectively. Pre‐treatment with the ‘Rafenib/sildenafil combination reduced expression of the Coxsackie and Adenovirus receptor in parallel with it also reducing the ability of a serotype 5 Adenovirus or Coxsackie virus B4 to infect and to reproduce. Sorafenib/pazopanib and sildenafil was much more potent than sorafenib/pazopanib as single agents at preventing Adenovirus, Mumps, Chikungunya, Dengue, Rabies, West Nile, Yellow Fever, and Enterovirus 71 infection and reproduction. ‘Rafenib drugs/pazopanib as single agents killed laboratory generated antibiotic resistant E. coli which was associated with reduced Dna K and Rec A expression. Marginally toxic doses of ‘Rafenib drugs/pazopanib restored antibiotic sensitivity in pan‐antibiotic resistant bacteria including multiple strains of bla_kpcKlebsiella pneumoniae. Thus, Dna K is an antibiotic target for sorafenib, and inhibition of GRP78/Dna K has therapeutic utility for cancer and for bacterial and viral infections. J. Cell. Physiol. 230: 2552–2578, 2015. © 2015 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

We determined whether the multi‐kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over‐expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK‐1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re‐expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by ‘rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti‐tumor therapy for solid tumor patients. J. Cell. Physiol. 230: 2281–2298, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Obatoclax is a small molecule which targets the Bcl-2 family, and is to treat leukemia, lymphoma and lung carcinoma. Previously, an obatoclax analogue, SC-2001, was found to disrupt the protein-protein interactions of the Bcl-2 family and also repress Bcl-XL and Mcl-1 expression via STAT3 inactivation. Here, we report a novel mechanism of autophagy induction by SC-2001 in liver cancer cells. The findings indicate that SC-2001 induced the autophagy marker LC3-II in four hepatocellular carcinoma (HCC) cells. Autophagosomes induced by SC-2001-treated cells were confirmed by electron microscopy. SC-2001 activated SHP-1, dephosphorylated STAT3 and Mcl-1, and subsequently released free beclin 1. Overexpression of STAT3 and Mcl-1 in PLC5 cells attenuated the induction of SC-2001 on autophagy. Abolishment of SHP-1 by a specific inhibitor aboragated the autophagic effects induced by SC-2001. In addition, it was further revealed that RFX-1, a transcription factor of SHP-1, is a critical regulator in SC-2001-mediated autophagy. Downregulation of RFX-1 by si-RNA protected cells from SC-2001-induced autophagy. Importantly, Huh7 tumor-bearing nude mice treated with SC-2001 showed downregulation of Mcl-1 and p-STAT3 protein expression and upregulation of SHP-1, LC3II, and RFX-1 protein expression. In summary, our data suggest that SC-2001 induces autophagic cell death in a RFX1/SHP-1/STAT3/Mcl-1 signaling cascade.

AIM: To investigate the role of sorafenib (SFN) in autophagy of hepatocellular carcinoma (HCC). We evaluated how SFN affects autophagy signaling pathway in human HCC cell lines.

METHODS: Two different human HCC cell lines, Hep3B and Huh7, were subjected to different concentrations of SFN. Cell viability and onset of apoptosis were determined with colorimetric assay and immunoblotting analysis, respectively. The changes in autophagy-related proteins, including LC3, ULK1, AMPK, and LKB, were determined with immunoblotting analysis in the presence or absence of SFN. To assess autophagic dynamics, autophagic flux was measured with chloroquine, a lysosomal inhibitor. The autophagic responsiveness between different HCC cell lines was compared under the autophagy enhancing conditions.

RESULTS: Hep3B cells were significantly more resistant to SFN than Huh7 cells. Immunoblotting analysis revealed a marked increase in SFN-mediated autophagy flux in Huh7 cells, which was, however, absent in Hep3B cells. While both starvation and rapamycin enhanced autophagy in Huh7 cells, only rapamycin increased autophagy in Hep3B cells. Immunoblotting analysis of autophagy initiation proteins showed that SFN substantially increased phosphorylation of AMPK and consequently autophagy in Huh7, but not in Hep3B cells.

CONCLUSION: The autophagic responsiveness to SFN is distinct between Hep3B and Huh7 cells. Resistance of Hep3B cells to SFN may be associated with altered autophagy signaling pathways.

• Autophagy
• Liver cancer
• Sorafenib

• P30 AG028740 NIA NIH HHS
• R01 DK079879 NIDDK NIH HHS
• R01 DK090115 NIDDK NIH HHS
• T32 CA106493 NCI NIH HHS

• apoptosis
• mucoepidermoid carcinoma
• myeloid cell leukemia-1 (Mcl-1)
• signal transducer and activator of transcription 3 (STAT3)
• sorafenib

AIM: To clarify whether histone deacetylase inhibitors histone deacetylase inhibitors (HDACIs) can sensitize hepatocellular carcinoma (HCC) cells to sorafenib treatment.

METHODS: Bax, Bcl-2, ATG5-ATG12, p21, and p27 protein levels in Hep3B, HepG2, and PLC/PRF/5 cells were examined by Western blot. CCK8 and a fluorometric caspase-3 assay were used to examine cellular viability and apoptosis levels. The effect of Beclin-1 on sensitization of HCC cells to sorafenib was examined by transfecting Beclin-1 siRNA into Hep3B, HepG2, and PLC/PRF/5 cells.

RESULTS: Autophagy inhibition enhances the inhibitory effects of vorinostat and sorafenib alone or in combination on HCC cell growth. Vorinostat and sorafenib synergistically induced apoptosis and cell cycle alterations. Western blot data indicated that HDACIs and Beclin-1 knockdown increased the p53 acetylation level. The knockdown of Beclin-1 enhanced the synergistic effect of the combination of vorinostat with sorafenib.

CONCLUSION: HDACIs can sensitize HCC cells to sorafenib treatment by regulating the acetylation level of Beclin-1.

• Hepatocellular carcinoma
• Histone deacetylase inhibitors
• Autophagy
• Sorafenib
• Chemoresistance

• Acetylation
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Autophagy
• Beclin-1
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Cycle Checkpoints/drug effects
• Cell Proliferation/drug effects
• Dose-Response Relationship, Drug
• Drug Synergism
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Hydroxamic Acids/pharmacology
• Liver Neoplasms/enzymology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Niacinamide/analogs & derivatives
• Niacinamide/pharmacology
• Phenylurea Compounds/pharmacology
• Protein Kinase Inhibitors/pharmacology
• RNA Interference
• Sorafenib
• Transfection
• Tumor Suppressor Protein p53/metabolism
• Vorinostat

• Bcl-2
• Beclin 1
• High grade prostatic intraepithelial neoplasia
• Prostate adenocarcinoma

• Apoptosis
• Autophagy
• BH3 mimetics
• Bcl-2 family
• Cancer therapy

• Aniline Compounds/pharmacology
• Aniline Compounds/therapeutic use
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Autophagy/drug effects
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/metabolism
• Humans
• Indoles
• Molecular Mimicry
• Protein Interaction Domains and Motifs
• Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
• Proto-Oncogene Proteins c-bcl-2/chemistry
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Pyrroles/pharmacology
• Pyrroles/therapeutic use
• Sulfonamides/pharmacology
• Sulfonamides/therapeutic use

• Hodgkin's lymphoma
• cancer
• cell fate
• lymphocytes
• non-Hodgkin's lymphoma

Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.

• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Drug Screening Assays, Antitumor
• Humans
• Ligands
• Mitochondria/metabolism
• Molecular Docking Simulation
• Myeloid Cell Leukemia Sequence 1 Protein
• Prodigiosin/analogs & derivatives
• Prodigiosin/chemistry
• Prodigiosin/metabolism
• Prodigiosin/pharmacology
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-bcl-2/chemistry
• Proto-Oncogene Proteins c-bcl-2/metabolism
• bcl-2 Homologous Antagonist-Killer Protein/metabolism

Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.

• Pancreatic cancer
• Histone deacetylases
• Histone deacetylase inhibitors
• Experimental studies

Deregulated apoptosis is a hallmark of cancer, and the B-cell lymphoma-2 (Bcl-2) family of proteins is pivotal to mediating the intrinsic pathway of this process. Recent advances have yielded both pan-Bcl-2 small molecule inhibitors (SMIs) that inhibit both the Bcl-2 and the Mcl-1 arm of the Bcl-2 family anti-apoptotic proteins, as well as selective SMIs to differentially target the two arms. Of these SMIs, ABT-263 (navitoclax), AT-101 [(-)-gossypol], and obatoclax (GX15-070) are currently in clinical trials for multiple cancers. While pan-Bcl-2 inhibitors such as AT-101 and obatoclax can be more toxic for inhibiting all members of the anti-apoptotic Bcl-2 family of proteins, resistance can quickly develop for ABT-263, a selective Bcl-2 inhibitor. In this article, we discuss the current status of Bcl-2 family SMIs in preclinical and clinical development. As Mcl-1 upregulation is a major mechanism of ABT-263 resistance, Mcl-1-specific inhibitors are expected to be efficacious both in combination/sequential treatments and as a single agent against cancers resistant to ABT-263. 

• Bcl-2
• Drug discovery
• Mcl-1
• apoptosis
• cancer

Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy.

• apoptosis
• autophagy
• cancer
• chloroquine
• lucanthone

• apoptosis
• chk 1 inhibitor
• glioma
• mek1/2 inhibitors

• Antineoplastic Agents/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Benzamides/pharmacology
• Benzimidazoles/pharmacology
• Checkpoint Kinase 1
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• Humans
• MAP Kinase Kinase 1/antagonists & inhibitors
• MAP Kinase Kinase 2/antagonists & inhibitors
• MAP Kinase Kinase 4/metabolism
• Medulloblastoma/drug therapy
• Medulloblastoma/pathology
• Phosphorylation
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases/metabolism
• Protein Kinase Inhibitors/pharmacology
• Protein Kinases/metabolism
• Radiation-Sensitizing Agents/pharmacology
• Staurosporine/analogs & derivatives
• Staurosporine/pharmacology
• Tumor Cells, Cultured
• bcl-2 Homologous Antagonist-Killer Protein/metabolism
• bcl-2-Associated X Protein/metabolism
• bcl-X Protein/metabolism
• src-Family Kinases/antagonists & inhibitors
• src-Family Kinases/metabolism

• T32 CA85159 NCI NIH HHS
• R01 CA100866 NCI NIH HHS
• T32 CA085159 NCI NIH HHS
• R01 CA141703 NCI NIH HHS
• R01 DK052825 NIDDK NIH HHS
• R01 CA150214 NCI NIH HHS

Aberrant Ras/Raf/MEK/ERK signaling is one of the most prevalent oncogenic alterations and confers survival advantage to tumor cells. Inhibition of this pathway can effectively suppress tumor cell growth. For example, sorafenib, a multi-kinase inhibitor targeting c-Raf and other oncogenic kinases, has been used clinically for treating advanced liver and kidney tumors, and also has shown efficacy against other malignancies. However, how inhibition of oncogenic signaling by sorafenib and other drugs suppresses tumor cell growth remains unclear. In this study, we found that sorafenib kills cancer cells by activating PUMA, a p53 target and a BH3-only Bcl-2 family protein. Sorafenib treatment induces PUMA in a variety of cancer cells irrespective of their p53 status. Surprisingly, the induction of PUMA by sorafenib is mediated by IκB-independent activation of NF-κB, which directly binds to the PUMA promoter to activate its transcription. NF-κB activation by sorafenib requires GSK3β activation, subsequent to ERK inhibition. Deficiency in PUMA abrogates sorafenib-induced apoptosis and caspase activation, and renders sorafenib resistance in colony formation and xenograft tumor assays. Furthermore, the chemosensitization effect of sorafenib is dependent on PUMA, and involves concurrent PUMA induction through different pathways. BH3 mimetics potentiate the anticancer effects of sorafenib, and restore sorafenib sensitivity in resistant cells. Together, these results demonstrate a key role of PUMA-dependent apoptosis in therapeutic inhibition of Ras/Raf/MEK/ERK signaling. They provide a rationale for manipulating the apoptotic machinery to improve sensitivity and overcome resistance to the therapies that target oncogenic kinase signaling.

• Animals
• Autophagy/drug effects
• Capecitabine
• Carcinoma, Pancreatic Ductal/pathology
• Cell Line, Tumor
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/therapeutic use
• Drug Resistance, Neoplasm
• Fluorouracil/analogs & derivatives
• Fluorouracil/therapeutic use
• Humans
• Pancreatic Neoplasms/pathology
• Prognosis
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic/physiology
• Gemcitabine