• chemotherapy
• gene and drug delivery
• gene therapy
• hepatocellular carcinoma
• hybrid nanosystem

• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/therapy
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Genetic Therapy/methods
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Cell Line, Tumor
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Membrane Potential, Mitochondrial/drug effects
• Apoptosis/drug effects
• Hep G2 Cells
• Nanoparticles/chemistry
• Combined Modality Therapy

• European Regional Development Fund (ERDF) through the COMPETE 2020 program (Operational Program for Competitiveness and Internationalization) and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia

Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.

• Pancreatic carcinoma
• Targeted therapy
• Cancer stem cell
• Monoclonal antibody
• Epigenetic modifier

• DNA damage response
• PARP inhibitors
• clinical trials
• combination therapy
• small molecular inhibitors

• Humans
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Neoplasms/drug therapy
• Neoplasms/pathology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Combined Modality Therapy
• Precision Medicine

• head and neck cancer
• cancer therapy

• ADP, adenosine diphosphate
• ATP, adenosine triphosphate
• Aha1, activator of Hsp90 ATPase homologue 1
• CTD, C-terminal domain
• Cdc37, cell division cycle 37
• Disruptors
• Grp94, 94-kD glucose-regulated protein
• HIF-1α, hypoxia-inducing factor-1α
• HIP, Hsp70-interaction protein
• HOP, Hsp70‒Hsp90 organizing protein
• HSQC, heteronuclear single quantum coherence
• Her-2, human epidermal growth factor receptor-2
• Hsp90
• Hsp90, 90-kD heat shock protein
• MD, middle domain
• NTD, N-terminal domain
• Natural products
• PPI, protein−protein interaction
• Peptidomimetics
• Protein−protein interactions
• SAHA, suberoylanilide hydroxamic acid
• SAR, structure–activity relationship
• SUMO, small ubiquitin-like modifier
• Small molecules
• TPR2A, tetratricopeptide-containing repeat 2A
• TRAP1, Hsp75tumor necrosis factor receptor associated protein 1
• TROSY, transverse relaxation-optimized spectroscopy
• hERG, human ether-à-go-go-related gene

Endometrial cancer is the most common cancer of the female reproductive system. Combination treatment with specific agents has been widely used as a targeted therapy for cancer. In this study, we aimed to investigate the anti-proliferative and apoptotic effects of varying concentrations of perifosine and vitamin D on the human endometrial cancer cell line (HEC-1A). HEC-1A cells were exposed to perifosine (10 μM, 30 μM), vitamin D (50 nM, 200 nM) and combinations of both for 48 h and 72 h. Monitoring of cell proliferation in a time-dependent manner was performed with the xCELLigence RTCA DP system. The levels of BCL2, BAX and P53 mRNA expression were examined using RT-qPCR. Apoptosis was determined using Annexin V, which were followed by flow cytometry analysis. Ultra-structural morphology of cells was analyzed by transmission electron microscopy (TEM) for 72 h. The anti-proliferative and apoptotic effects of the perifosine+vitamin D combination (30 μM + 200 nM at 48 h and 10 μM + 200 nM at 72 h) on HEC-1A cells were higher than in perifosine and vitamin D alone. It was observed that perifosine has increased the expression of BAX mRNA in HEC-1A cells in a dose-dependent manner. While perifosine+vitamin D combinations increased P53 mRNA expression in HEC-1A cells we did not find any significant change in BCL2, BAX mRNA expression levels. In TEM examinations of HEC-1A cells, perifosine appeared to lead autophagic cell death, whereas vitamin D caused paraptosis-like cell death and combination of perifosine+vitamin D caused apoptotic and non-apoptotic (paraptotic, autophagic and necrotic) cell death. Therefore, it is considered that the combination of both drugs in the treatment of endometrial cancer might be an alternative and effective treatment option through activating the apoptotic and non-apoptotic cell death mechanisms in cancer cells.

• BAX
• BCL2
• P53
• apoptosis
• endometrial cancer
• proliferation

• Dual PI3K/mTOR inhibitor
• Hepatocellular carcinoma
• PI3K/AKT/mTOR pathway
• Sorafenib

• AKT
• enolase-phosphatase 1
• hepatocellular carcinoma
• omics technologies

• Animals
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/physiopathology
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Liver Neoplasms/pathology
• Liver Neoplasms/physiopathology
• Liver Neoplasms/secondary
• Metabolomics
• Mice
• Multienzyme Complexes/analysis
• Multienzyme Complexes/metabolism
• Proteomics
• Survival Analysis

• chemoresistance
• detection
• pancreatic cancer
• prevention
• treatment

• azurin
• cancer therapy
• membrane modulation
• membrane rafts
• membrane targeted therapy

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Biophysical Phenomena
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Humans
• Molecular Targeted Therapy
• Neoplasms/metabolism
• Neoplasms/pathology

• UID/BIO/04565/2013 Fundação para a Ciência e a Tecnologia

Piwi like RNA-mediated gene silencing 1 (Hiwi) is a human homolog of the Piwi gene family that has been reported to be upregulated in hepatocellular carcinoma (HCC). The present study aimed to investigate the role of Hiwi in the initiation and development of HCC in vitro and in vivo. Adenovirus-mediated Hiwi overexpression was established in primary murine hepatocytes and SMMC7721 HCC cells. Cell viability and proliferation were assessed using MTT and EdU assays, respectively. Cell migration was measured using a scratch migration assay. The cell cycle was assessed using flow cytometry, and the expression of genes associated with the epithelial mesenchymal transition (EMT) was assessed using reverse transcription-quantitative polymerase chain reaction. SMMC7721 cells that stably express Hiwi were also generated and injected subcutaneously into the nude mice, and tumor growth was examined. Recombinant adenovirus encoding green fluorescent protein or Hiwi was delivered by injection into the tail vein, and its effect on murine hepatocyte gene expression was studied. The present study revealed that the overexpression of Hiwi did not affect the proliferation or migration of liver cancer cells and failed to suppress perifosine- or doxorubicin-induced apoptosis in vitro. The tumors of mice that were injected with Hiwi-expressing SMMC7721 cells were not significantly larger compared with mice that were injected with control SMMC7721 cells. Hiwi overexpression did not noticeably alter the expression of genes involved in EMT, either in vitro or in vivo. The results of the present study indicate that although expression of Hiwi is associated with HCC development and progression in the clinic, it does not act as an oncogene in liver cancer cells.

• Hiwi
• apoptosis
• hepatocellular carcinoma
• proliferation

• AKT
• Neuregulin1 (NRG1)
• biological behavior
• inhibition
• lung adenocarcinoma (LUAD)

Atractylenolide II (AT-II) exhibits several biological and pharmacological functions, especially anti-cancer activity as the major sesquiterpene lactones isolated from Atractylodes macrocephala (also named Baizhu in Chinese). However, the effects and mechanisms of AT-II on human gastric cancer remain unclear. Cell Counting Kit-8 (CCK-8) assay, morphological changes, flow cytometry, wound healing assay and Western blot analysis were used to investigate the effects of AT-II on cell proliferation, apoptosis and motility of human gastric carcinoma cell lines HGC-27 and AGS. Our results indicated that AT-II could significantly inhibit cell proliferation, motility and induce apoptosis in a dose and time-dependent manner. Western blot analysis showed that the expression level of Bax was upregulated and the expression levels of B-cell lymphoma-2 (Bcl-2), phosphorylated-protein kinase B (p-Akt) and phosphorylated-ERK (p-ERK) were downregulated compared to control group. In conclusion, the findings suggested that AT-II exerted significant anti-tumor effects on gastric carcinoma cells by modulating Akt/ERK signaling pathway, which might shed light on therapy of gastric carcinoma.

• Atractylenolide II
• apoptosis
• gastric carcinoma
• motility
• proliferation

Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies. In vivo, we further revealed that the chronic administration of low-doses of paclitaxel - i.e. metronomic scheduling - and the anti-Akt perifosine was the most efficient and the best tolerated treatment against NSCLC. Regarding drug mechanism of action, perifosine potentiated the pro-apoptotic effects of paclitaxel, independently of cell cycle arrest, and combining paclitaxel/perifosine resulted in a sustained suppression of glycolytic and mitochondrial metabolism. This study points out that targeting cancer cell bioenergetics may represent a novel therapeutic avenue in NSCLC, and provides a strong foundation for future clinical trials of metronomic MTAs combined with Akt inhibitors.

• Alkylphospholipid
• Antileishmanial activity
• Antitumour lipid
• Antitumour therapy

There is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine.

Phospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients (n = 100). Data were analyzed by Fisher and log-rank test. In vitro studies were performed in 14 PDAC cells, including seven primary cultures, characterized for their Akt1 mRNA and phospho-Akt/Akt levels by quantitative-RT-PCR and immunocytochemistry. Growth inhibitory effects of Akt inhibitors and gemcitabine were evaluated by SRB assay, whereas modulation of Akt and phospho-Akt was investigated by Western blotting and ELISA. Cell cycle perturbation, apoptosis-induction, and anti-migratory behaviors were studied by flow cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method.

Immunohistochemistry of TMAs revealed a correlation between phospho-Akt expression and worse outcome, particularly in patients with the highest phospho-Akt levels, who had significantly shorter overall and progression-free-survival. Similar expression levels were detected in LPC028 primary cells, while LPC006 were characterized by low phospho-Akt. Remarkably, Akt inhibitors reduced cancer cell growth in monolayers and spheroids and synergistically enhanced the antiproliferative activity of gemcitabine in LPC028, while this combination was antagonistic in LPC006 cells. The synergistic effect was paralleled by a reduced expression of ribonucleotide reductase, potentially facilitating gemcitabine cytotoxicity. Inhibition of Akt decreased cell migration and invasion, which was additionally reduced by the combination with gemcitabine. This combination significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028, but not in LPC006 cells. However, targeting the key glucose transporter Glut1 resulted in similar apoptosis induction in LPC006 cells.

These data support the analysis of phospho-Akt expression as both a prognostic and a predictive biomarker, for the rational development of new combination therapies targeting the Akt pathway in PDAC. Finally, inhibition of Glut1 might overcome resistance to these therapies and warrants further studies.

The online version of this article (doi:10.1186/s13045-016-0371-1) contains supplementary material, which is available to authorized users.

• Akt
• Gemcitabine
• Pancreatic ductal adenocarcinoma
• Synergism

• BA
• Hepatocellular carcinoma
• PI3K/Akt
• Sponge

• the National Natural Science Foundation of China
• the National Science and Technology Major Projects for “Major New Drugs Innovation and Development”

• Akt/NF-κB signaling pathway
• cancer metastasis
• hepatocytic precursor (stem-like) cells
• hepatoma cells

• Animals
• Cytokine Receptor gp130/genetics
• Cytokine Receptor gp130/metabolism
• Female
• Hematologic Neoplasms/genetics
• Hematologic Neoplasms/metabolism
• Hematologic Neoplasms/pathology
• Humans
• Male
• Membrane Transport Proteins/genetics
• Membrane Transport Proteins/metabolism
• Mice
• Multiple Myeloma/genetics
• Multiple Myeloma/metabolism
• Multiple Myeloma/pathology
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism
• Urea Transporters

• HL97794 NHLBI NIH HHS
• R01 HL044851 NHLBI NIH HHS
• HL044851 NHLBI NIH HHS
• U01 HL100402 NHLBI NIH HHS
• NHLBI U01HL100402 PHS HHS
• R01 HL097794 NHLBI NIH HHS

• 5-FU resistance
• B7 molecules
• B7-H3
• Colon cancer
• PI3K-Akt
• Thymidylate synthase

• angiogenesis
• glioblastoma
• signalling pathways

• AKT
• Perifosine
• Rhabdomyosarcoma (RMS)
• Signaling and apoptosis

• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Humans
• MAP Kinase Signaling System/drug effects
• Male
• Mice
• Mice, SCID
• Phosphorylcholine/analogs & derivatives
• Phosphorylcholine/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Reactive Oxygen Species/metabolism
• Rhabdomyosarcoma/drug therapy
• Rhabdomyosarcoma/metabolism
• Rhabdomyosarcoma/pathology
• Signal Transduction/drug effects
• Xenograft Model Antitumor Assays

Sorafenib, a tyrosine kinase inhibitor, has been demonstrated to exert anti-tumor effects. However, the molecular mechanisms underlying its effects on bladder cancer remain unknown.

Here, we evaluated the mechanisms responsible for the sorafenib-induced anti-tumor effects on 5637 and T24 bladder cancer cells. We demonstrated that sorafenib reduces cell viability, stimulates lysosome permeabilization and induces apoptosis of bladder cancer cells. These effects are dependent by the activation of cathepsin B released from lysosomes. The sorafenib-increased cathepsin B activity induced the proteolysis of Bid into tBid that stimulates the intrinsic pathway of apoptosis characterized by mitochondrial membrane depolarization, oxygen radical generation and cytochrome c release. Moreover, we found that cathepsin B enzymatic activity, induced by sorafenib, is dependent on its dephosphorylation via PTEN activation and Akt inactivation. Pretreatment with orthovanadate rescued bladder cancer cells from apoptosis. In addition, the Akt inhibitor perifosine increased the sensitivity of bladder cancer cells to sorafenib-induced cytotoxicity.

Overall, our results show that apoptotic cell death induced by sorafenib in bladder cancer cells is dependent on cathepsin B activity and involved PTEN and Akt signaling pathways. The Akt inhibitor perifosine increased the cytotoxic effects of sorafenib in bladder cancer cells.

• Akt
• TKI
• bladder cancer cells
• cathepsin B
• perifosine
• sorafenib

• biomarkers
• hepatocellular carcinoma
• immune therapy
• liver transplantation
• locoregional therapy
• partial hepatectomy
• sorafenib

Lup-20(29)-en-3H-ol (Lupeol), a dietary triterpene, has been shown to possess multiple pharmacological activities including anti-tumor effects

In the current study, we noted that low doses of lupeol (<40 μM) promoted the growth of hepatocellular carcinoma (HCC) cells with a significant activation of the PI3-kinase/Akt signaling pathway. We further investigated the combined anti-tumor effect of lupeol and S14161, a newly identified PI3-Kinase inhibitor in vitro and in vivo

The results demonstrated that lupeol and S14161 could exert a synergistic antitumor effect resulting in chemo-sensitization of HCC to low doses of lupeol. Using an in vivo HCC model, we further demonstrated that lupeol and S14161 synergistically inhibited tumor growth without any adverse effects on body weight

Our studies showed that the activation of PI3-kinase/Akt pathway resulted in the tumor-promoting effect with low doses of lupeol. Combining PI3-kinase inhibitor with lupeol could synergistically augment the anti-tumor effect of lupeol and might be an applicable strategy for HCC therapy.

Recent studies indicated that a synthetic oligonucleotide containing un-methylated CpG oligodeoxynucleotides (CpG-ODN) has a potential function for cancer therapy. In this study, we evaluated the chemosensitizing effects of CpG-ODN in 5-fluorouracil (5-FU)-treated HepG2 human hepatoma cells.

Cell viability assay were utilized to evaluate the direct cytotoxicity of CpG-ODN in the presence or absence of 5-FU in HepG2 cells, and apoptosis as well as cell-cycle was examined by flow cytometry analysis. The mRNA expression of Bcl-2, Livin and Survivin within HepG2 cells treated with CpG-ODN and/or 5-FU were analyzed by Real Time PCR assay in vitro.

CpG-ODN in combination with 5-FU could decrease cell viability, increase apoptosis and further induce HepG2 cells cycle arrest at S phase when compared with CpG-ODN or 5-FU. CpG-ODN or 5-FU could down-regulate the mRNA expression of Bcl-2 within HepG2 cells. The mRNA expression of Livin and Survivin decreased in cells treated with CpG-ODN alone but increased in cells treated with 5-FU alone. However, CpG-ODN in combination with 5-FU could down-regulate the mRNA expression of Livin and Survivin within HepG2 cells.

Our finding demonstrated that CpG-ODN enhanced the chemosentivity of 5-FU in HepG2 human hepatoma cells at least in part by down-regulating the expression of Livin and Survivin, leading to apoptosis and further inducing cell cycle arrest at S phase. Therefore, CpG-ODN may be a potential candidate as chemosensitizer for human hepatocellular carcinoma.

• AMPK
• ERK
• Kawasaki disease
• LPS
• Perifosine
• TNFα

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Blotting, Western
• Caspase 3/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Dose-Response Relationship, Drug
• Doxorubicin/pharmacology
• Drug Synergism
• Enzyme-Linked Immunosorbent Assay
• Etoposide/pharmacology
• Humans
• JNK Mitogen-Activated Protein Kinases/metabolism
• Mechanistic Target of Rapamycin Complex 1
• Multiprotein Complexes/metabolism
• Osteosarcoma/drug therapy
• Osteosarcoma/metabolism
• Osteosarcoma/pathology
• Phosphorylcholine/analogs & derivatives
• Phosphorylcholine/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism
• Tumor Suppressor Protein p53/metabolism

• P50 HD098580 NICHD NIH HHS
• R01 CA254367 NCI NIH HHS

Achieving a cure for high-risk neuroblastoma, the most common extracranial solid tumor in children, remains a formidable task despite the recent addition of antibody-mediated anti-GD2 immunotherapy to established multimodality therapy. The PI3K/Akt pathway is a pivotal signaling pathway utilized by a plethora of receptor tyrosine kinases that contribute to the aggressive phenotype of high-risk neuroblastoma. Akt is aberrantly activated in high-risk neuroblastoma and is therefore an attractive therapeutic target. Perifosine is the best-characterized Akt inhibitor in preclinical studies and in clinical trials in adults, although safety in children is not yet confirmed. It is a synthetic third-generation alkylphospholipid with good oral bioavailability and modest side effects. Perifosine targets the lipid-binding PH domain of Akt and inhibits the translocation of Akt to the cell membrane, an essential step for Akt activation. It decreases Akt phosphorylation and increases caspase-dependent apoptosis in neuroblastoma cell lines, inhibits growth of neuroblastoma xenografts, and overcomes RTK/ligand-mediated chemoresistance. It is currently being studied in two Phase I clinical trials in children with recurrent or refractory solid tumors including neuroblastoma. In the single agent trial (ClinicalTrials.gov identifier NCT00776867), maximum tolerated dose has not yet been reached and pharmacokinetic data has been accrued. In the second study (ClinicalTrials.gov identifier NCT01049841), patients are treated with a combination of perifosine and the mTOR-inhibitor temsirolimus based on preclinical data showing synergy of the two agents, and the premise that direct Akt inhibition may overcome Akt activation secondary to mTOR inhibition. Based on results from adult trials, it is unlikely that perifosine alone will produce dramatic therapeutic effects against high-risk neuroblastoma. However, given the recent encouraging early-phase combination therapy results in adults with multiple myeloma and colorectal carcinoma, rational perifosine-containing combination regimens hold promise for neuroblastoma therapy. These will be explored after safety in children is established in Phase I studies.

• Akt pathway
• neuroblastoma
• perifosine

Thalictrum fortunei S. Moore, a perennial plant distributed in the southeastern part of China, has been used in Traditional Chinese Medicine for thousands of years for its antitumor, antibacterial and immunoregulatory effects. In order to investigate the active components and the mechanism of the anti-tumor effects of Thalictrum fortunei, the growth inhibitory effects of eight triterpenoids isolated from the aerial parts of the plant on tumor cell lines were examined by 3-(4,5)-dimethylthiazoy1-3,5-diphenyltetrazolium bromide (MTT) assay. The MTT-assay results showed that the inhibitory activity of 3-O-β-d-glucopyranosyl-(1→4)-β-d-fucopyranosyl(22S,24Z)-cycloart-24-en-3β,22,26-triol 26-O-β-d-glucopyranoside (1) was stronger than that of the other seven tested triterpenoids on human hepatoma Bel-7402 cell line (Bel-7402), human colon lovo cells (LoVo), human non-small cells lung cancer NCIH-460 cells (NCIH-460) and human gastric carcinoma SGC-7901 cells (SGC-7901) after 48 h treatment in vitro, with the IC₅₀ values of 66.4, 84.8, 73.5, 89.6 μM, respectively. Moreover, the antitumor mechanism of compound 1 on Bel-7402 cell was explored through nucleus dyeing, fluorescence assay, flow cytometry and western blot. The flow cytometric analysis results revealed that compound 1 caused apoptosis and mitochondrial membrane potential (MMP) loss in Bel-7402 cells. A fluorescence assay indicated that intracellular reactive oxygen species (ROS) were markedly provoked by compound 1 treatment compared to control cells. Immunoblot results showed that compound 1 significantly increased the expression levels of cleaved caspase-3, P53 and Bax protein, and decreased the expression level of Bcl-2 protein. These findings indicate that compound 1 inhibits the growth activity of tumor cells, probably through the P53 protein-induced apoptosis pathway.

• Antineoplastic Agents, Phytogenic
• Apoptosis/drug effects
• Bone Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Chondrosarcoma/pathology
• Extracellular Signal-Regulated MAP Kinases/drug effects
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Humans
• JNK Mitogen-Activated Protein Kinases/drug effects
• JNK Mitogen-Activated Protein Kinases/metabolism
• Mitogen-Activated Protein Kinases/drug effects
• Mitogen-Activated Protein Kinases/metabolism
• Phosphorylation/drug effects
• Proto-Oncogene Proteins c-akt/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Xanthones/pharmacology