Cancer Research and Treatment

Original Articles

A Prospective, Single-Cohort, Open, Multi-Center, Observational Study of Sublingual Fentanyl for Breakthrough Cancer Pain: Effectiveness, Safety, and Tolerability in Korean Cancer Patients: Youn Seon Choi, Su-Jin Koh, Woo Kyun Bae, Se Hyung Kim, Seong Hoon Shin, So Yeon Oh, Sang Byung Bae, Yaewon Yang, Eun-Kee Song, Yoon Young Cho, Pyung Bok Lee, Ho-Suk Oh, MinYoung Lee, Jin Seok Ahn; Received June 13, 2024 Accepted December 24, 2024 Published online December 26, 2024; DOI: https://doi.org/10.4143/crt.2024.557 [Accepted]

Abstract PDF: Purpose
Fentanyl, a highly lipophilic opioid, was developed as a sublingual fentanyl tablet (SFT) for the management of breakthrough cancer pain (BTcP), and its efficacy and safety were confirmed in a randomized, controlled study. We investigated the effectiveness and safety of SFT administered to alleviate BTcP in a real-world setting.
Materials and Methods
In this prospective, open, single-cohort study, conducted in 13 referral hospitals in South Korea, opioid-tolerant cancer patients receiving around-the-clock opioids for persistent cancer pain were enrolled if the individual had BTcP ≥ 1 episode/day during the preceding week. The primary outcome was the SFT titration success rate.
Results
Among 113 patients evaluated for effectiveness, 103 patients (91.2%) had a successful titration of SFT, with an effective dose range between 100 µg and 400 µg. The most frequent dose was 100 µg, administered to 65.0%, 72.1%, and 81.8% of the patients at Week 1, 4, and 12, respectively. The proportion of patients achieving the personalized pain goal assessed in the first week was 75.2%. The mean change in pain intensity measured with a numeric rating scale at 30 and 60 minutes after taking SFT was -2.57 and -3.62, respectively (p<0.0001 for both). The incidence rate of adverse events related to SFT among 133 patients included for safety evaluation was 9.0% (12/133), which included vomiting (3.0%), nausea (2.3%), and headache (1.5%).
Conclusion
In a real-world setting, SFT provides rapid and effective analgesia in BTcP, even at the lowest dose (100 μg), and the safety profile was acceptable.

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Lung and Thoracic cancer

MLL4 Regulates the Progression of Non–Small-Cell Lung Cancer by Regulating the PI3K/AKT/SOX2 Axis: Yang Yang, Rongfang Qiu, Qiaoyou Weng, Ziwei Xu, Jingjing Song, Siyu Zhao, Miaomiao Meng, Dengke Zhang, Chunli Kong, Hailin Wang, Min Xu, Zhongwei Zhao, Jiansong Ji; Cancer Res Treat. 2023;55(3):778-803. Published online January 26, 2023; DOI: https://doi.org/10.4143/crt.2022.1042

Abstract PDF Supplementary Material PubReader ePub

Purpose
Mixed-lineage leukemia protein 4 (MLL4/KMT2D) is a histone methyltransferase, and its mutation has been reported to be associated with a poor prognosis in many cancers, including lung cancer. We investigated the function of MLL4 in lung carcinogenesis.
Materials and Methods
RNA sequencing (RNA-seq) in A549 cells transfected with control siRNA or MLL4 siRNA was performed. Also, we used EdU incorporation assay, colony formation assays, growth curve analysis, transwell invasion assays, immunohistochemical staining, and in vivo bioluminescence assay to investigate the function of MLL4 in lung carcinogenesis.
Results
We found that MLL4 expression was downregulated in non–small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues and tended to decrease with disease stage progression. We analyzed the transcriptomes in control and MLL4- deficient cells using high-throughput RNA deep sequencing (RNA-seq) and identified a cohort of target genes, such as SOX2, ATF1, FOXP4, PIK3IP1, SIRT4, TENT5B, and LFNG, some of which are related to proliferation and metastasis. Our results showed that low expression of MLL4 promotes NSCLC cell proliferation and metastasis and is required for the maintenance of NSCLC stem cell properties.
Conclusion
Our findings identify an important role of MLL4 in lung carcinogenesis through transcriptional regulation of PIK3IP1, affecting the PI3K/AKT/SOX2 axis, and suggest that MLL4 could be a potential prognostic indicator and target for NSCLC therapy.

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Role and potential therapeutic value of histone methyltransferases in drug resistance mechanisms in lung cancer
Linxiang Zhang, Xueying Zhang, Yan Shi, Yuhan Ni, Jiaojiao Fei, Zhixin Jin, Wenjuan Li, Xiaojing Wang, Nan Wu
Frontiers in Oncology.2024;[Epub] CrossRef
The multifaceted role of SOX2 in breast and lung cancer dynamics
Kiavash Hushmandi, Seyed Hassan Saadat, Seyedalireza Mirilavasani, Salman Daneshi, Amir Reza Aref, Noushin Nabavi, Rasoul Raesi, Afshin Taheriazam, Mehrdad Hashemi
Pathology - Research and Practice.2024; 260: 155386. CrossRef
PIK3IP1: structure, aberration, function, and regulation in diseases
Yingjie Jia, Pengxing He, Xubin Ma, Kaili Lv, Ying Liu, Yichao Xu
European Journal of Pharmacology.2024; 977: 176753. CrossRef
UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway
Li He, Heng Chen, Bin Ruan, Li He, Ming Luo, Yulun Fu, Rui Zou
Journal of Cancer Research and Clinical Oncology.2024;[Epub] CrossRef
Role of histone methyltransferase KMT2D in BMSC osteogenesis via AKT signaling
Zhichun Zhang, Yanyan Guo, Xuejun Gao, Xiaoyan Wang, Chanyuan Jin
Regenerative Therapy.2024; 26: 775. CrossRef
Landscape of targeted therapies for lung squamous cell carcinoma
Qiuxuan Chen, Xiaoshuo Zheng, Weiting Cheng, Jian Li
Frontiers in Oncology.2024;[Epub] CrossRef

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Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells: Miso Lee, Kyung-Hun Lee, Ahrum Min, Jeongeun Kim, Seongyeong Kim, Hyemin Jang, Jee Min Lim, So Hyeon Kim, Dong-Hyeon Ha, Won Jae Jeong, Koung Jin Suh, Yae-Won Yang, Tae Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2019;51(2):451-463. Published online June 6, 2018; DOI: https://doi.org/10.4143/crt.2017.341

Abstract PDF Supplementary Material PubReader ePub

Purpose
Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells.
Materials and Methods
The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis.
Results
AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines.
Conclusion
Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.

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A literature review of recent advances in gastric cancer treatment: exploring the cross-talk between targeted therapies
Reza Panahizadeh, Padideh Panahi, Vahid Asghariazar, Shima Makaremi, Ghasem Noorkhajavi, Elham Safarzadeh
Cancer Cell International.2025;[Epub] CrossRef
PIM1 attenuates cisplatin-induced AKI by inhibiting Drp1 activation
Yuzhen Li, Lang Shi, Fan Zhao, Yanwen Luo, Mingjiao Zhang, Xiongfei Wu, Jiefu Zhu
Cellular Signalling.2024; 113: 110969. CrossRef
Prognostic Model Construction of Disulfidptosis-Related Genes and Targeted Anticancer Drug Research in Pancreatic Cancer
Hongtao Duan, Li Gao, Aiminuer Asikaer, Lingzhi Liu, Kuilong Huang, Yan Shen
Molecular Biotechnology.2024;[Epub] CrossRef
PIM1 kinase and its diverse substrate in solid tumors
Rituparna Choudhury, Chandan Kumar Bahadi, Ipsa Pratibimbita Ray, Pragyanshree Dash, Isha Pattanaik, Suman Mishra, Soumya R. Mohapatra, Srinivas Patnaik, Kumar Nikhil
Cell Communication and Signaling.2024;[Epub] CrossRef
The evaluation of six genes combined value in glioma diagnosis and prognosis
Ping Lin, Lingyan He, Nan Tian, Xuchen Qi
Journal of Cancer Research and Clinical Oncology.2023; 149(13): 12413. CrossRef
Toxic effects of AZD1208 on mouse oocytes and its possible mechanisms
Feng‐Ze Yan, Ying‐Chun Ouyang, Tie‐Gang Meng, Hong‐Yong Zhang, Wei Yue, Xin‐Ran Zhang, Yue Xue, Zhen‐Bo Wang, Qing‐Yuan Sun
Journal of Cellular Physiology.2022; 237(9): 3661. CrossRef
Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects
Aanchal Rathi, Dhiraj Kumar, Gulam Mustafa Hasan, Mohammad Mahfuzul Haque, Md Imtaiyaz Hassan
Biochimica et Biophysica Acta (BBA) - General Subjects.2021; 1865(11): 129995. CrossRef
TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy
Jin Won Kim, Ahrum Min, Seock-Ah Im, Hyemin Jang, Yu Jin Kim, Hee-Jun Kim, Kyung-Hun Lee, Tae-Yong Kim, Keun Wook Lee, Do-Youn Oh, Jee-Hyun Kim, Yung-Jue Bang
Cancers.2020; 12(2): 334. CrossRef
PIM1 (Moloney Murine Leukemia Provirus Integration Site) Inhibition Decreases the Nonhomologous End-Joining DNA Damage Repair Signaling Pathway in Pulmonary Hypertension
Marie-Claude Lampron, Géraldine Vitry, Valérie Nadeau, Yann Grobs, Renée Paradis, Nolwenn Samson, Ève Tremblay, Olivier Boucherat, Jolyane Meloche, Sébastien Bonnet, Steeve Provencher, François Potus, Roxane Paulin
Arteriosclerosis, Thrombosis, and Vascular Biology.2020; 40(3): 783. CrossRef
Inhibition of PIM1 attenuates the stem cell–like traits of breast cancer cells by promoting RUNX3 nuclear retention
Hui Liu, Cheng Chen, Dongshen Ma, Yubing Li, Qianqian Yin, Qing Li, Chenxi Xiang
Journal of Cellular and Molecular Medicine.2020; 24(11): 6308. CrossRef
Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer
Dong-Hyeon Ha, Ahrum Min, Seongyeong Kim, Hyemin Jang, So Hyeon Kim, Hee-Jun Kim, Han Suk Ryu, Ja-Lok Ku, Kyung-Hun Lee, Seock-Ah Im
Scientific Reports.2020;[Epub] CrossRef
Pim kinase inhibitors in cancer: medicinal chemistry insights into their activity and selectivity
Soraya Alnabulsi, Enas A. Al-Hurani
Drug Discovery Today.2020; 25(11): 2062. CrossRef
New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations
Maiara Bernardes Marques, Michael González-Durruthy, Bruna Félix da Silva Nornberg, Bruno Rodrigues Oliveira, Daniela Volcan Almeida, Ana Paula de Souza Votto, Luis Fernando Marins
Current Topics in Medicinal Chemistry.2019; 19(11): 914. CrossRef
Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia
Francesca Musumeci, Chiara Greco, Giancarlo Grossi, Alessio Molinari, Silvia Schenone
Cancers.2018; 10(11): 430. CrossRef

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A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro: Saketh S. Dinavahi, Rajagopalan Prasanna, Sriram Dharmarajan, Yogeeswari Perumal, Srikant Viswanadha; Cancer Res Treat. 2015;47(4):913-920. Published online January 2, 2015; DOI: https://doi.org/10.4143/crt.2014.057

Abstract PDF PubReader ePub

Purpose
Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point. A novel scaffold of Akt inhibitors was developed through virtual screening of chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad, based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6) was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50 of 256 nM.
Materials and Methods
BIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transfer kit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170 cell lines. The effect of the compound on p-Akt (S473) was estimated.
Results
BIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a half maximal growth inhibition (GI50) range of 0.49 μM to 6.6 μM. Cell cycle analysis indicated that BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA- 6 also exhibited synergism with standard chemotherapeutic agents.
Conclusion
BIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer cell lines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high margin selectivity towards normal cells.

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Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development
Saketh S. Dinavahi, Yu-Chi Chen, Raghavendra Gowda, Pavan Kumar Dhanyamraju, Kishore Punnath, Dhimant Desai, Arthur Berg, Scot R. Kimball, Shantu Amin, Jin-Ming Yang, Gavin P. Robertson
International Journal of Molecular Sciences.2022; 23(7): 3481. CrossRef
Targeting WEE1/AKT Restores p53-Dependent Natural Killer–Cell Activation to Induce Immune Checkpoint Blockade Responses in “Cold” Melanoma
Saketh S. Dinavahi, Yu-Chi Chen, Kishore Punnath, Arthur Berg, Meenhard Herlyn, Momeneh Foroutan, Nicholas D. Huntington, Gavin P. Robertson
Cancer Immunology Research.2022; 10(6): 757. CrossRef
Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent
Saketh S. Dinavahi, Raghavendra Gowda, Krishne Gowda, Christopher G. Bazewicz, Venkat R. Chirasani, Madhu Babu Battu, Arthur Berg, Nikolay V. Dokholyan, Shantu Amin, Gavin P. Robertson
Molecular Cancer Therapeutics.2020; 19(2): 447. CrossRef
Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy
Sabrina Borchert, Pia-Maria Suckrau, Michael Wessolly, Elena Mairinger, Balazs Hegedus, Thomas Hager, Thomas Herold, Wildfried E. E. Eberhardt, Jeremias Wohlschlaeger, Clemens Aigner, Agnes Bankfalvi, Kurt Werner Schmid, Robert F. H. Walter, Fabian D. Mai
Journal of Oncology.2019; 2019: 1. CrossRef
Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations
Saketh S. Dinavahi, Mohammad A. Noory, Raghavendra Gowda, Joseph J. Drabick, Arthur Berg, Rogerio I. Neves, Gavin P. Robertson
Molecular Pharmacology.2018; 93(3): 190. CrossRef
Novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, MHY-449, induces cell cycle arrest and apoptosis via the downregulation of Akt in human lung cancer cells
HYUN SOOK LIM, YONG JUNG KANG, BOKYUNG SUNG, SEON HEE KIM, MIN JEONG KIM, HYE RIM KIM, SEONG JIN KIM, YUNG HYUN CHOI, HYUNG RYONG MOON, HAE YOUNG CHUNG, NAM DEUK KIM
Oncology Reports.2015; 34(5): 2431. CrossRef

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Synergistic Effect of Sulindac and Simvastatin on Apoptosis in Lung Cancer A549 Cells through AKT-Dependent Downregulation of Survivin: Young-Suk Kim, Chang-Hwan Seol, Jae-Wan Jung, Su-Jin Oh, Ki-Eun Hwang, Hwi-Jung Kim, Eun-Taik Jeong, Hak-Ryul Kim; Cancer Res Treat. 2015;47(1):90-100. Published online October 27, 2014; DOI: https://doi.org/10.4143/crt.2013.194

Abstract PDF PubReader ePub

Purpose
Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells.
Materials and Methods
Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin.
Results
Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis.
Conclusion
Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer.

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Regulatory effects of statins on Akt signaling for prevention of cancers
Fatemeh Sadat Hosseini, Abdolreza Ahmadi, Prashant Kesharwani, Hossein Hosseini, Amirhossein Sahebkar
Cellular Signalling.2024; 120: 111213. CrossRef
Sulindac exhibits anti-proliferative and anti-invasive effects in uterine serous carcinoma cells
Shuning Chen, Weimin Kong, Xiaochang Shen, Boer Deng, Jennifer Haag, Nikita Sinha, Catherine John, Wenchuan Sun, Chunxiao Zhou, Victoria L. Bae-Jump
Journal of Cancer Research and Clinical Oncology.2024;[Epub] CrossRef
BAPST. A Combo of Common Use Drugs as Metabolic Therapy for Cancer: A Theoretical Proposal
Adriana Romo-Perez, Guadalupe Dominguez-Gomez, Alma Chavez-Blanco, Lucia Taja-Chayeb, Aurora Gonzalez-Fierro, Elisa Garcia-Martinez, Jose Correa-Basurto, Alfonso Duenas-Gonzalez
Current Molecular Pharmacology.2022; 15(6): 815. CrossRef
Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis
Navneet Kumar, Chandi C. Mandal
Frontiers in Genetics.2021;[Epub] CrossRef
Small molecules regulating reactive oxygen species homeostasis for cancer therapy
Junmin Zhang, Dongzhu Duan, Zi‐Long Song, Tianyu Liu, Yanan Hou, Jianguo Fang
Medicinal Research Reviews.2021; 41(1): 342. CrossRef
Lanthanum(III) and neodymium(III) complexes with anti-inflammatory drug sulindac: Synthesis, characterization, thermal investigation using coupled techniques TG-FTIR, and in vitro biological studies
Renan B. Guerra, Thais Fernanda de Campos Fraga-Silva, Julia Aguiar, Paula B. Oshiro, Bruno B.C. Holanda, James Venturini, Gilbert Bannach
Inorganica Chimica Acta.2020; 503: 119408. CrossRef
A remarkable in vitro cytotoxic, cell cycle arresting and proapoptotic characteristics of low-dose mixed micellar simvastatin combined with alendronate sodium
Sandip A. Bandgar, Namdeo R. Jadhav, Arehalli S. Manjappa
Drug Delivery and Translational Research.2020; 10(4): 1122. CrossRef
Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets
Giridhar Mudduluru, Wolfgang Walther, Dennis Kobelt, Mathias Dahlmann, Christoph Treese, Yehuda G. Assaraf, Ulrike Stein
Drug Resistance Updates.2016; 26: 10. CrossRef
Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway
Mathias Woschek, Niels Kneip, Katrin Jurida, Ingo Marzi, Borna Relja
Nutrition and Cancer.2016; 68(3): 420. CrossRef
Celecoxib and sulindac inhibit TGF-β1-induced epithelial-mesenchymal transition and suppress lung cancer migration and invasion via downregulation of sirtuin 1
Byong-Ki Cha, Young-Suk Kim, Ki-Eun Hwang, Kyung-Hwa Cho, Seon-Hee Oh, Byoung-Ryun Kim, Hong-Young Jun, Kwon-Ha Yoon, Eun-Taik Jeong, Hak-Ryul Kim
Oncotarget.2016; 7(35): 57213. CrossRef
Ultra-structure changes and survivin expression in uterine fibroids after radiofrequency ablation
Shan-rong Shu, Xin Luo, Wen-Xia Song, Pei-Wen Chen
International Journal of Hyperthermia.2015; 31(8): 896. CrossRef

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Synergistic Effect of COX-2 Inhibitor on Paclitaxel-Induced Apoptosis in the Human Ovarian Cancer Cell Line OVCAR-3: Hee Jung Kim, Ga Won Yim, Eun Ji Nam, Young Tae Kim; Cancer Res Treat. 2014;46(1):81-92. Published online January 15, 2014; DOI: https://doi.org/10.4143/crt.2014.46.1.81

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PURPOSE
Celecoxib, a highly selective cyclooxygenase-2 inhibitor, regulates apoptosis of several types of human cancer cells. The purpose of this study was to investigate whether celecoxib in combination with paclitaxel modulates apoptosis of ovarian cancer cells, and to identify the signal pathway by which celecoxib mediates apoptosis.
MATERIALS AND METHODS
OVCAR-3 cells were exposed to paclitaxel (20 microM) in the absence or presence of celecoxib (10 microM). Cell viability was evaluated using a Cell Counting Kit-8 assay. Apoptosis was evaluated using Annexin-V/7-aminoactinomycin D staining and a cellular DNA fragmentation enzyme-linked immunosorbent assay. Caspase-3, -9, and cleavage of poly ADP-ribose polymerase (PARP) were determined by western blotting. Expression of nuclear factor-kappaB (NF-kappaB) and vascular endothelial growth factor (VEGF) and Akt activation were assessed using reverse transcriptase-polymerase chain reaction and western blotting.
RESULTS
Celecoxib enhanced paclitaxel-induced growth inhibition of OVCAR-3 cells. Celecoxib significantly increased paclitaxel-induced apoptosis of OVCAR-3 cells. Pretreatment with celecoxib also increased activation of caspase-9, -3 and cleaved PARP following paclitaxel-treatment. Exposure of OVCAR-3 cells to celecoxib in combination with paclitaxel resulted in downregulation of NF-kappaB activation and VEGF expression. Furthermore, combining celecoxib and paclitaxel inhibited phosphorylation of Akt.
CONCLUSION
OVCAR-3 cells were sensitized to paclitaxel-induced apoptosis by celecoxib through downregulation of NF-kappaB and Akt activation, suggesting that celecoxib may work synergistically with paclitaxel to inhibit different targets and ultimately produce anticancer effects. Combining celecoxib with paclitaxel may prove beneficial in the clinical treatment of ovarian cancer.

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Zhuyan Shao, Qiang Wen, Tao Zhu, Wei Jiang, Yu Kang, Conjian Xu, Shihua Wang
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Xiaobin Zheng, Neal Andruska, Michael J. Lambrecht, Sisi He, Amadeo Parissenti, Paul J. Hergenrother, Erik R. Nelson, David J. Shapiro
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Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma
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Maspin Suppresses Survival of Lung Cancer Cells through Modulation of Akt Pathway: Eunsook Nam, Chaehwa Park; Cancer Res Treat. 2010;42(1):42-47. Published online March 31, 2010; DOI: https://doi.org/10.4143/crt.2010.42.1.42

Abstract PDF PubReader ePub

Purpose

Maspin is a tumor suppressor protein that has been reported to stimulate the cell death of cancer and inhibit the metastasis of cancer. The present study aimed to explore the survival pathway by which maspin modulates the resistance of human lung cancer cells to chemotherapeutic drugs, and the consequences of maspin gene therapy in an animal model.

Materials and Methods

NCI-H157 and A549 cells were transfected with either a mock vector (pCMVTaq4C), maspin (pCMV-maspin), siControl or siMaspin. RT-PCR and Western blot analysis were performed to study the expressions of survival proteins in lung cancer. cDNA microarray analysis was carried out to compare the maspin-modulated gene expression between the xenograft tumors derived from the lung cancer cells that were stably transfected with pCMVTaq4C or pCMV-maspin. Maspin gene therapy was performed by intra-tumoral injections of pCMVTaq4C or pCMV-maspin into the pre-established subcutaneous tumors in nude mice.

Results

Maspin significantly decreased the survival to doxorubicin and etoposide, whereas did not affect the survival to cisplatin in the NCI-H157 cells. Interestingly, transfection with a maspin plasmid resulted in a significant reduction of the phosphorylation of Akt in the NCI-H157 cells, whereas knockdown of maspin increased the phosphorylation of Akt in the A549 cells. Microarray analysis of the xenograft tumors revealed a specific gene expression profile, demonstrating that maspin is associated with the differential expressions of PTEN and IGF2R. Direct transfer of pCMV-maspin into the tumor significantly retarded the tumor growth in the animal experiments (p=0.0048).

Conclusion

Lung cancer cells lacking maspin could be resistant to chemotherapeutic drugs such as doxorubicin or etoposide, at least in part by maintaining Akt phosphorylation.

Citations

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