Search tips
Search criteria

Results 1-25 (716)

Clipboard (0)

Select a Filter Below

Year of Publication
1.  Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice 
Cancer Biology & Therapy  2015;16(4):580-588.
Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T-ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (≥0.5 µM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (≥0.5 µM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC.
PMCID: PMC4622865  PMID: 25793663
cell cycle deregulation; Dlx5 homeobox gene; mouse tumor model; Myc and Akt oncogenes; T cell lymphoma
2.  Circulating tumor cell levels are elevated in colorectal cancer patients with high tumor burden in the liver 
Cancer Biology & Therapy  2015;16(5):690-698.
Background: Metastatic spread is the most common cause of cancer-related death in colorectal cancer (CRC) patients, with the liver being the mostly affected organ. Circulating tumor cells (CTCs) are a prognostic marker in stage IV CRC. We hypothesized that tumor burden in the liver correlates with CTC quantity. Methods: Blood (7.5 ml) was prospectively collected from 24 patients with novel stage IV CRC diagnosis. Baseline EpCAM+ CTCs were analyzed with the FDA-approved CellSearch® system. Clinicopathological data were collected, and hepatic tumor burden was determined by radiographic liver volumetry with contrast-enhanced CT scans. CRC primary tumors were immunohistochemically stained for EpCAM expression with BerEP4 monoclonal antibody. Statistical analyses were performed using 2-sample T-test, non-parametric Wilcoxon Rank-Sum test, and Fisher's exact test. Results: CTCs were detected n 17 (71%) of 24 patients. The overall mean CTC number as determined by EpCAM-based CellSearch® detection was 6.3 (SEM 2.9). High baseline CTC numbers (≥3) correlated significantly with a high tumor/liver ratio (≥30%), and with high serum CEA levels, as determined by two-sample T-test on log-transformed data and by Fisher's Exact test on categorical data analysis (P < 0.05). The CRC primary tumors were consistently expressing EpCAM by immunostaining. Conclusions: High tumor burden in the liver and high baseline serum CEA levels are associated with high number of baseline CTCs in stage IV CRC patients. Future studies should further investigate the biological role and expression patterns of single CTCs in cancer patients to further improve personalized treatment strategies.
PMCID: PMC4622723  PMID: 25785486
Colorectal cancer; circulating tumor cells; liver metastasis; stage IV; tumor burden; liver volumetry
3.  4th international conference on tumor progression and therapeutic resistance: meeting report 
Cancer Biology & Therapy  2015;16(3):363-376.
The fourth international conference on tumor progression and therapeutic resistance organized in association with GTCbio was held in Boston, MA from March 9 to 11, 2014. The meeting attracted a diverse group of experts in the field of cancer biology, therapeutics and medical oncology from academia and industry. The meeting addressed the current challenges in the treatment of cancer including tumor heterogeneity, therapy resistance and metastasis along with the need for improved biomarkers of tumor progression and clinical trial design. Keynote speakers included Clifton Leaf, Editor at Fortune Magazine, Dr. Mina Bissell from the Lawrence Berkeley National Laboratory and Dr. Levi Garraway from the Dana Farber Cancer Institute. The meeting featured cutting edge tools, preclinical models and the latest basic, translational and clinical research findings in the field.
PMCID: PMC4622493  PMID: 25782066
cancer therapy; cancer stem cell; metastasis; driver mutation; therapeutic resistance; translational medicine; tumor heterogeneity; tumor microenvironment; tumor progression
4.  Hes1: a key role in stemness, metastasis and multidrug resistance  
Cancer Biology & Therapy  2015;16(3):353-359.
Hes1 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability. Recent studies have shown that Hes1 functions in the maintenance of cancer stem cells (CSCs), metastasis and antagonizing drug-induced apoptosis. Pathways that are involved in the up-regulation of Hes1 level canonically or non-canonically, such as the Hedgehog, Wnt and hypoxia pathways are frequently aberrant in cancer cells. Here, we summarize the recent data supporting the idea that Hes1 may have an important function in the maintenance of cancer stem cells self-renewal, cancer metastasis, and epithelial–mesenchymal transition (EMT) process induction, as well as chemotherapy resistance, and conclude with the possible mechanisms by which Hes1 functions have their effect, as well as their crosstalk with other carcinogenic signaling pathways.
PMCID: PMC4622741  PMID: 25781910
cancer stem cell; chemotherapy resistance; Hes1; metastasis; Notch signaling pathway; non-canonical Notch
5.  Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells 
Cancer Biology & Therapy  2015;16(3):420-429.
Recent studies indicate that post-translational protein neddylation is required for the maintenance of cell viability in several lymphoma cell lines, while inhibition of the neddylation pathway with an NEDD8-activating enzyme (NAE) inhibitor MLN4924 induces apoptosis in lymphoma cells. However, the mechanism by which neddylation inhibition induces apoptosis in lymphoma cells has not been fully elucidated. Moreover, it is unknown whether neddylation inhibition triggers non-apoptotic cell-killing responses, such as cell senescence, in lymphoma cells. Here, we report that MLN4924 specifically inhibited protein neddylation, inactivated cullin-RING E3 ligase (CRL), the best-known neddylation substrate, and induced the accumulation of tumor-suppressive CRL substrates in lymphoma cells. Moreover, MLN4924 potently suppressed the growth of lymphoma cells by inducing G2 cell-cycle arrest, followed by apoptosis or senescence in a cell line-dependent manner. MLN4924-induced apoptosis was mediated by intrinsic apoptotic signaling with substantial up-regulation of pro-apoptotic Bik and Noxa as well as down-regulation of anti-apoptotic XIAP, c-IAP1 and c-IAP2, while senescence induction upon neddylation inhibition seemed dependent on the expression of tumor suppressor p21/p27. Together, these findings expand our understanding on how lymphoma cells respond to neddylation inhibition and support the development of neddylation inhibitors (e.g. MLN4924) for the treatment of lymphoma.
PMCID: PMC4623239  PMID: 25782162
apoptosis; lymphoma; MLN4924; neddylation; senescence
6.  Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells 
Cancer Biology & Therapy  2015;16(3):466-476.
Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.
PMCID: PMC4622576  PMID: 25778879
autophagy; apoptosis; dexamethasone; glucocorticoid resistance; lymphoid malignancy
7.  Repression of breast cancer cell growth by proteasome inhibitors in vitro: impact of mitogen-activated protein kinase phosphatase 1 
Cancer Biology & Therapy  2015;16(5):780-789.
Mitogen activated protein kinase phosphatase-1 (MKP-1) has emerged as an important protein mediating breast cancer oncogenesis and chemoresistance to cancer chemotherapies, especially proteasome inhibitors. In this in vitro study, we utilized the breast cancer epithelial cell lines MCF-7 and MDA-MB-231, in comparison to MCF-10A control cells, to examine the impact of MKP-1 on breast cancer cell growth and repression by proteasome inhibitors. We confirm that proteasome inhibitors MG-132 and bortezomib induce MKP-1 protein upregulation and we show that one of the ways in which bortezomib increases MKP-1 in breast cancer cells, in addition to inhibition of ubiquitin-proteasome system, is via upregulation of MKP-1 mRNA expression in p38 MAPK-mediated manner. Notably, these effects are specific to cancer cells, as bortezomib activated p38 MAPK and induced MKP-1 in MCF-7 and MDA-MB-231 breast cancer cells, but not in control cells (MCF-10A). We took a dual approach toward targeting MKP-1 to show that bortezomib-induced effects are enhanced. Firstly, treatment with the non-specific MKP-1 inhibitor triptolide reduces breast cancer cell growth and augments proteasome inhibitor-induced effects. Secondly, specific knock-down of MKP-1 with siRNA significantly repressed cell viability by reduced cyclin D1 expression, and enhanced repression of cancer cell growth by proteasome inhibitors. Taken together, these results indicate that removing the unwanted (MKP-1-inducing) effects of bortezomib significantly improves the efficacy of proteasome inhibition in breast cancer cells. Thus, future development of drugs targeting MKP-1 offer promise of combination therapies with reduced toxicity and enhanced cell death in breast cancer.
PMCID: PMC4622627  PMID: 25774547
bortezomib; breast cancer; cell viability; MG-132; MKP-1; p38 MAPK
8.  Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) 
Cancer Biology & Therapy  2015;16(4):634-643.
Lung cancers express non-neuronal, cholinergic autoparacrine loop, which facilitates tumor growth. Interruption of M3 muscarinic cholinergic signaling has been reported to inhibit small cell lung cancer (SCLC) growth. The purpose of this study is to investigate if blocking autoparacrine muscarinic cholinergic signaling could inhibit non-small cell lung cancer (NSCLC) growth and possible underlying mechanisms. Our results showed that PC9 and A549 cells expressed all 5 subtypes of muscarinic receptor (mAChR) and blocking M2 mAChR (M2R) signaling using selective antagonist methoctramine or short hairpin RNA (shRNA) inhibited tumor cell proliferation in vitro and in vivo. Consistent with AChR agonists stimulating p44/42 MAPK (Erk1/2) and Akt phosphorylation, blocking M2R signaling decreased MAPK and Akt phosphorylation, indicating that non-neuronal ACh functions as an autoparacrine growth factor signaling in part through activation of M2R and downstream MAPK and Akt pathways. Importantly, further studies revealed that blocking M2R signaling also reversed epithelial-mesenchymal transition (EMT) in vitro and in vivo, indicating that non-neuronal ACh promotes EMT partially through activation of M2R. These findings demonstrate that M2R plays a role in the growth and progression of NSCLC and suggest M2R antagonists may be an efficacious adjuvant therapy for NSCLC.
PMCID: PMC4622973  PMID: 25778781
autoparacrine; AKT; epithelial-mesenchymal transition; MAPK ERK; M2 muscarinic receptor; non-neuronal acetylcholine; non-small cell lung cancer
9.  Tumor profiling of gastric and esophageal carcinoma reveal different treatment options 
Cancer Biology & Therapy  2015;16(5):764-769.
Background: NCCN states that chemotherapies for advanced esophageal and gastric cancers may be used interchangeably. Biomarkers from gastroesophageal cancer patients were interrogated to identify actionable alterations with therapeutic implications. Methods: 666 gastric and 640 esophageal cancer cases referred to Caris Life Sciences between 2009 thru 2013 were evaluated. Specific testing was performed, which included a combination of sequencing (Sanger, NGS) and protein expression (IHC). Results: In the complete cohort (n = 1306), 30 of 45 genes tested harbored mutations; highest rates were seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%), and PIK3CA (5.1%). IHC of TOP2A was high in 76% of cases, TOPO1 in 51% and SPARC in 25%; low IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating potential benefit from epirubicin, irinotecan, nab-paclitaxel, platinum-based agents, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2+ cohort (n = 88), 50% of patients demonstrated possible benefit from a combination of trastuzumab with 5FU/capecitabine based on concurrent low TS, 53% with irinotecan (high TOPO1), 63% with cisplatin (low ERCC1) and 55% with gemcitabine (low RRM1). Subgroup analysis by tumor origin demonstrated significant differences in actionable biomarker profiles with HER2 (13% vs. 4.6%), SPARC (34% vs. 15%), TOP2A (86% vs. 67%), and TOPO1 (55% vs. 46%) in esophageal and gastric adenocarcinoma cases respectively (P < 0.05). Conclusion: A comprehensive multiplatform biomarker analysis suggested significant biomarker differences between gastric and esophageal cancers. These results can assist in the development of future clinical trials.
PMCID: PMC4622996  PMID: 25778705
biomarker; esophageal cancer; gastric cancer; molecular profiling; personalized medicine
10.  Arginine deprivation by arginine deiminase of Streptococcus pyogenes controls primary glioblastoma growth in vitro and in vivo 
Cancer Biology & Therapy  2015;16(7):1047-1055.
Arginine auxotrophy constitutes a weak point of several tumors, among them glioblastoma multiforme (GBM). Hence, those tumors are supposed to be sensitive for arginine-depleting substances, such as arginine deiminase (ADI). Here we elucidated the sensitivity of patient-individual GBM cell lines toward Streptococcus pyogenes-derived ADI. To improve therapy, ADI was combined with currently established and pre-clinical cytostatic drugs. Additionally, effectiveness of local ADI therapy was determined in xenopatients. Half of the GBM cell lines tested responded well toward ADI monotherapy. In those cell lines, viability decreased significantly (up to 50 %). Responding cell lines were subjected to combination therapy experiments to test if any additive or even synergistic effects may be achieved. Such promising results were obtained in 2/3 cases. In cell lines HROG02, HROG05 and HROG10, ADI and Palomid 529 combinations were most effective yielding more than 70 % killing after 2 rounds of treatment. Comparable boosted antitumoral effects were observed after adding chloroquine to ADI (>60% killing). Apoptosis, as well as cell cycle dysregulation were found to play a minor role. In some, but clearly not all cases, (epi-) genetic silencing of arginine synthesis pathway genes (argininosuccinate synthetase 1 and argininosuccinate lyase) explained obtained results. In vivo, ADI as well as the combination of ADI and SAHA efficiently controlled HROG05 xenograft growth, whereas adding Palomid 529 to ADI did not further increase the strong antitumoral effect of ADI. The cumulative in vitro and in vivo results proved ADI as a very promising candidate therapeutic, especially for development of adjuvant GBM combination treatments.
PMCID: PMC4623118  PMID: 25774632
arginine-catabolizing enzymes; cellular metabolism; combination therapy; patient-derived GBM cell lines; xenopatient
11.  PTEN inhibits macrophage polarization from M1 to M2 through CCL2 and VEGF-A reduction and NHERF-1 synergism 
Cancer Biology & Therapy  2015;16(2):297-306.
PTEN has been studied in several tumor models as a tumor suppressor. In this study, we explored the role of PTEN in the inhibition state of polarized M2 subtype of macrophage in tumor microenvironment (TME) and the underlying mechanisms. To elucidate the potential effect in TME, RAW 264.7 macrophages and 4T1 mouse breast cancer cells were co-cultured to reconstruct tumor microenvironment. After PTEN was down-regulated with shRNA, the expression of CCL2 and VEGF-A, which are definited to promote the formation of M2 macrophages, have a dramatically increase on the level of both gene and protein in co-cultured RAW 264.7 macrophages. And at the same time, NHERF-1 (Na+/H+ exchanger regulating factor-1), another tumor suppressor has a similar tendency to PTEN. Q-PCR and WB results suggested that PTEN and NHERF-1 were consistent with one another no matter at mRNA or protein level when exposed to the same stimulus. Coimmunoprecipitation and immunofluorescence techniques confirmed that PTEN and NHERF-1 were coprecipitated, and NHERF-1 protein expression was properly reduced with rCCL2 effect. In addition, cell immunofluorescence images revealed a profound transferance, in co-cultured RAW 264.7 macrophages, an up-regulation of NHERF-1 could promote the PTEN marked expression on the cell membrane, and this form for the interaction was not negligible. These observations illustrate PTEN with a certain synergy of NHERF-1, as well as down-regulation of CCL2 suppressing M2 macrophage transformation pathway. The results suggest that the activation of PTEN and NHERF-1 may impede the evolution of macrophages beyond the M1 into M2 phenotype in tumor microenvironment.
PMCID: PMC4622010  PMID: 25756512
CCL2; co-culture; NHERF-1; TAM; PTEN; transformation
12.  Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma  
Cancer Biology & Therapy  2015;16(2):325-335.
Hypoxia-inducible factor-1 (HIF-1) is one of the most promising pharmacological targets for all types of cancer, including ovarian cancer. Ovarian clear cell carcinoma (OCCC) has poor prognosis because of its insensitivity to chemotherapy. To elucidate the characteristics of this troublesome cancer, we examined HIF-1α expression under normoxia or hypoxia in various ovarian cancer cell lines. HIF-1α was highly expressed under normoxia only in RMG-1, an OCCC cell line. To examine whether HIF-1 is involved in the tumorigenesis of RMG-1 cells, we established HIF-1α-silenced cells, RMG-1HKD. The proliferation rate of RMG-1HKD cells was faster than that of RMG-1 cells. Furthermore, the activity of MEK/ERK in the Ras pathway increased in RMG-1HKD cells, whereas that of mTOR in the PI3K pathway did not change. Activation of the Ras pathway was attributable to the increase in phosphorylated MEK via PP2A inactivation. To confirm the crosstalk between the PI3K and Ras pathways in vivo, RMG-1 or RMG-1HKD cells were transplanted into the skin of nude mice with rapamycin (an inhibitor of mTOR), PD98059 (an inhibitor of MEK), or both. RMG-1HKD cells showed higher sensitivity to PD98059 than that observed in RMD-1 cells, whereas the combination therapy resulted in synergistic inhibition of both cells. These findings suggest that inhibition of HIF-1, a downstream target of mTOR in the PI3K pathway, activates the Ras pathway on account of the increase in MEK phosphorylation via PP2A inactivation, and the crosstalk between the 2 pathways could be applied in the combination therapy for HIF-1-overexpressing cancers such as OCCC.
PMCID: PMC4622433  PMID: 25756515
HIF-1; mTOR; MEK inhibitor; ovarian clear cell carcinoma; PI3K pathway; PP2A; Ras pathway
13.  EGFR signaling defines Mcl-1 survival dependency in neuroblastoma 
Cancer Biology & Therapy  2015;16(2):276-286.
The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl-1, for survival through Mcl-1 sequestration of pro-apoptotic Bim. High affinity Mcl-1 inhibitors currently do not exist such that novel methods to inhibit Mcl-1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl-1 in many cancers and play a role in NB survival, yet how they regulate Bcl-2 family interactions in NB is unknown. We found that NB cell lines derived to resist the Bcl-2/-xl/-w antagonist, ABT-737, acquire a dependence on Mcl-1 and show increased expression and activation of the RTK, EGFR. Mcl-1 dependent NB cell lines derived at diagnosis and from the same tumor following relapse also have increased EGFR expression compared to those dependent on Bcl-2. Inhibition of EGFR by shRNA or erlotinib in Mcl-1 dependent NBs disrupts Bim binding to Mcl-1 and enhances its affinity for Bcl-2, restoring sensitivity to ABT-737 as well as cytotoxics in vitro. Mechanistically treatment of NBs with small molecule inhibitors of EGFR (erlotinib, cetuximab) and ERK (U0126) increases Noxa expression and dephosphorylates Bim to promote Bim binding to Bcl-2. Thus, EGFR regulates Mcl-1 dependence in high-risk NB via ERK-mediated phosphorylation of Bim such that EGFR/ERK inhibition renders Mcl-1 dependent tumors now reliant on Bcl-2. Clinically, EGFR inhibitors are ineffective as single agent compounds in patients with recurrent NB, likely due to this transferred survival dependence to Bcl-2. Likewise, EGFR or ERK inhibitors warrant further testing in combination with Bcl-2 antagonists in vivo as a novel future combination to overcome therapy resistance in the clinic.
PMCID: PMC4622539  PMID: 25756510
ABT-737; apoptosis; Bcl-2 homology proteins; Bcl-2 antagonist; bim regulation; EGFR; EGFR; Mcl-1
14.  Calcium calmodulin dependent kinase kinase 2 - a novel therapeutic target for gastric adenocarcinoma  
Cancer Biology & Therapy  2015;16(2):336-345.
Gastric cancer is one of the most common gastrointestinal malignancies and is associated with poor prognosis. Exploring alterations in the proteomic landscape of gastric cancer is likely to provide potential biomarkers for early detection and molecules for targeted therapeutic intervention. Using iTRAQ-based quantitative proteomic analysis, we identified 22 proteins that were overexpressed and 17 proteins that were downregulated in gastric tumor tissues as compared to the adjacent normal tissue. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was found to be 7-fold overexpressed in gastric tumor tissues. Immunohistochemical labeling of tumor tissue microarrays for validation of CAMKK2 overexpression revealed that it was indeed overexpressed in 94% (92 of 98) of gastric cancer cases. Silencing of CAMKK2 using siRNA significantly reduced cell proliferation, colony formation and invasion of gastric cancer cells. Our results demonstrate that CAMKK2 signals in gastric cancer through AMPK activation and suggest that CAMKK2 could be a novel therapeutic target in gastric cancer.
PMCID: PMC4622549  PMID: 25756516
invasion; in vitro labeling; mass spectrometry; proliferation; targeted therapy
15.  Dexamethasone may be the most efficacious corticosteroid for use as monotherapy in castration-resistant prostate cancer 
Cancer Biology & Therapy  2015;16(2):207-209.
Corticosteroids have been used in the therapy for castration-resistant prostate cancer (CRPC) for decades, both as monotherapy and in combination with additional agents. In this article the authors report the results of a phase II trial of dexamethasone versus prednisolone as monotherapy for CRPC. The study suggests improved PSA and radiographic response rates as well as improved time to PSA progression for dexamethasone over prednisolone therapy; however the differences only trend toward statistical significance. Nonetheless, in light of these data, when treating patients with corticosteroid monotherapy for CRPC it may be prudent to consider using daily dexamethasone over prednisone/prednisolone.
PMCID: PMC4622618  PMID: 25756508
castration-resistant prostate cancer; dexamethasone; prednisolone; prednisone
16.  Targeted PI3Kδ inhibition by the small molecule idelalisib as a novel therapy in indolent non-Hodgkin lymphoma 
Cancer Biology & Therapy  2015;16(2):204-206.
Indolent Non-Hodgkin Lymphomas (iNHL) are typically B-cell malignancies and are incurable with current standard approaches. Thus, there is a demand for novel agents specific for this group of disorders. In a phase II study published by Gopal et al. in the New England Journal of Medicine, idelalisib, a small molecule inhibitor of PI3Kδ that was FDA approved in July of 2014, was shown to be effective when combined with rituximab in patients who cannot tolerate chemotherapy and as last line therapy in patients with iNHL refractory to 2 prior systemic therapies. Idelalisib demonstrated tolerable diarrhea, fatigue, nausea, pyrexia, and cough. While this novel agent is a clinically significant addition to the iNHL arsenal, further research is needed to determine its most appropriate place in iNHL therapy.
PMCID: PMC4622714  PMID: 25756507
B-cell chronic lymphocytic leukemia; follicular lymphoma; Furman et al; Gopal et al; indolent Non-Hogkin Lymphoma; idelalisb; PI3Kδ Inhibition; rituximab; small lymphocytic lymphoma; targeted therapy
17.  MiR-1204 sensitizes nasopharyngeal carcinoma cells to paclitaxel both in vitro and in vivo 
Cancer Biology & Therapy  2015;16(2):261-267.
Nasopharyngeal carcinoma (NPC) is an endemic tumor with a relatively high incidence in Southern China and Southeast Asia. Paclitaxel combination chemotherapy has been used for treatment of advanced NPC. However, treatment failure often occurs due to development of acquired paclitaxel resistance. In this study, we first established a paclitaxel-resistant CNE-1/Taxol, HNE-2/Taxol and 5–8F/Taxol cell sublines by treating the parental CNE-1, HNE-2 and 5–8F cells with increasing doses of paclitaxel for about 5 months, respectively. Then, microRNA arrays were used to screen differentially expressed miRNAs between the CNE-1/Taxol cells and the parental CNE-1 cells. We found 13 differentially expressed miRNAs, of which miR-1204 was significantly downregulated in the paclitaxel-resistant CNE-1/Taxol cells. We restored miR-1204 expression in the CNE-1/Taxol, HNE-2/Taxol and 5–8F/Taxol cells and found that restoration of miR-1204 re-sensitized the paclitaxel-resistant CNE-1/Taxol, HNE-2/Taxol and 5–8F/Taxol cells to paclitaxel both in vitro. Finally, we demonstrated that restoration of miR-1204 in significantly inhibits tumor growth in vivo. Thus, our study provides important information for the development of targeted gene therapy for reversing paclitaxel resistance in NPC.
PMCID: PMC4622873  PMID: 25756509
chemotherapy; microRNAs; miR-1204; nasopharyngeal carcinoma; paclitaxel
18.  Network-based approach to identify prognostic biomarkers for estrogen receptor–positive breast cancer treatment with tamoxifen 
Cancer Biology & Therapy  2015;16(2):317-324.
This study aims to identify effective gene networks and prognostic biomarkers associated with estrogen receptor positive (ER+) breast cancer using human mRNA studies. Weighted gene coexpression network analysis was performed with a complex ER+ breast cancer transcriptome to investigate the function of networks and key genes in the prognosis of breast cancer. We found a significant correlation of an expression module with distant metastasis-free survival (HR = 2.25; 95% CI .21.03–4.88 in discovery set; HR = 1.78; 95% CI = 1.07–2.93 in validation set). This module contained genes enriched in the biological process of the M phase. From this module, we further identified and validated 5 hub genes (CDK1, DLGAP5, MELK, NUSAP1, and RRM2), the expression levels of which were strongly associated with poor survival. Highly expressed MELK indicated poor survival in luminal A and luminal B breast cancer molecular subtypes. This gene was also found to be associated with tamoxifen resistance. Results indicated that a network-based approach may facilitate the discovery of biomarkers for the prognosis of ER+ breast cancer and may also be used as a basis for establishing personalized therapies. Nevertheless, before the application of this approach in clinical settings, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed.
PMCID: PMC4622923  PMID: 25756514
biomarker; breast cancer; gene expression profiling; systems biology; tamoxifen resistance
20.  Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice 
Cancer Biology & Therapy  2015;16(2):307-316.
We have recently discovered the potential involvement of angiotensin II type 2 receptor (AT2R) signaling in pancreatic cancer using AT2R deficient mice. To examine the involvement of AT2R expression in human PDAC, expressions of AT2R as well as the major angiotensin II receptor (type 1 receptor, AT1R) in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using surgically dissected human PDAC specimens. In immunohistochemical analysis, relatively strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, whereas moderate AT2R expression was detected in 78.5% of PDAC specimens and 100% of normal area of the pancreas. AT1R, but not AT2R, mRNA levels were significantly higher in the PDAC area than in the normal pancreas. AT2R mRNA levels showed a negative correlation trend with overall survival. In cell cultures, treatment with a novel AT2R agonist significantly attenuated both murine and human PDAC cell growth with negligible cytotoxicity in normal epithelial cells. In a mouse study, administrations of the AT2R agonist in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in syngeneic mice. The AT2R agonist treatment induced apoptosis primarily in tumor cells but not in stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development and pinpoint that the novel AT2R agonist could serve as an effective therapeutic for PDAC treatment.
PMCID: PMC4623015  PMID: 25756513
angiotensin II type 2 receptor (AT2R); apoptosis; pancreatic ductal adenocarcinoma; selective AT2R agonist
21.  Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil as palliative treatment in recurrent head and neck squamous cell carcinoma 
Cancer Biology & Therapy  2015;16(2):346-351.
This study compared the efficacy and toxicity of Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil (5-FU) in patients of recurrent squamous cell carcinoma of head and neck (SCCHN) treated with palliative intent. Patients with recurrent SCCHN not amenable to curative treatment were randomly assigned to Gefitinib, Methotrexate or Methotrexate plus 5-FU arm. The primary end point was overall survival. Secondary end points of interest were objective response rate, toxicity and quality of life. Total 117 patients were analyzed. Median overall survival and objective response rates were 8.8 months, 7.8 months and 8.1 months and 7.7%, 5.0% and 7.9% in Gefitinib, Methotrexate and Methotrexate plus 5-FU arms respectively with no statistically significant difference between 3 arms. Gefitinib had different toxicity profile compared with other arms. Majority of toxicities were Grade 1 or Grade 2. Gefitinib had significant improvement in quality of life during initial months over Methotrexate. There was no suggestion that Gefitinib significantly prolonged overall survival compared with Methotrexate and Methotrexate plus 5-FU. However, improved Quality of Life with manageable toxicities was observed.
PMCID: PMC4623054  PMID: 25756517
gefitinib; head and neck; methotrexate; recurrent; squamous cell carcinoma
22.  NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer 
Cancer Biology & Therapy  2015;16(2):287-296.
Castration resistance is a major issue during castration therapy for prostate cancer and thus more effective treatment are needed for castration-resistant prostate cancer (CRPC). NDRG2 (N-Myc downstream regulated gene 2), a recently identified tumor suppressor, was previously shown to inhibit the proliferation and invasion of prostate cancer, but whether NDRG2 is involved in CRPC remains to be known. Because androgen receptor (AR) axis plays an important role in castration resistance, we evaluate the role of NDRG2 in AR signaling and CRPC. Immunohistochemistry examination of prostate cancer tissues demonstrated that the expression of NDRG2 is negatively correlated with that of AR and c-Myc. Furthermore, AR negatively regulates NDRG2, as well as alters levels of c-Myc and prostate specific antigen (PSA). Forced expression of NDRG2 significantly inhibits the in vitro growth of androgen-dependent and castration-resistant prostate cancer cells; this was accompanied by alterations in PSA, but not by those of AR and c-Myc. Finally, by mimicking castration therapy in a xenograft mouse model, we showed that lentivirus-mediated NDRG2 overexpression efficiently overcomes castration resistance. Thus, by acting as a negative regulator downstream of AR, NDRG2 may emerge as a potential therapy molecule for CRPC.
PMCID: PMC4623552  PMID: 25756511
AR; c-Myc; castration resistance; lentivirus; NDRG2
23.  Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking 
Cancer Biology & Therapy  2015;16(4):589-601.
Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.
PMCID: PMC4622430  PMID: 25729885
diffuse large B cell lymphoma; natural compounds; mTOR-AKT signaling; schweinfurthins; trans-Golgi-network
24.  Five years of stable disease with maintenance therapy using bevacizumab and tamoxifen in a patient with metastatic breast cancer 
Cancer Biology & Therapy  2015;16(4):493-497.
Bevacizumab and Tamoxifen are valid therapeutic options for metastatic breast cancer (mBC) patients. In this report, we describe a 47 year old woman with mBC successfully treated with a maintenance therapy with Bevacizumab+Tamoxifen. A maintenance approach using 2 different drugs with different targets and mechanism of action, such as anti-angiogenic and anti-hormonal treatment is particularly intriguing because they affect different pathways involved in mBC progression. Further studies including a large number of patients are needed, in order to select women who could benefit from this maintenance approach.
PMCID: PMC4622062  PMID: 25719413
bevacizumab; metastatic breast cancer; maintenance therapy; tamoxifen
25.  Downregulation of phosphoglycerate dehydrogenase inhibits proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma cells by regulating Bcl-2 and caspase-3 
Cancer Biology & Therapy  2015;16(4):541-548.
Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis. Previous reports have demonstrated that PHGDH plays an important role in some malignancies. However, the biological role of PHGDH in human cervical adenocarcinoma has not been explored. We examined the expression of PHGDH in 54 cervical adenocarcinoma samples by immunohistochemistry and evaluated the association with clinicopathological parameters and prognosis. We performed shRNA transfection to knock down PHGDH gene expression in HeLa cells. A cell proliferation test, cisplatin cytotoxicity test and apoptosis test examined the HeLa cell line after PHGDH knockdown in vitro. In vivo tumorigenesis was assessed using a mouse xenograft model. Moreover, we examined the effects on Bcl-2 and cleaved caspase-3 expression after knockdown of PHGDH and treatment of cisplatin for 48h by Western blot. In this study, we demonstrated that elevated PHGDH expression was found in cervical adenocarcinoma and was associated with tumor size and prognosis. Knocking down PHGDH in HeLa cells significantly inhibited cell proliferation and increased cisplatin chemotherapy sensitivity. Silencing PHGDH resulted in inhibition of tumorigenesis in vivo. Furthermore, PHGDH knockdown reduced Bcl-2 and increased cleaved caspase-3 expression. Collectively, our study indicates the novel roles of PHGDH in cervical adenocarcinoma and identifies PHGDH as a new anticancer target.
PMCID: PMC4622468  PMID: 25719555
Bcl-2; caspase-3; chemotherapy sensitivity; cervical adenocarcinoma; PHGDH; metabolism; proliferation

Results 1-25 (716)