Publications by authors named "Helen H W Chen"

61 Publications

Accelerated coronary calcium burden in breast cancer patients after radiotherapy: a comparison with age and race matched healthy women.

Radiat Oncol 2021 Nov 2;16(1):210. Epub 2021 Nov 2.

Department of Medical Imaging, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138 Sheng-Li Rd, Tainan, Taiwan.

Background: Radiotherapy (RT) might lead to atherosclerotic plaque buildup and coronary artery stenosis of breast cancer (BC) survivors, and coronary artery calcium (CAC) might be a sign of preclinical atherosclerosis. This study explores possible determinants affecting the acceleration of CAC burden in BC patients after adjuvant RT.

Methods: Female BC patients receiving adjuvant RT from 2002 to 2010 were included. All patients received noncontrast computed tomography (NCCT) of thorax before and after adjuvant RT. Their CAC burden was compared with healthy controls from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The progression of the CAC burden was manifested by the increment of CAC percentiles (%CACinc).

Results: Ninety-four patients, including both left- and right-side BC, were enrolled in this study. From undergoing the first to second NCCT, the %CACinc in BC patients significantly increased rather than non-BC women. In addition, the %CACinc was significantly higher in left-side than right-side BC patients (p < 0.05), and significant differences in most heart outcomes were found between the two groups. Besides, the lower the mean right coronary artery (RCA) dose, the lower the risks of CAC percentiles increase ≥ 50% after adjusting the disease's laterality.

Conclusions: A significantly higher accelerated CAC burden in BC patients than non-BC women represents that BC could affect accelerated CAC. A higher risk of accelerated CAC burden was found in left-side than right-side BC patients after adjuvant RT. A decrease of the mean RCA dose could reduce more than 50% of the risk of accelerated CAC burden in BC patients.
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http://dx.doi.org/10.1186/s13014-021-01936-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561949PMC
November 2021

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy.

Pharmaceuticals (Basel) 2021 Jun 8;14(6). Epub 2021 Jun 8.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.
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http://dx.doi.org/10.3390/ph14060549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227247PMC
June 2021

Association of Primary Treatment Modality for Advanced-Stage Oropharyngeal Squamous Cell Carcinoma With Survival Outcomes.

JAMA Netw Open 2021 06 1;4(6):e2112067. Epub 2021 Jun 1.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Importance: Definitive chemoradiotherapy and upfront surgical treatment are both accepted as the standard of care for advanced-stage oropharyngeal squamous cell carcinoma. However, the optimal primary treatment modality remains unclear.

Objective: To evaluate the comparative effectiveness of definitive chemoradiotherapy and upfront surgical treatment for advanced-stage oropharyngeal cancer.

Design, Setting, And Participants: This retrospective comparative effectiveness analysis used data from the population-based Taiwan Cancer Registry. Included patients were diagnosed with clinical stage III or IV oropharyngeal squamous cell carcinoma from 2007 to 2015 and were identified from the registry. Patients with T4b or N3 disease were excluded. Data were analyzed from June 2019 through December 2020.

Interventions: Definitive chemoradiotherapy or upfront surgical treatment.

Main Outcomes And Measures: The primary outcome was overall survival, for which data were available through December 31, 2018. Secondary outcomes were progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival.

Results: Among 1180 patients, 694 patients (58.8%) were in the definitive chemoradiotherapy group and 486 patients (41.2%) were in the upfront surgical treatment group. The median (interquartile range) follow-up was 3.62 (1.63-5.47) years, and most patients were men (1052 [89.1%] men) with a primary tumor in the tonsils (712 patients [60.3%]), moderately differentiated histology (604 patients [51.2%]), clinical N2 disease (858 patients [72.7%]), and clinical stage IVA disease (938 patients [79.5%]). The mean (SD) age was 54.59 (10.35) years. Primary treatment with an upfront surgical procedure was associated with a decreased risk of death during the study period (hazard ratio [HR], 0.81; 95% CI, 0.69-0.97; P = .02). However, when adjusted for age, subsite, histological grade, and T and N classification, upfront surgical treatment was no longer associated with an increased risk of death during the study period (HR, 0.96; 95% CI, 0.80-1.16; P = .70). Progression-free survival was worse in the group receiving upfront surgical treatment than in the group receiving chemoradiotherapy (HR, 1.64; 95% CI, 1.09-2.46; P = .02), and this difference persisted after adjusting for other factors associated with prognosis (ie, age, tumor subsite, histological grade, and T and N classification) (HR, 1.72; 95% CI, 1.12-2.66; P = .01).

Conclusions And Relevance: This study found that definitive chemoradiotherapy was associated with effectiveness that was comparable with that of upfront surgical treatment when adjusted for baseline factors associated with prognosis. These findings suggest that definitive chemoradiotherapy should be considered to avoid accumulating toxic effects associated with surgical treatment and chemoradiotherapy.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.12067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170546PMC
June 2021

Targeting the Proline-Glutamine-Asparagine-Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy.

Pharmaceuticals (Basel) 2021 Jan 18;14(1). Epub 2021 Jan 18.

Division of Hematology and Oncology, Miami Veterans Affairs Heaithcare System, Miami, FL 33136, USA.

Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.
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http://dx.doi.org/10.3390/ph14010072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830038PMC
January 2021

Collaboration Between RSK-EphA2 and Gas6-Axl RTK Signaling in Arginine Starvation Response That Confers Resistance to EGFR Inhibitors.

Transl Oncol 2020 Feb 27;13(2):355-364. Epub 2019 Dec 27.

Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Division of Hematology and Oncology, Miami Veterans Affairs Healthcare System, Miami, FL, USA. Electronic address:

Many human malignancies require extracellular arginine (Arg) for survival because the key enzyme for de novo Arg biosynthesis, argininosuccinate synthetase 1 (ASS1), is silenced. Recombinant arginine deiminase (ADI-PEG20), which digests extracellular Arg, has been in clinical trials for treating ASS1-negative tumors. Reactivation of ASS1 is responsible for the treatment failure. We previously demonstrated that ASS1 reactivation is transcriptionally regulated by c-Myc via the upstream Gas6-Axl tyrosine kinase (RTK) signal. Here, we report that another RTK EphA2 is coactivated via PI3K-ERK/RSK1 pathway in a ligand-independent mechanism. EphA2 is also regulated by c-Myc. Moreover, we found that knockdown Axl upregulates EphA2 expression, demonstrating cross-talk between these RTKs. ADI cell lines exhibits enhanced sensitivities to nutrient deprivation such as charcoal-stripped FBS and multiple RTK inhibitor foretinib but resistance to EGFR inhibitors. Knockdown EphA2, and to lesser extent, Axl, overcomes EGFRi resistance. c-Myc inhibitor JQ1 can also sensitize ADI cells to ADI-PEG20. This study elucidates molecular interactions of multiple RTKs in Arg-stress response and offers approaches for developing strategies of overcoming ADI-PEG20 resistance.
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http://dx.doi.org/10.1016/j.tranon.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938815PMC
February 2020

Prognostic value of volumetric metabolic parameter changes determined by during and after radiotherapy-based F-FDG PET/CT in stage III non-small cell lung cancer.

Kaohsiung J Med Sci 2019 Mar;35(3):151-159

Nuclear Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

The aim of this prospective study was to evaluate the prognostic value of volumetric metabolic parameters assessed by during and after radiation-based therapy F-FDG PET/CT in patients with stage III non-small cell lung cancer (NSCLC). We enrolled stage III NSCLC patients who had planned to receive definitive chemo-radiation or radiotherapy (RT) and underwent F-FDG PET/CT before treatment (PET1), during RT (at the fifth week, PET2) and after treatment (3 months later, PET3). By comparing with PET1, percentage changes of metabolic tumor volume (ΔMTV) and tumor total lesion glycolysis (ΔTLG) of PET2 and PET3 were calculated. We used medians of ΔTLG and ΔMTV as cut-off values to stratify patients. Their prognostic values were evaluated by progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled initially. Five were excluded due to multiple metastases or double cancer. The remaining 25 patients had PET2 at a median of 46 Gy. Data on PET3 were available in 19 patients. During-RT ΔTLG (cut-off: 65%) was a significant prognostic factor for PFS (P = 0.02) and OS (P < 0.01). During-RT ΔMTV (cut-off: 42%) had marginal significance for PFS (P = 0.07) and was significant for OS (P = 0.02). Of the PET3 parameters, neither ΔTLG nor ΔMTV was a significant prognostic factor for PFS and OS. We conclude that ΔTLG of during-RT F-FDG PET/CT may predict treatment response and thus provide opportunities to modify treatment for poor responders.
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http://dx.doi.org/10.1002/kjm2.12027DOI Listing
March 2019

Adjuvant radiotherapy after curative surgery for oral cavity squamous cell carcinoma and treatment effect of timing and duration on outcome-A Taiwan Cancer Registry national database analysis.

Cancer Med 2018 Jun 14. Epub 2018 Jun 14.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population-based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra-nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause-specific survival (CSS), local-regional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P < .001). Extreme RT dose (>70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.
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http://dx.doi.org/10.1002/cam4.1611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051157PMC
June 2018

Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis.

Int J Mol Sci 2018 May 16;19(5). Epub 2018 May 16.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan.

Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting-carried out by the high-affinity copper (Cu) transporter (), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively-cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates . Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.
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http://dx.doi.org/10.3390/ijms19051486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983780PMC
May 2018

Wheat germ agglutinin-induced paraptosis-like cell death and protective autophagy is mediated by autophagy-linked FYVE inhibition.

Oncotarget 2017 Oct 24;8(53):91209-91222. Epub 2017 Aug 24.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Wheat germ agglutinin (WGA) is a lectin that specifically binds cell surface glycoproteins and disrupts nuclear pore complex function through its interaction with POM121. Our data indicate WGA induces paraptosis-like cell death without caspase activation. We observed the main features of paraptosis, including cytoplasmic vacuolation, endoplasmic reticulum dilation and increased ER stress, and the unfolded protein response in WGA-treated cervical carcinoma cells. Conversion of microtubule-associated protein I light chain 3 (LC3-I) into LC3-II and punctuate formation suggestive of autophagy were observed in WGA-treated cells. WGA-induced autophagy antagonized paraptosis in HeLa and CaSKi cells, which expressed autophagy-linked FYVE (Alfy) protein, but not in SiHa cells that did not express Alfy. Alfy knockdown in HeLa cells induced paraptosis-like cell death. These data indicate that WGA-induced cell death occurs through paraptosis and that autophagy may exert a protective effect. WGA treatment and Alfy inhibition could be an effective therapeutic strategy for apoptosis-resistant cervical cancer cells.
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http://dx.doi.org/10.18632/oncotarget.20436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710917PMC
October 2017

Improving radiotherapy in cancer treatment: Promises and challenges.

Oncotarget 2017 Sep 8;8(37):62742-62758. Epub 2017 Jun 8.

Division of Clinical Radiation Oncology, Department of Radiation Oncology, National Cheng Kung University Hospital, Department of Radiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Effective radiotherapy for cancer has relied on the promise of maximally eradicating tumor cells while minimally killing normal cells. Technological advancement has provided state-of-the-art instrumentation that enables delivery of radiotherapy with great precision to tumor lesions with substantial reduced injury to normal tissues. Moreover, better understanding of radiobiology, particularly the mechanisms of radiation sensitivity and resistance in tumor lesions and toxicity in normal tissues, has improved the treatment efficacy of radiotherapy. Previous mechanism-based studies have identified many cellular targets that can affect radiation sensitivity, notably reactive oxygen species, DNA-damaging response signals, and tumor microenvironments. Several radiation sensitizers and protectors have been developed and clinically evaluated; however, many of these results are inconclusive, indicating that improvement remains needed. In this era of personalized medicine in which patients' genetic variations, transcriptome and proteomics, tumor metabolism and microenvironment, and tumor immunity are available. These new developments have provided opportunity for new target discovery. Several radiotherapy sensitivity-associated "gene signatures" have been reported although clinical validations are needed. Recently, several immune modifiers have been shown to associate with improved radiotherapy in preclinical models and in early clinical trials. Combination of radiotherapy and immunocheckpoint blockade has shown promising results especially in targeting metastatic tumors through abscopal response. In this article, we succinctly review recent advancements in the areas of mechanism-driven targets and exploitation of new targets from current radio-oncogenomic and radiation-immunotherapeutic approaches that bear clinical implications for improving the treatment efficacy of radiotherapy.
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http://dx.doi.org/10.18632/oncotarget.18409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617545PMC
September 2017

Chromatin remodeling system p300-HDAC2-Sin3A is involved in Arginine Starvation-Induced HIF-1α Degradation at the ASS1 promoter for ASS1 Derepression.

Sci Rep 2017 09 7;7(1):10814. Epub 2017 Sep 7.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Texas, USA.

Argininosuccinate synthetase 1 (ASS1) is the key enzyme that controls biosynthesis of arginine (Arg). ASS1 is silenced in many human malignancies therefore, these tumors require extracellular Arg for growth. The Arg-degrading recombinant protein, pegylated arginine deiminase (ADI-PEG20), has been in clinical trials for targeting Arg auxotrophic tumors by Arg starvation therapy. Resistance to Arg starvation is often developed through reactivation of ASS1 expression. We previously demonstrated that ASS1 silencing is controlled by HIF-1α and Arg starvation-reactivated ASS1 is associated with HIF-1α downregulation. However, mechanisms underlying ASS1 repression and HIF-1α turnover are not known. Here, we demonstrate that interplay of p300-HDAC2-Sin3A in the chromatin remodeling system is involved in HIF-1α degradation at the ASS1 promoter. The histone acetyltransferase p300 is normally associated with the ASS1 promoter to maintain acetylated H3K14ac and H3K27ac for ASS1 silencing. Arg starvation induces p300 dissociation, allowing histone HDAC2 and cofactor Sin3A to deacetylate these histones at the ASS1 promoter, thereby facilitating HIF-1α-proteasomal complex, driven by PHD2, to degrade HIF-1α in situ. Arg starvation induces PHD2 and HDAC2 interaction which is sensitive to antioxidants. This is the first report describing epigenetic regulation of chromosomal HIF-1α turnover in gene activation that bears important implication in cancer therapy.
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http://dx.doi.org/10.1038/s41598-017-11445-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589935PMC
September 2017

Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy.

Cancer Lett 2017 03 30;388:54-63. Epub 2016 Nov 30.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme that catalyzes the biosynthesis of arginine (Arg). Many malignant human tumors are auxotrophic for Arg because ASS1 is silenced. ASS1 has been established as a sensor of Arg auxotrophic response and a chemosensitivity marker for Arg starvation therapy. Here, we report that ASS1 is also a sensor for glutamine (Gln)-deprivation response, and that upregulation of ASS1 expression is associated with resistance to Gln-starvation treatments. Knockdown of ASS1 expression resulted in increased sensitivity to both Arg- and Gln-starvation, whereas increased ASS1 expression by ectopic transfection is associated with resistance to both Arg- and Gln-starvation. The addition of permeable fumarate, a metabolite that bridges the tricarboxylic acid and urea cycles, resulted in downregulation of ASS1 expression and increased sensitivity to both Arg- and Gln-deprivation treatments. Mechanistically, the Gln-deprivation response, like the arginine-auxotrophic response, downregulates HIF-1α resulting in de-silencing of ASS1. Our results demonstrate that ASS1 is a common biosensor for Arg and Gln deprivation response and a shared target for Arg- and Gln-starvation therapies which have been in several current clinical trials.
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http://dx.doi.org/10.1016/j.canlet.2016.11.028DOI Listing
March 2017

Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation.

Oncotarget 2016 Dec;7(50):82658-82670

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression. Moreover, it was reported that cisplatin suppresses ASS1 expression through ASS1 promoter methylation, leading to synthetic lethality to ADI-PEG20 treatment. We report here that cisplatin supppresses ASS1 expression is due to upregulation of HIF-1α and downregulation of c-Myc, which function as negative and positive regulators of ASS1 expression, respectively, by reciprocal bindings to the ASS1 promoter. In contrast, we found that Aza-dC induces ASS1 expression by downregulation of HIF-1α but upregulation of c-Myc. We further demonstrated that the clock protein DEC1 is the master regulator of HIF-1α and c-Myc that regulate ASS1. cDDP upregulates DEC1, whereas Aza-dC suppresses its expression. Using two proteasomal inhibitors bortezomib and carfilzomib which induce HIF-1α accumulation, we further demonstrated that HIF-1α is involved in ASS1 silencing for the maintenance of Arg auxotrophy for targeted Arg-starvation therapy.
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http://dx.doi.org/10.18632/oncotarget.12308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347722PMC
December 2016

Cost effectiveness of cancer treatment in Taiwan.

J Formos Med Assoc 2016 Aug 11;115(8):609-18. Epub 2016 Jun 11.

Department of Public Health, National Cheng Kung University College of Medicine, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department Occupational and Environmental Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Background/purpose: This study aims to examine the cost effectiveness of treating major cancers compared with other major illnesses in Taiwan.

Methods: We collected data on 395,330 patients with cancer, 125,277 patients with end-stage renal disease, and 50,481 patients under prolonged mechanical ventilation during 1998-2007. They were followed for 10-13 years to estimate lifetime survival functions using a semiparametric method. EuroQol five-dimension was used to measure the quality of life for 6189 cancer patients and 1401 patients with other illnesses. The mean utility values and healthcare costs reimbursed by the National Health Insurance were multiplied with the corresponding survival probabilities to estimate quality-adjusted life expectancies and lifetime costs, respectively. Data of 22,344 cancer patients under hospice care (considered as a comparison group) were used to conduct a cost-effectiveness analysis. Sensitivity analysis was conducted by assuming patients without treatment survived for 2 years with a quality of life value of 0.5.

Results: The costs of care for patients under prolonged mechanical ventilation and those with end-stage renal disease were US$41,780-53,708 per quality-adjusted life year (QALY) and US$18,222-18,465 per QALY, respectively, which are equivalent to 2.17-2.79 gross domestic product (GDP) per capita per QALY and 1.18-1.25 GDP per capita per QALY. The costs of care for the nine different cancers were less than 1 GDP per capita per QALY, with those of lung, esophagus, and liver cancers being the highest. Sensitivity analysis showed the same conclusion. Lifetime risks of six out of nine cancer sites show an increased trend.

Conclusion: Cancer care in Taiwan seemed cost effective compared with that of other illnesses, but prevention is necessary to make the National Health Insurance more sustainable.
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http://dx.doi.org/10.1016/j.jfma.2016.04.002DOI Listing
August 2016

Effects of Cu(II) and cisplatin on the stability of Specific protein 1 (Sp1)-DNA binding: Insights into the regulation of copper homeostasis and platinum drug transport.

J Inorg Biochem 2016 08 27;161:37-9. Epub 2016 Apr 27.

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States. Electronic address:

The human high-affinity copper transporter 1 (hCtr1) transports both Cu(I) and cisplatin (cDDP). Because Cu deficiency is lethal yet Cu overload is poisonous, hCtr1 expression is transcriptionally upregulated in response to Cu deficiency but is downregulated under Cu replete conditions in controlling Cu homeostasis. The up- and down-regulation of hCtr1 is regulated by Specific protein 1 (Sp1), which itself is also correspondingly regulated under these Cu conditions. hCtr1 expression is also upregulated by cDDP via upregulation of Sp1. The underlying mechanisms of these regulations are unknown. Using gel-electrophoretic mobility shift assays, we demonstrated here that Sp1-DNA binding affinity is reduced under Cu replete conditions but increased under reduced Cu conditions. Similarly, Sp1-DNA binding affinity is increased by cDDP treatment. This in vitro system demonstrated, for the first time, that regulation of Sp1/hCtr1 expression by these agents is modulated by the stability of Sp1-DNA binding, the first step in the Sp1-mediated transcriptional regulation process.
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http://dx.doi.org/10.1016/j.jinorgbio.2016.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912872PMC
August 2016

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy.

Expert Opin Ther Targets 2015 25;19(10):1307-17. Epub 2015 May 25.

i 9 The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology , Unit 2951, LSP 9.4206, 2130 W. Holcombe Blvd, Houston, TX 77030, USA +1 713 834 6038 ; +1 713 834 6085 ;

Introduction: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy.

Area Covered: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated.

Expert Opinion: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.
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http://dx.doi.org/10.1517/14728222.2015.1043269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846984PMC
May 2016

Comparison of expected health impacts for major cancers: integration of incidence rate and loss of quality-adjusted life expectancy.

Cancer Epidemiol 2015 Feb 30;39(1):126-32. Epub 2014 Dec 30.

Department of Public Health, National Cheng Kung University College of Medicine, Tainan 704, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan. Electronic address:

Purpose: The study aims to quantify the expected impacts of different cancers through multiplying the incidence rate by loss-of-QALE (quality-adjusted life expectancy), with QALY (quality-adjusted life year) as the common unit, to aid prevention policy decisions.

Methods: 464,722 patients with pathologically verified cancer registered in the Taiwan Cancer Registry during 1998-2009 were used to estimate lifetime survival through Kaplan-Meier estimation combined with a semi-parametric method. A convenience sample for measuring the utility value with EQ-5D was conducted with 11,453 cancer patients, with the results then multiplied by the survival functions to estimate QALE. The loss-of-QALE was calculated by subtracting the QALE of each cancer cohort from the life expectancy of the corresponding age- and gender-matched reference population. The cumulative incidence rates from age 20 to 79 (CIR₂₀₋₇₉) were calculated to estimate the lifetime risk of cancer for each organ-system.

Results: Liver and lung cancer were found the highest expected lifetime health impacts in males and females, or expected lifetime losses of 0.97 and 0.41 QALYs that could be averted, respectively. While the priority changes for prevention based on expected health impacts were slightly different for females based on standardized mortality rates, those of males involve a broader spectrum, including oral, colorectal, esophageal and stomach cancer.

Conclusion: The integration of incidence rate with loss-of-QALE could be used to represent the expected losses that could be averted by prevention, which may be useful in prioritizing strategies for cancer control.
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http://dx.doi.org/10.1016/j.canep.2014.12.004DOI Listing
February 2015

Estimation of loss of quality-adjusted life expectancy (QALE) for patients with operable versus inoperable lung cancer: adjusting quality-of-life and lead-time bias for utility of surgery.

Lung Cancer 2014 Oct 18;86(1):96-101. Epub 2014 Aug 18.

Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, No. 138, Sheng Li Road, Tainan 704, Taiwan; Department of Public Health, National Cheng Kung University College of Medicine and Hospital, No. 138, Sheng Li Road, Tainan 704, Taiwan. Electronic address:

Objectives: This study attempts to quantify the difference in loss of quality-adjusted life expectancy (QALE) for patients with operable and inoperable non-small-cell lung cancer (NSCLC).

Patients And Methods: A cohort consisting of 1652 pathologically verified NSCLC patients with performance status 0-1 was monitored for 7 years (2005-2011) to obtain the survival function. This was further extrapolated to lifetime, based on the survival ratios between patients and age- and sex-matched referents simulated from the life tables of the National Vital Statistics of Taiwan. Between 2011 and 2012, EuroQol 5-dimension questionnaires were used to prospectively measure the quality-of-life (QoL) of a 518 consecutive, cross-sectional subsample. We adjusted the lifetime survival function by the utility values of QoL for the cancer cohort to obtain the QALE, while that for the age and sex-matched referents were adjusted to the values collected from the 2009 National Health Interview Survey, and the difference between them was the loss-of-QALE.

Results: The QALE for patients with operable and inoperable NSCLC were 11.66±0.18 and 1.43±0.05 quality-adjusted life year (QALY), with the corresponding loss-of-QALE of 5.25±0.18 and 14.24±0.05 QALY, respectively. The lifetime utility difference for patients with operable and inoperable NSCLC was 9.00±0.18 QALY, after adjustment for QoL and lead-time bias.

Conclusion: The utility gained from surgical operation for operable lung cancer is substantial, even after adjustment for lead-time bias. Future studies should compare screening programs with treatment strategies when carrying out cost-utility assessments to improve patients' values.
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http://dx.doi.org/10.1016/j.lungcan.2014.08.006DOI Listing
October 2014

Estimating the lifelong health impact and financial burdens of different types of lung cancer.

BMC Cancer 2013 Dec 5;13:579. Epub 2013 Dec 5.

Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, 138 Sheng Li Road, Tainan 70403, Taiwan.

Background: Owing to the high mortality and rapidly growing costs related to lung cancer, it is worth examining the health benefits of prevention for major types of lung cancer. This study attempts to quantify the quality-adjusted life expectancy (QALE), loss-of-QALE, and lifetime healthcare expenditures of patients with different pathological types of lung cancer.

Methods: A national cohort consisting of 66,535 patients with pathologically verified lung cancer was followed for 13 years (1998-2010) to obtain the survival function, which was further extrapolated to lifetime. Between 2011 and 2012, EuroQol 5-dimension questionnaires were used to measure the quality of life (QoL) for 1,314 consecutive, cross-sectional samples. After multiplying the lifetime survival function by the utility values of QoL, we estimated the QALE and loss-of-QALE. We also collected the monthly healthcare expenditures, which included National Health Insurance-reimbursed and out-of-pocket direct medical costs, for 2,456 patients from 2005 to 2012. These values were multiplied by the corresponding survival probabilities to calculate lifetime healthcare expenditures after adjustments with medical care inflation rates and annual discount rates.

Results: The QALE for patients with small cell lung cancer, squamous cell carcinoma, and adenocarcinoma were 1.21, 2.37, and 3.03 quality-adjusted life year (QALY), with the corresponding loss-of-QALE of 13.69, 12.22, and 15.03 QALY, respectively. The lifetime healthcare expenditures were US$ 18,455 ± 1,137, 20,599 ± 1,787, and 36,771 ± 1,998, respectively.

Conclusions: The lifelong health impact and financial burdens in Taiwan are heavier for adenocarcinoma than for squamous cell carcinoma. The cost-effectiveness of prevention programs could be directly compared with that of treatment strategies to improve patient value. And the methodology could be applied to other chronic diseases for resources planning of healthcare services.
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http://dx.doi.org/10.1186/1471-2407-13-579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234193PMC
December 2013

Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals.

J Biol Inorg Chem 2014 Jan 17;19(1):17-27. Epub 2013 Oct 17.

Department of Translational Molecular Pathology (Route 2951), The University of Texas MD Anderson Cancer Center, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.

Platinum-based antitumor agents have been the mainstay in cancer chemotherapy for many human malignancies. Drug resistance is an important obstacle to achieving the maximal therapeutic efficacy of these drugs. Understanding how platinum drugs enter cells is of great importance in improving therapeutic efficacy. It has been demonstrated that human high-affinity copper transporter 1 (hCtr1) is involved in transporting cisplatin into cells to elicit cytotoxic effects, although other mechanisms may exist. In this communication, we demonstrate that cisplatin transcriptionally induces the expression of hCtr1 in time- and concentration-dependent manners. Cisplatin functions as a competitor for hCtr1-mediated copper transport, resulting in reduced cellular copper levels and leading to upregulated expression of Sp1, which is a positive regulator for hCtr1 expression. Thus, regulation of hCtr1 expression by cisplatin is an integral part of the copper homeostasis regulation system. We also demonstrate that Ag(I) and Zn(II), which are known to suppress hCtr1-mediated copper transport, can also induce hCtr1/Sp1 expression. In contrast, Cd(II), another inhibitor of copper transport, downregulates hCtr1 expression by suppressing Sp1 expression. Collectively, our results demonstrate diverse mechanisms of regulating copper metabolism by these heavy metals.
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http://dx.doi.org/10.1007/s00775-013-1051-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889686PMC
January 2014

Overcoming platinum drug resistance with copper-lowering agents.

Anticancer Res 2013 Oct;33(10):4157-61

Department of Translational Molecular Pathology (Unit 951), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

Platinum (Pt)-based antitumor agents have been the mainstay of cancer chemotherapy for the last three decades. While multiple mechanisms are responsible for treatment failure, deficiency in drug transport is an important contributor. The human high-affinity copper (Cu) transporter-1 (hCtr1) can also transport Pt-based drugs including cisplatin (cDDP) and carboplatin. Reduced hCtr1 expression frequently occurs in cDDP-resistant cell lines and in cancer in patients who failed chemotherapy with these drugs. We previously demonstrated that Cu chelation induces the expression of transcription factor Sp1 which binds the promoters of Sp1 and hCtr1, thereby, up-regulating their expression, whereas Cu overload shuts down hCtr1 and Sp1 expression by dissociating Sp1 from their promoter promoters. Thus, mammalian Cu homeostasis is transcriptionally regulated within a loop consisting of Sp1, hCtr1, and Cu in a three-way mutually regulated manner. These findings suggest that it is feasible to module cDDP transport capacity through intervention of mammalian Cu homeostasis. Indeed, we found that cDDP resistance can be overcome by Cu-lowering agents through enhanced hCtr1 expression by up-regulation of Sp1 in cultured cells. This discovery provided a mechanistic basis for the ongoing clinical study using Cu chelator to overcome cDDP resistance in ovarian cancer chemotherapy. Preliminary study using copper chelator (trientine) for enhancing the treatment efficacy of carboplatin in 5 ovarian cancer patients showed encouraging results. This short review describes the perspectives of using Cu-lowering agents in overcoming Pt resistance in cancer chemotherapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001922PMC
October 2013

The increment in standardized uptake value determined using dual-phase 18F-FDG PET is a promising prognostic factor in non-small-cell lung cancer.

Eur J Nucl Med Mol Imaging 2013 Oct 7;40(10):1478-85. Epub 2013 Jun 7.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan.

Purpose: We aimed to determine whether the increment in the maximal standardized uptake value (SUVmax) of the primary lung tumour between the initial and delayed imaging by dual-phase (18)F-FDG PET has prognostic value in patients with non-small-cell lung cancer (NSCLC).

Methods: We reviewed the records of patients with NSCLC who underwent pretreatment dual-phase (18)F-FDG PET/CT scans acquired at 1 h and 2 h after injection. The SUVmax increment (SUVinc) of the primary lung tumour was the 2-h SUVmax minus the 1-h SUVmax. Univariate and multivariate analyses were used to assess the prognostic significance of SUVinc, retention index, whole-body total metabolic tumour volume, whole-body total lesion glycolysis (TLGwb), 1-h SUVmax, 2-h SUVmax, gender, age, performance status, histological subtype, T stage, N stage and clinical stage.

Results: The records of 187 consecutive patients were reviewed. The median follow-up time was 3.9 years. The estimated median progression-free survival (PFS) and overall survival (OS) were 1.3 years and 4.4 years, respectively. An SUVinc cut-off value of >1 had the best discriminative yield for PFS. The 3-year PFS and OS were 61.6 % and 87.8 % in patients with SUVinc ≤ 1 versus 21.1 % and 46.2 % in patients with SUVinc >1 (all P < 0.01). Using the forward stepwise multivariate Cox proportional hazards model, SUVinc, TLGwb, and clinical stage were significant factors for PFS (all P < 0.01). A subgroup analysis of 117 patients treated with surgery showed that SUVinc (P = 0.02) and clinical stage (P < 0.01) were significant prognostic factors for PFS. Furthermore, in stage I patients treated with surgery alone, SUVinc was the only significant prognostic factor (HR 28.07; 95 % CI 2.42 - 326.41).

Conclusion: SUVinc determined from dual-phase (18)F-FDG PET is a promising prognostic factor for NSCLC. It adds to the value of dual-phase (18)F-FDG PET.
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http://dx.doi.org/10.1007/s00259-013-2452-5DOI Listing
October 2013

Interleukin-17-producing cell infiltration in the breast cancer tumour microenvironment is a poor prognostic factor.

Histopathology 2013 Aug 6;63(2):225-33. Epub 2013 Jun 6.

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Aims: Interleukin-17 (IL-17) is a proinflammatory cytokine that is most prominently produced by T-helper type 17 (Th17) cells, a distinct CD4+ T-helper cell subset. The aim of this study was to investigate the level of IL-17-producing cells in the breast cancer tumour microenvironment and its prognostic role.

Methods And Results: A total of 207 breast carcinoma specimens were assessed by IL-17 immunohistochemistry, and the findings were correlated with clinicopathological parameters. We found that increased numbers of IL-17-producing cells were correlated with high histological grade, negative ER/PR status, and triple-negative molecular subtypes segregated by immunoprofiles. However, they did not correlate with stage, tumour size, nodal status, HER2 status, or histological type. Patients with tumours with high numbers of IL-17-producing cells had shorter disease-free survival (DFS) than patients with tumours with low numbers of IL-17-producing cells (P < 0.01). In multivariate analysis, high IL-17 level [hazard ratio (HR) 2.24; 95% CI 1.06-4.75], advanced T stage (HR 2.73; 95% CI 1.30-5.73), positive HER2 status (HR 4.88; 95% CI 1.47-16.18) and triple-negative subtype (HR 7.46; 95% CI 1.38-40.36) were significant prognostic factors for DFS.

Conclusions: Our results indicate that a high level of IL-17-producing cells in the breast cancer tumour microenvironment is a poor prognostic factor.
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http://dx.doi.org/10.1111/his.12156DOI Listing
August 2013

Routine defunctioning stoma after chemoradiation and total mesorectal excision: a single-surgeon experience.

World J Gastroenterol 2013 Mar;19(11):1797-804

Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Aim: To investigate the 10-year results of treating low rectal cancer by a single surgeon in one institution.

Methods: From Oct 1998 to Feb 2009, we prospectively followed a total of 62 patients with cT2-4 low rectal cancer with lower tumor margins measuring at 3 to 6 cm above the anal verge. All patients received neoadjuvant chemoradiation (CRT) for 6 wk. Among them, 85% of the patients received 225 mg/m(2)/d 5-fluorouracil using a portable infusion pump. The whole pelvis received a total dose of 45 Gy of irradiation in 25 fractions over 5 wk. The interval from CRT completion to surgical intervention was planned to be approximately 6-8 wk. Total mesorectal excision (TME) and routine defunctioning stoma construction were performed by one surgeon. The distal resection margin, circumferential resection margin, tumor regression grade (TRG) and other parameters were recorded. We used TRG to evaluate the tumor response after neoadjuvant CRT. We evaluated anal function outcomes using the Memorial Sloan-Kettering Cancer Center anal function scores after closure of the defunctioning stoma.

Results: The median distance from the lower margin of rectal cancer to the anal verge was 5 cm: 6 cm in 9 patients, 5 cm in 32 patients, 4 cm in 10 patients, and 3 cm in 11 patients. Before receiving neoadjuvant CRT, 45 patients (72.6%) had a cT3-4 tumor, and 21 (33.9%) patients had a cN1-2 lymph node status. After CRT, 30 patients (48.4%) had a greater than 50% clinical reduction in tumor size. The final pathology reports revealed that 33 patients (53.2%) had a ypT3-4 tumor and 12 (19.4%) patients had ypN1-2 lymph node involvement. All patients completed the entire course of neoadjuvant CRT. Most patients developed only Grade 1-2 toxicities during CRT. Thirteen patients (21%) achieved a pathologic complete response. Few post-operative complications occurred. Nearly 90% of the defunctioning stomas were closed within 6 mo. The local recurrence rate was 3.2%. Pathologic lymph node involvement was the only prognostic factor predicting disease recurrence (36.5% vs 76.5%, P = 0.006). Nearly 90% of patients recovered sphincter function within 2 year after closure of the defunctioning stoma.

Conclusion: Neoadjuvant CRT followed by TME, combined with routine defunctioning stoma construction and high-volume surgeon experience, can provide excellent surgical quality and good local disease control.
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http://dx.doi.org/10.3748/wjg.v19.i11.1797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607756PMC
March 2013

Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway.

Am J Respir Cell Mol Biol 2013 Aug;49(2):241-50

Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Metformin has been used as first-line treatment in patients with type 2 diabetes, and is reported to reduce cancer risk and progression by activating the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Cisplatin remains the main drug for treating advanced non-small-cell lung cancer. However, drug resistance often develops through several mechanisms during the treatment course, including one mechanism mediated by the activation of the IL-6/signal transducer and activator of transcription (STAT)-3 pathway, related to the generation of reactive oxygen species (ROS). This study demonstrated a correlation between STAT3 phosphorylation and cisplatin cytotoxicity, using AS2 (PC14PE6/AS2)-derived cell lines (AS2/S3C) that contained constitutively active STAT3 plasmids as a model. A STAT3 inhibitor (JSI-124) enhanced the cisplatin sensitivity in AS2 cells, whereas metformin inhibited STAT3 phosphorylation and enhanced cisplatin cytotoxicity. By contrast, another AMPK activator (5-aminoimidazole-4-carboxamide-riboside) failed to produce these effects. LKB1-AMPK silencing by small, interfering RNA or mammalian target of rapamycin (mTOR) inhibition by rapamycin or pp242 did not alter the effect of metformin on STAT3 activity suppression, suggesting that metformin can modulate the STAT3 pathway through an LKB1-AMPK-independent and probably mTOR-independent mechanism. Metformin also inhibited cisplatin-induced ROS production and autocrine IL-6 secretion in AS2 cells. Both mechanisms contributed to the ability of metformin to suppress STAT3 activation in cancer cells, which resulted in the decreased secretion of vascular endothelial growth factor by cancer cells. The growth of subcutaneous tumor xenografts was significantly delayed by a combination of cisplatin and metformin. This is the first study to demonstrate that metformin suppresses STAT3 activation via LKB1-AMPK-mTOR-independent but ROS-related and autocrine IL-6 production-related pathways. Thus, metformin helps to overcome tumor drug resistance by targeting STAT3.
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http://dx.doi.org/10.1165/rcmb.2012-0244OCDOI Listing
August 2013

Role of the human high-affinity copper transporter in copper homeostasis regulation and cisplatin sensitivity in cancer chemotherapy.

Cancer Res 2012 Sep 7;72(18):4616-21. Epub 2012 Sep 7.

Department of Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77054, USA.

The high-affinity copper transporter (Ctr1; SCLC31A1) plays an important role in regulating copper homeostasis because copper is an essential micronutrient and copper deficiency is detrimental to many important cellular functions, but excess copper is toxic. Recent research has revealed that human copper homeostasis is tightly controlled by interregulatory circuitry involving copper, Sp1, and human (hCtr1). This circuitry uses Sp1 transcription factor as a copper sensor in modulating hCtr1 expression, which in turn controls cellular copper and Sp1 levels in a 3-way mutual regulatory loop. Posttranslational regulation of hCtr1 expression by copper stresses has also been described in the literature. Because hCtr1 can also transport platinum drugs, this finding underscores the important role of hCtr1 in platinum-drug sensitivity in cancer chemotherapy. Consistent with this notion is the finding that elevated hCtr1 expression was associated with favorable treatment outcomes in cisplatin-based cancer chemotherapy. Moreover, cultured cell studies showed that elevated hCtr1 expression can be induced by depleting cellular copper levels, resulting in enhanced cisplatin uptake and its cell-killing activity. A phase I clinical trial using a combination of trientine (a copper chelator) and carboplatin has been carried out with encouraging results. This review discusses new insights into the role of hCtr1 in regulating copper homeostasis and explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445735PMC
September 2012

Mechanistic basis for overcoming platinum resistance using copper chelating agents.

Mol Cancer Ther 2012 Nov 21;11(11):2483-94. Epub 2012 Aug 21.

Department of Molecular Pathology, Unit 951, Room 2SCR4.3025, The University of Texas MD Anderson Cancer Center, 7435 Fannin Blvd, Houston, TX 77054, USA.

Platinum-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we conducted a clinical trial using a copper-lowering agent to overcome platinum drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in platinum-based chemotherapy, we showed that cDDP resistance associated with reduced expression of the high-affinity copper transporter (hCtr1), which is also a cDDP transporter, can be preferentially resensitized by copper-lowering agents because of enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by copper chelation can be explained by the mammalian copper homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a copper-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after platinum drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using copper chelation to overcome cDDP resistance in clinical investigations.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-0580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496003PMC
November 2012

Mitochondrial uncoupling protein 2 regulates the effects of paclitaxel on Stat3 activation and cellular survival in lung cancer cells.

Carcinogenesis 2012 Nov 30;33(11):2065-75. Epub 2012 Jul 30.

Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 35, Xiao-dong Rd, Tainan 704, Taiwan.

Growing evidence suggests that Stat3 contributes to chemoresistance. However, the impact of chemotherapy on Stat3 activity is unclear. We found that paclitaxel activated Stat3 in the human lung cancer cell lines PC14PE6AS2 (AS2) and H157, whereas it reduced Stat3 activation in A549 and H460 cells. Pretreatment of AS2 and H157 cells with rotenone, an inhibitor of mitochondrially produced reactive oxygen species (ROS), or carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler, suppressed the paclitaxel-induced activation of Stat3. Uncoupling protein 2 (UCP-2), located in the inner membrane of the mitochondria, can reduce ROS production in conditions of oxidative stress. UCP-2 protein expression in the four cancer cell lines was higher than that in normal lung epithelial cells (NL-20), but its expression was lower in AS2 and H157 cells relative to A549 and H460 cells. Silencing high UCP-2 expression with small interfering RNA (siRNA) in A549 and H460 cells restored paclitaxel-induced Stat3 activation. In addition, paclitaxel-induced Stat3 activation led to the upregulation of survivin and Mcl-1, which in turn facilitated cell survival. Moreover, the CL1-5 subline had lower UCP-2 expression relative to the parental CL1-0 cells. Treatment with paclitaxel activated Stat3 in CL1-5 but not in CL1-0 cells, whereas in CL1-5 cells, the overexpression of UCP-2 with complementary DNA (cDNA) blocked Stat3 activation. In lung cancer patients, low UCP-2 expression in cancer cells was a predictor of a poor response to chemotherapy. Therefore, UCP-2 modulates the ROS/Stat3 signaling pathway and response to chemotherapy treatment in lung cancer cells. Targeting UCP-2, ROS and Stat3 pathways may improve anticancer therapies.
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http://dx.doi.org/10.1093/carcin/bgs253DOI Listing
November 2012

Prognostic value of whole-body total lesion glycolysis at pretreatment FDG PET/CT in non-small cell lung cancer.

Radiology 2012 Aug 12;264(2):559-66. Epub 2012 Jun 12.

Department of Radiation Oncology, National Cheng Kung University, Tainan, Taiwan.

Purpose: To determine whether whole-body total lesion glycolysis (TLG), which combines volumetric and metabolic information from fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), can provide a better evaluation of the prognosis for non-small cell lung cancer (NSCLC).

Materials And Methods: The institutional review board approved this retrospective study, and the requirement to obtain informed consent was waived. The authors identified 105 consecutive patients with NSCLC who underwent staging FDG PET/CT before any therapy. These patients were free of brain metastasis and underwent standard treatment and subsequent clinical follow-up. Metabolic tumor volume (MTV), mean standardized uptake value (SUV), and maximum SUV of each tumor over the whole body were determined. Whole-body MTV and whole-body TLG are the summation of all the MTVs and summation of individual tumor volume multiplied by its mean SUV, respectively. Univariate and multivariate analyses were performed to assess the prognostic significance of whole-body TLG and other factors, including whole-body MTV, lung TLG, lung MTV, maximum SUV, sex, age, performance status, histologic subtype, T stage, N stage, clinical stage, and treatment method.

Results: The median follow-up time was 3.1 years. The estimated median progression-free survival (PFS) and overall survival (OS) for the cohort was 10.8 months and 2.8 years, respectively. The 1-year PFS was 0.0% for patients with high whole-body TLG (>655) and 50.0% for those with low whole-body TLG (≤655). The 1-year OS was 58.8% for patients with high whole-body TLG and 84.1% for those with low whole-body TLG. Univariate analysis showed that whole-body TLG, whole-body MTV, lung TLG, lung MTV, maximum SUV, performance status, T stage, N stage, clinical stage, and treatment type (surgery vs other) were significant prognostic factors for PFS (P < .01 for all). With use of the forward stepwise multivariate Cox proportional hazards model, whole-body TLG (hazard ratio = 2.92; 95% confidence interval: 1.62, 5.26; P < .01) and surgical treatment (hazard ratio = 4.24; 95% confidence interval: 2.54, 7.07; P < .01) remained significant in PFS.

Conclusion: Whole-body TLG is of prognostic value for NSCLC. It may be a promising tool for stratifying patients with NSCLC for risk-adapted therapies.
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http://dx.doi.org/10.1148/radiol.12111148DOI Listing
August 2012

Intensity-modulated radiotherapy improves outcomes in postoperative patients with squamous cell carcinoma of the oral cavity.

Oral Oncol 2012 Aug 7;48(8):747-52. Epub 2012 Mar 7.

Department of Radiation Oncology, Sinlau Christian Hospital, Tainan, Taiwan; Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138 Cheng-Li Road, Tainan, Taiwan.

Objectives: We compared the outcomes and survival rates of patients with oral cavity squamous cell carcinoma receiving postoperative conventional radiotherapy (RT) or intensity-modulated radiotherapy (IMRT).

Materials And Methods: From January 2005 to September 2008, medical records of 131 consecutive patients with oral cancer receiving postoperative radiotherapy in the Department of Radiation Oncology of National Cheng Kung University Hospital were reviewed. Patients were divided into two groups according to the administration of postoperative conventional RT or IMRT. The loco-regional control, survival, and other prognostic factors were compared.

Results: The 3-year Kaplan-Meier estimates of overall survival for patients receiving conventional RT and IMRT groups were 51.2% vs. 69.4% (p=0.079), respectively. The 3-year local-regional control (53.5% vs. 76.3%; p=0.020) and disease-free survival rates (47.8% vs. 70.0%; p=0.027) were significantly increased in the IMRT group. This retrospective study also identified that extracapsular spreading, margin positive/close (≤ 2mm), more advanced T stage (T3-4 vs. T1-2), and conventional RT method were associated with worse prognosis.

Conclusions: The addition of chemotherapy to adjuvant radiotherapy is recommended in patients with above risk factors. Our result underscores that IMRT should be considered to apply to OSCC patients referred for postoperative treatment.
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http://dx.doi.org/10.1016/j.oraloncology.2012.02.010DOI Listing
August 2012
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