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Yao CJ, Chang CL, Hu MH, Liao CH, Lai GM, Chiou TJ, Ho HL, Kuo HC, Yang YY, Whang-Peng J, Chuang SE. Drastic Synergy of Lovastatin and Antrodia camphorata Extract Combination against PC3 Androgen-Refractory Prostate Cancer Cells, Accompanied by AXL and Stemness Molecules Inhibition. Nutrients 2023; 15:4493. [PMID: 37960146 PMCID: PMC10647293 DOI: 10.3390/nu15214493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/20/2023] [Accepted: 10/21/2023] [Indexed: 11/15/2023] Open
Abstract
Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in males worldwide. Early-stage PC patients can benefit from surgical, radiation, and hormonal therapies; however, once the tumor transitions to an androgen-refractory state, the efficacy of treatments diminishes considerably. Recently, the exploration of natural products, particularly dietary phytochemicals, has intensified in response to addressing this prevailing medical challenge. In this study, we uncovered a synergistic effect from combinatorial treatment with lovastatin (an active component in red yeast rice) and Antrodia camphorata (AC, a folk mushroom) extract against PC3 human androgen-refractory PC cells. This combinatorial modality resulted in cell cycle arrest at the G0/G1 phase and induced apoptosis, accompanied by a marked reduction in molecules responsible for cellular proliferation (p-Rb/Rb, Cyclin A, Cyclin D1, and CDK1), aggressiveness (AXL, p-AKT, and survivin), and stemness (SIRT1, Notch1, and c-Myc). In contrast, treatment with either AC or lovastatin alone only exerted limited impacts on the cell cycle, apoptosis, and the aforementioned signaling molecules. Notably, significant reductions in canonical PC stemness markers (CD44 and CD133) were observed in lovastatin/AC-treated PC3 cells. Furthermore, lovastatin and AC have been individually examined for their anti-PC properties. Our findings elucidate a pioneering discovery in the synergistic combinatorial efficacy of AC and clinically viable concentrations of lovastatin on PC3 PC cells, offering novel insights into improving the therapeutic effects of dietary natural products for future strategic design of therapeutics against androgen-refractory prostate cancer.
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Affiliation(s)
- Chih-Jung Yao
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan;
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
| | - Chia-Lun Chang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (M.-H.H.); (G.-M.L.); (T.-J.C.); (J.W.-P.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Ming-Hung Hu
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (M.-H.H.); (G.-M.L.); (T.-J.C.); (J.W.-P.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Chien-Huang Liao
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Gi-Ming Lai
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (M.-H.H.); (G.-M.L.); (T.-J.C.); (J.W.-P.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Tzeon-Jye Chiou
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (M.-H.H.); (G.-M.L.); (T.-J.C.); (J.W.-P.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Hsien-Ling Ho
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Hui-Ching Kuo
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Ya-Yu Yang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan;
| | - Jacqueline Whang-Peng
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (M.-H.H.); (G.-M.L.); (T.-J.C.); (J.W.-P.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (C.-H.L.); (H.-L.H.); (H.-C.K.)
| | - Shuang-En Chuang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan;
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Korte V, Gademann G, Gawish A, Ochel HJ. Modulation of radiosensitivity of DU145 prostate carcinoma cells by simvastatin. J Cancer Res Clin Oncol 2023; 149:4509-4514. [PMID: 36127484 PMCID: PMC10349728 DOI: 10.1007/s00432-022-04364-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/14/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE To investigate antiproliferative effects of simvastatin in combination with ionizing radiation on DU145 prostate cancer cells and its influence on cellular HMG-CoA-reductase levels. METHODS Proliferative responses of DU145 cells were estimated by means of a clonogenic assay or the crystal violet procedure. HMG-CoA-reductase levels were measured by western blot analysis. RESULTS The antiproliferative effects of simvastatin and radiation are dependent on simvastatin dose, radiation dose and treatment time. In vitro treatment of DU145 cells with simvastatin induced HMG-CoA-reductase levels. CONCLUSION Ionizing radiation more profoundly reduces proliferation as compared to simvastatin exposure, while the combined application of both modalities is synergistic. The inhibition of CoA-reductase may contribute to these effects.
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Affiliation(s)
- Verena Korte
- Laboratory for Radiation Biology, Clinic for Radiotherapy, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Germany
| | - Guenther Gademann
- Laboratory for Radiation Biology, Clinic for Radiotherapy, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Germany
| | - Ahmed Gawish
- Laboratory for Radiation Biology, Clinic for Radiotherapy, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Germany.
- Radiation Oncology, Universitätsklinikum Magdeburg, Leipziger Str. 44, DE 39120, Magdeburg, Germany.
| | - Hans-Joachim Ochel
- Laboratory for Radiation Biology, Clinic for Radiotherapy, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Germany
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A Liposomal Formulation of Simvastatin and Doxorubicin for Improved Cardioprotective and Anti-Cancer Effect. Int J Pharm 2022; 629:122379. [DOI: 10.1016/j.ijpharm.2022.122379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/19/2022] [Accepted: 11/04/2022] [Indexed: 11/11/2022]
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Shou Y, Liu Y, Xu J, Liu J, Xu T, Tong J, Liu L, Hou Y, Liu D, Yang H, Cheng G, Zhang X. TIMP1 Indicates Poor Prognosis of Renal Cell Carcinoma and Accelerates Tumorigenesis via EMT Signaling Pathway. Front Genet 2022; 13:648134. [PMID: 35281807 PMCID: PMC8914045 DOI: 10.3389/fgene.2022.648134] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/11/2022] [Indexed: 12/29/2022] Open
Abstract
Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. The mortality of advanced RCC remains high despite advances in systemic therapy of RCC. Considering the misdiagnosis of early-stage RCC, the identification of effective biomarkers is of great importance. Tissue inhibitor matrix metalloproteinase 1 (TIMP1), which belongs to TIMP gene family, is a natural inhibitor of the matrix metalloproteinases (MMPs). In this study, we found TIMP1 was significantly up-regulated in cell lines and RCC tissues. Kaplan-Meier analysis revealed that high expression of TIMP1 indicated a poor prognosis. Multivariate analysis further indicated that TIMP1 overexpression was an independent prognostic factor of RCC patients. Furthermore, knockdown of TIMP1 in vitro suppressed the proliferation, migration, and invasion of RCC cells, while upregulating TIMP1 accelerated the proliferation, migration, and invasion of RCC cells. In addition, we also found that TIMP1 prompted the progression of RCC via epithelial-to-mesenchymal transition (EMT) signaling pathway. In conclusion, the present results suggested that TIMP1 indicated poor prognosis of renal cell carcinoma and could serve as a potential diagnostic and prognostic biomarker for RCC.
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Affiliation(s)
- Yi Shou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuenan Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaju Xu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingchong Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianbo Xu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junwei Tong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lilong Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaxin Hou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongmei Yang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gong Cheng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Gong Cheng, ; Xiaoping Zhang,
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urologic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Gong Cheng, ; Xiaoping Zhang,
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Statins decrease the expression of c-Myc protein in cancer cell lines. Mol Cell Biochem 2020; 476:743-755. [PMID: 33070276 DOI: 10.1007/s11010-020-03940-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 10/09/2020] [Indexed: 10/23/2022]
Abstract
Statins are potent inhibitors of the mevalonate/cholesterol biosynthetic pathway and are widely prescribed for the prevention of cardiovascular diseases. Here, we carried out a comprehensive analysis of the effects of three statins, simvastatin, atorvastatin, and lovastatin, on six different cancer cell lines that include a P-glycoprotein-expressing, multidrug resistant variant of an ovarian cancer cell line. Incubation of all cancer cell lines with statins resulted in suppression of cell proliferation without inducing apoptotic cell death. The cell proliferation arrest could be reversed upon transfer of cells to statin-free growth media as well as by the supplementation of the growth media with mevalonate. Further analysis suggested that statins induced cell cycle arrest at G0/G1 phase in four cancer cell lines and the loss of c-Myc protein in three cancer cell lines. The c-Myc expression and the progression of cell division cycle were restored upon the addition of mevalonate to the culture media containing statins. Finally, cells incubated with statins contained an increased level of phosphorylated histone H2AX, an observation previously correlated to cellular senescence. Together, these data demonstrate that statins inhibit the mevalonate pathway which is tightly coupled to oxidative branch of the pentose phosphate pathway, c-Myc expression, cell division cycle progression, and cellular senescence. Implications of these observations in the application of statins as cancer therapeutics are discussed.
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Zhao L, Ma B, Yang Y, Li T, Han L, Gao Q. Chemotherapy Reverses Anti-PD-1 Resistance in One Patient With Advanced Non-small Lung Cell Cancer. Front Oncol 2020; 10:507. [PMID: 32373522 PMCID: PMC7186846 DOI: 10.3389/fonc.2020.00507] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 03/20/2020] [Indexed: 12/02/2022] Open
Abstract
Background: Programmed cell death protein 1(PD-1) blockade has become a standard second-line treatment option for patients with advanced non-small cell lung cancer (NSCLC) without a driver gene mutation. Previous clinical studies showed that the objective response rate (ORR) of PD-1 blockade as second-line treatment for patients with NSCLC was ~20%, and the median progression-free survival (PFS) was ~4 months, with most patients eventually developing a resistance to PD-1 blockade. Although the ORR to chemotherapy after PD-1 blockade resistance was relatively high, the survival time of patients could not be significantly prolonged. Clinical oncologists are unclear about which treatment regimen should be selected after PD-1 blockade failure. Here, we report about a patient with advanced NSCLC and initial PD-1 blockade resistance who was observed to have a rapid partial response (PR) following one dose of chemotherapy and subsequent PD-1 blockade treatment. Case presentation: A 70-year-old woman with a history of left lower lobe lung surgery in March 2018 (pathological stage T1N2M0, EGFR wild-type) presented to our hospital. After six cycles of adjuvant chemotherapy, multiple nodules in both the lungs developed, and were suspected to be metastatic lesions. After another 2 months, the nodules in both the lungs enlarged. From November 2018 to March 2019, the patient received six cycles of pembrolizumab, and computed tomography (CT) confirmed a progressive disease status. She was then managed with 260 mg/m2 albumin paclitaxel once every 3 weeks. Subsequently, chemotherapy was discontinued after one cycle owing to grade three neuromuscular toxicity. Follow-up CT revealed a stable disease in May 2019. She then received another six cycles of pembrolizumab, which resulted in a PR. Conclusion: Chemotherapy may play a role in reversing PD-1 blockade resistance. If failure of PD-1 blockade occurs at first, re-administration of PD-1 blockade may be implemented if first followed by several cycles of chemotherapy. Because there are few reports on the use of chemotherapy to reverse PD-1 resistance, it is necessary to conduct clinical studies with larger patient cohorts to investigate whether chemotherapy can reverse PD-1 blockade resistance.
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Affiliation(s)
- Lingdi Zhao
- Department of Immunotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Baozhen Ma
- Department of Immunotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yonghao Yang
- Department of Immunotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Tiepeng Li
- Department of Immunotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Lu Han
- Department of Immunotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Quanli Gao
- Department of Immunotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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Manchana T, Phowthongkum P, Teerapakpinyo C. Germline mutations in Thai patients with nonmucinous epithelial ovarian cancer. World J Clin Oncol 2019; 10:358-368. [PMID: 31815095 PMCID: PMC6895001 DOI: 10.5306/wjco.v10.i11.358] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 08/13/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Genetic testing is widely recommended for all epithelial ovarian cancer (EOC) patients. However, an increased probability of identifying germline mutations has been reported in selected patients with risk factors such as a family history or personal history of cancer and high-grade serous carcinoma (HGSC) subtype. HGSC has been reported to be the most common subtype of EOC worldwide (approximately 70%). However, this subtype is less prevalent in Thai patients (reported as only 20%). The difference in the distribution of various subtypes of EOC may reflect the incidence of germline mutations in Thai EOC patients. AIM To evaluate the frequencies of germline mutations in EOC patients and to compare the frequencies in those with and without clinical risk factors for hereditary ovarian cancer. METHODS This cross-sectional study included 112 nonmucinous EOC patients who underwent primary surgery at our tertiary care hospital. Clinical risk factors for hereditary ovarian cancer were defined as follows: Age below 40 years, a significant family history of cancer, synchronous ovarian and endometrial cancer, and HGSC. Comprehensive germline mutations were detected by next-generation sequencing. RESULTS Of a total of 112 patients, 82 (73.2%) patients had ≥ 1 risk factor and 30 (26.8%) patients had no risk factors. Germline mutations were detected in 26 patients: 20 (17.8%) patients had BRCA1/2 mutations, but 6 (5.4%) patients had mutations in other genes, including 1 in MLH1, 1 in MSH2, 1 in RAD51C, 2 in ATM and 1 in CDH1. Germline mutations were only detected in patients with risk factors (26 of 82, 31.7%), not in patients without risk factors (P < 0.001). A significant family history of cancer and HGSC were the only two significant risk factors associated with a higher proportion of germline mutations (56.3% vs 10% for those with and without a history of cancer, respectively, 40.8% vs 9.5% for those with and without HGSC). Germline BRCA mutations were detected in 38.8% of patients with HGSC but in only 1.6% of those with non-HGSC. An age below 40 years, personal history of breast cancer, and synchronous ovarian and endometrial cancer were not significant factors (14.3% vs 23.5%, 33.3% vs 21%, 22.2% vs 22.3%). CONCLUSION Approximately one-third of EOC patients with risk factors had germline mutations. Almost all germline BRCA mutations were found in patients with the HGSC subtype. Selected patients with HGSC and a family history of cancer should be initially considered for genetic analysis in Thailand.
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Affiliation(s)
- Tarinee Manchana
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Prasit Phowthongkum
- Division of Medical Genetics, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Medical Genetics Center, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Chinachote Teerapakpinyo
- Chulalongkorn GenePRO Center, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Gheewala T, Skwor T, Munirathinam G. Photosensitizers in prostate cancer therapy. Oncotarget 2018; 8:30524-30538. [PMID: 28430624 PMCID: PMC5444762 DOI: 10.18632/oncotarget.15496] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 02/06/2017] [Indexed: 01/17/2023] Open
Abstract
The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies are being constantly developed to offer treatments similar to radical therapies, with limited side effects. Photodynamic therapy (PDT) is a promising strategy in delivering focal treatment in primary as well as post radiotherapy prostate cancer. PDT involves activation of a photosensitizer (PS) by appropriate wavelength of light, generating transient levels of reactive oxygen species (ROS). Several photosensitizers have been developed with a focus on treating prostate cancer like mTHPC, motexafin lutetium, padoporfin and so on. This article will review newly developed photosensitizers under clinical trials for the treatment of prostate cancer, along with the potential advantages and disadvantages in delivering focal therapy.
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Affiliation(s)
- Taher Gheewala
- Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL, USA
| | - Troy Skwor
- Department of Chemical and Biological Sciences, Rockford University, Rockford, IL, USA
| | - Gnanasekar Munirathinam
- Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL, USA
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Papanagnou P, Stivarou T, Papageorgiou I, Papadopoulos GE, Pappas A. Marketed drugs used for the management of hypercholesterolemia as anticancer armament. Onco Targets Ther 2017; 10:4393-4411. [PMID: 28932124 PMCID: PMC5598753 DOI: 10.2147/ott.s140483] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The design of novel pharmacologic agents as well as their approval for sale in markets all over the world is a tedious and pricey process. Inevitably, oncologic patients commonly experience unwanted effects of new anticancer drugs, while the acquisition of clinical experience for these drugs is largely based on doctor–patient partnership which is not always effective. The repositioning of marketed non-antineoplastic drugs that hopefully exhibit anticancer properties into the field of oncology is a challenging option that gains ground and attracts preclinical and clinical research in an effort to override all these hindrances and minimize the risk for reduced efficacy and/or personalized toxicity. This review aims to present the anticancer properties of drugs used for the management of hypercholesterolemia. A global view of the antitumorigenicity of all marketed antihypercholesterolemic drugs is of major importance, given that atherosclerosis, which is etiologically linked to hypercholesterolemia, is a leading worldwide cause of morbidity and mortality, while hypercholesterolemia and tumorigenesis are known to be interrelated. In vitro, in vivo and clinical literature data accumulated so far outline the mechanistic basis of the antitumor function of these agents and how they could find application at the clinical setting.
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Affiliation(s)
| | - Theodora Stivarou
- Immunology Laboratory, Immunology Department, Hellenic Pasteur Institute, Athens, Greece
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Mikkelsen MK, Thomsen FB, Berg KD, Jarden M, Larsen SB, Hansen RB, Brasso K. Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy. Scand J Urol 2017; 51:464-469. [DOI: 10.1080/21681805.2017.1362032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
| | - Frederik Birkebæk Thomsen
- Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen N, Denmark
| | - Kasper Drimer Berg
- Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen N, Denmark
| | - Mary Jarden
- University Hospitals Center for Health Research, Rigshospitalet, University of Copenhagen, Copenhagen Ø, Denmark
| | - Signe Benzon Larsen
- Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen N, Denmark
- Danish Cancer Society Research Center, Copenhagen Ø, Denmark
| | - Rikke Bølling Hansen
- Department of Urology, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Klaus Brasso
- Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen N, Denmark
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Moon DC, Lee HS, Lee YI, Chung MJ, Park JY, Park SW, Song SY, Chung JB, Bang S. Concomitant Statin Use Has a Favorable Effect on Gemcitabine-Erlotinib Combination Chemotherapy for Advanced Pancreatic Cancer. Yonsei Med J 2016; 57:1124-1130. [PMID: 27401642 PMCID: PMC4960377 DOI: 10.3349/ymj.2016.57.5.1124] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/21/2015] [Accepted: 01/05/2016] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Erlotinib-gemcitabine combined chemotherapy is considered as the standard treatment for unresectable pancreatic cancer. This study aimed to determine the clinical factors associated with response to this treatment. MATERIALS AND METHODS This retrospective study included 180 patients with unresectable pancreatic cancer who received ≥2 cycles of gemcitabine-erlotinib combination therapy as first-line palliative chemotherapy between 2006 and 2014. "Long-term response" was defined as tumor stabilization after >6 chemotherapy cycles. RESULTS The median progression-free survival (PFS) and overall survival (OS) were 3.9 and 8.1 months, respectively. On univariate analysis, liver metastasis (p=0.023) was negatively correlated with long-term response. Locally advanced stage (p=0.017), a history of statin treatment (p=0.01), and carcinoembryonic antigen levels <4.5 (p=0.029) had a favorable effect on long-term response. On multivariate analysis, a history of statin treatment was the only independent favorable factor for long-term response (p=0.017). Prognostic factors for OS and PFS were significantly correlated with liver metastasis (p=0.031 and 0.013, respectively). A history of statin treatment was also significantly associated with OS after adjusting for all potential confounders (hazard ratio, 0.48; 95% confidence interval, 0.26-0.92; p=0.026). CONCLUSION These results suggest that statins have a favorable effect on "long-term response" to gemcitabine-erlotinib chemotherapy in unresectable pancreatic cancer patients. Statins may have a chemoadjuvant role in stabilizing long-term tumor growth.
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Affiliation(s)
- Do Chang Moon
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Yong Il Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Jae Bock Chung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine and Yonsei Institute of Gastroenterology, Seoul, Korea.
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Harshman LC, Wang X, Nakabayashi M, Xie W, Valenca L, Werner L, Yu Y, Kantoff AM, Sweeney CJ, Mucci LA, Pomerantz M, Lee GSM, Kantoff PW. Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer. JAMA Oncol 2016; 1:495-504. [PMID: 26181260 DOI: 10.1001/jamaoncol.2015.0829] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
IMPORTANCE Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells. OBJECTIVE To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. MAIN OUTCOMES AND MEASURES To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors. RESULTS In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72). CONCLUSIONS AND RELEVANCE Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.
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Affiliation(s)
- Lauren C Harshman
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Xiaodong Wang
- Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Mari Nakabayashi
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Wanling Xie
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Loana Valenca
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Lillian Werner
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Yongjiang Yu
- Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts4Department of Urology, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai, China
| | | | - Christopher J Sweeney
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Lorelei A Mucci
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Mark Pomerantz
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Gwo-Shu Mary Lee
- Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Philip W Kantoff
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts2Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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Licarete E, Sesarman A, Banciu M. Exploitation of pleiotropic actions of statins by using tumour-targeted delivery systems. J Microencapsul 2015; 32:619-31. [PMID: 26299551 DOI: 10.3109/02652048.2015.1073383] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins are drugs traditionally used to lower cholesterol levels in blood. At concentrations 100- to 500-fold higher than those needed for reaching cholesterol lowering activity, they have anti-tumour activity. This anti-tumour activity is based on statins pleiotropic effects derived from their ability to inhibit the mevalonate synthesis and include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-inflammatory, anti-metastatic actions and modulatory effects on intra-tumour oxidative stress. Thus, in this review, we summarise the possible pleiotropic actions of statins involved in tumour growth inhibition. Since the administration of these high doses of statins is accompanied by severe side effects, targeted delivery of statins seems to be the appropriate strategy for efficient application of statins in oncology. Therefore, we also present an overview of the current status of targeted delivery systems for statins with possible utilisation in oncology.
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Affiliation(s)
- Emilia Licarete
- a Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology , Babes-Bolyai University , Cluj-Napoca , Romania and.,b Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Alina Sesarman
- a Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology , Babes-Bolyai University , Cluj-Napoca , Romania and.,b Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Manuela Banciu
- a Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology , Babes-Bolyai University , Cluj-Napoca , Romania and.,b Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
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14
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Metabolic syndrome, dyslipidemia and prostate cancer recurrence after primary surgery or radiation in a veterans cohort. Prostate Cancer Prostatic Dis 2015; 18:190-5. [DOI: 10.1038/pcan.2015.12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/20/2015] [Accepted: 02/18/2015] [Indexed: 12/31/2022]
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Wang W, Macaulay RJB. Cell-Cycle Gene Expression in Lovastatin-Induced Medulloblastoma Apoptosis. Can J Neurol Sci 2014; 30:349-57. [PMID: 14672267 DOI: 10.1017/s0317167100003061] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background:3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors both for cholesterol biosynthesis and for the production of nonsteroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferation in vitro, but also induces near-complete cell death via apoptosis. The mechanism of this phenomenon is unclear. Possible involvement of changes in expression of certain cell-cycle related genes led us to study some of them in more detail.Methods:Medulloblastoma cell lines were exposed in vitro to lovastatin, and the effects of gene expression changes were studied using RT-PCR, antisense oligonucleotide, DNA electrophoresis and Western blotting analysis.Results:1) Levels of total Ras gene mRNA and individual Ras gene mRNA are stable in lovastatin treatment in all examined medulloblastoma cell lines. 2) Blocking c-myc gene over-expression does not enhance medulloblastoma cell sensitivity to lovastatin. 3) Following lovastatin treatment, p16 expression exhibits no change, but pronounced increases of p27KIP1 protein are observed in all examined cell lines. Lovastatin induces pronounced increases of p21WAF1 protein only in Daoy and UW228, but not in D283 Med and D341 Med. 4) Following lovastatin treatment, increased p53 protein is detected only in D341 Med, and bax protein is unchanged in all cell lines.Conclusion:Lovastatin-induced growth inhibition and apoptosis in medulloblastoma are not dependent on the regulation of Ras and c-myc gene expression, but may be mediated by p27KIP1 gene expression. Lovastatin-induced apoptosis in medulloblastoma is probably p53 independent, but p53 and p21WAF1 gene expression may also mediate anti-proliferative effects of lovastatin on specific medulloblastoma cell lines.
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Affiliation(s)
- Wei Wang
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Shi Y, Fung KZ, Freedland SJ, Hoffman RM, Tang VL, Walter LC. Statin medications are associated with a lower probability of having an abnormal screening prostate-specific antigen result. Urology 2014; 84:1058-65. [PMID: 25443902 PMCID: PMC4254664 DOI: 10.1016/j.urology.2014.06.069] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 06/02/2014] [Accepted: 06/18/2014] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To investigate how statin use is associated with the probability of having an abnormal screening prostate-specific antigen (PSA) result according to common PSA thresholds for biopsy (>2.5, >4.0, and >6.5 ng/mL). METHODS We conducted a cross-sectional study of 323,426 men aged ≥65 years who had a screening PSA test in 2003 at a Veterans Affairs facility. The primary predictor was the use of statin medications at the time of index screening PSA test. The main outcome was the screening PSA value. Poisson regressions were performed to calculate adjusted relative risks for having an abnormal screening PSA result according to statin usage. RESULTS Percentages of men with PSA results exceeding commonly used thresholds of >2.5, >4.0, and >6.5 ng/mL were 21.0%, 7.6%, and 1.6%, respectively. These percentages decreased with statin use, increasing statin dose, duration of statin use, and potency of the statin. For example, after adjusting for age, the percentage of men having a PSA level >4.0 ng/mL ranged from 8.2% in non-statin users to 6.2% in men prescribed with >40 mg of simvastatin dose. Adjusted relative risks of having a PSA level >4.0 ng/mL were 0.89 (95% confidence interval [CI], 0.86-0.93), 0.87 (95% CI, 0.84-0.91), and 0.83 (95% CI, 0.80-0.87), respectively for men on simvastatin dose of 5-20, >20-40, and >40 mg vs non-statin users. CONCLUSION Statin use is associated with a reduction in the probability that an older man will have an abnormal screening PSA result, regardless of the PSA threshold. This reduction is more pronounced with higher statin dose, longer statin duration, and higher statin potency.
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Affiliation(s)
- Ying Shi
- Division of Geriatrics, San Francisco VA Medical Center and University of California, San Francisco, CA.
| | - Kathy Z Fung
- Division of Geriatrics, San Francisco VA Medical Center and University of California, San Francisco, CA
| | - Stephen J Freedland
- Durham VA Medical Center and Duke Prostate Center, Duke University, Durham, NC
| | - Richard M Hoffman
- New Mexico VA Health Care System and Department of Medicine, University of New Mexico, Albuquerque, NM
| | - Victoria L Tang
- Division of Geriatrics, San Francisco VA Medical Center and University of California, San Francisco, CA
| | - Louise C Walter
- Division of Geriatrics, San Francisco VA Medical Center and University of California, San Francisco, CA
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Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer 2014; 50:2822-30. [PMID: 25218337 DOI: 10.1016/j.ejca.2014.08.005] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 07/09/2014] [Accepted: 08/06/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE We aimed to the addition of synthetic 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to capecitabine-cisplatin (XP) in patients with previously untreated advanced gastric cancer (AGC). METHODS In this double-blind, placebo-controlled, phase III study, we enrolled patients aged 18 years or older with histological or cytological confirmed metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) at nine centres in Korea. Patients, stratified by disease measurability and participating site, were randomly assigned (1:1) to receive capecitabine 1000mg/m(2) twice daily for 14 days and cisplatin 80 mg/m(2) on day 1 every 3 weeks plus either simvastatin 40 mg or placebo, once daily. Cisplatin was given for 8 cycles; capecitabine and simvastatin were administered until disease progression or unacceptable toxicities. This study is registered with ClinicalTrials.gov, number NCT01099085. RESULTS Between February 2009 and November 2012, 244 patients were enrolled and assigned to treatment groups (120 simvastatin, 124 placebo). Median progression free survival (PFS) for 120 patients allocated XP plus simvastatin was 5.2 months (95% confidence interval (CI) 4.3-6.1) compared with 4.63 months (95% CI 3.5-5.7) for 124 patients who were allocated to XP plus placebo (hazard ratio 0.930, 95% CI 0.684-1.264; p=0.642). 63 (52.5%) of 120 patients in simvastatin group and 70 (56.4%) of 124 had grade 3 or higher adverse events. CONCLUSIONS Addition of 40 mg simvastatin to XP does not increase PFS in our trial, although it does not increase toxicity. Low dose of simvastatin (40 mg) to chemotherapy is not recommended in untargeted population with AGC.
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jung Hun Kang
- Division of Hematology-Oncology, Department of Medicine, College of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - In Gyu Hwang
- Division of Hematology-Oncology, Department of Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea
| | - Sang-Cheol Lee
- Division of Hematology-Oncology, Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Keon-Woo Park
- Division of Hematology-Oncology, Department of Medicine, College of Medicine, Dankook University, Cheonan, South Korea
| | - Hyo Rak Lee
- Division of Hematology-Oncology, Department of Medicine, Korea Cancer Center Hospital, Seoul, South Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
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Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, potentiate the anti-angiogenic effects of bevacizumab by suppressing angiopoietin2, BiP, and Hsp90α in human colorectal cancer. Br J Cancer 2014; 111:497-505. [PMID: 24945998 PMCID: PMC4119970 DOI: 10.1038/bjc.2014.283] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/07/2014] [Accepted: 04/30/2014] [Indexed: 02/07/2023] Open
Abstract
Background: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are commonly prescribed because of their therapeutic and preventive effects on cardiovascular diseases. Even though they have been occasionally reported to have antitumour activity, it is unknown whether statins have anti-angiogenic effect in human colorectal cancer (CRC). Methods: A total of 11 human CRC cell lines were used to test the effects of bevacizumab, statins, and bevacizumab plus statins on human umbilical vein endothelial cell (HUVEC) viability and invasion in vitro. To determine the molecular mechanism of statins as anti-angiogenic agents, we performed an angiogenesis antibody array and proteomics analysis and confirmed the results using immunoblot assay, HUVEC invasion rescue assay, and siRNA assay. The antitumoural effects of bevacizumab and statins were evaluated in xenograft models. Results: A conventional dose of statins (simvastatin 0.2 μM, lovastatin 0.4 μM, atorvastatin 0.1 μM, and pravastatin 0.4 μM) in combination with bevacizumab directly reduced the cell viability, migration, invasion, and tube formation of HUVECs. The culture media of the CRC cells treated with bevacizumab or statins were also found to inhibit HUVEC invasion by suppressing angiogenic mediators, such as angiopoietin2, binding immunoglobulin protein (BiP), and Hsp90α. The combined treatment with bevacizumab and simvastatin significantly reduced the growth and metastases of xenograft tumours compared with treatment with bevacizumab alone. Conclusions: The addition of simvastatin at a dose used in patients with cardiovascular diseases (40–80 mg once daily) may potentiate the anti-angiogenic effects of bevacizumab on CRC by suppressing angiopoietin2, BiP, and Hsp90α in cancer cells. A clinical trial of simvastatin in combination with bevacizumab in patients with CRC is needed.
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Ting H, Deep G, Agarwal C, Agarwal R. The strategies to control prostate cancer by chemoprevention approaches. Mutat Res 2014; 760:1-15. [PMID: 24389535 DOI: 10.1016/j.mrfmmm.2013.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 11/23/2013] [Accepted: 12/12/2013] [Indexed: 02/07/2023]
Abstract
Prostate cancer (PCA) is the most commonly diagnosed cancer in men in the United States with growing worldwide incidence. Despite intensive investment in improving early detection, PCA often escapes timely detection and mortality remains high; this malignancy being the second highest cancer-associated mortality in American men. Collectively, health care costs of PCA results in an immense financial burden that is only expected to grow. Additionally, even in cases of successful treatment, PCA is associated with long-term and pervasive effects on patients. A proactive alternative to treat PCA is to prevent its occurrence and progression prior to symptomatic malignancy. This may serve to address the issue of burgeoning healthcare costs and increasing number of sufferers. One potential regimen in service of this alternative is PCA chemoprevention. Here, chemical compounds with cancer preventive efficacy are identified on the basis of their potential in a host of categories: their historical medicinal use, correlation with reduced risk in population studies, non-toxicity, their unique chemical properties, or their role in biological systems. PCA chemopreventive agents are drawn from multiple broad classes of chemicals, themselves further subdivided based on source or potential effect, with most derived from natural products. Many such compounds have shown efficacy, varying from inhibiting deregulated PCA cell signaling, proliferation, epithelial to mesenchymal transition (EMT), invasion, metastasis, tumor growth and angiogenesis and inducing apoptosis. Overall, these chemopreventive agents show great promise in PCA pre-clinical models, though additional work remains to be done in effectively translating these findings into clinical use.
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Affiliation(s)
- Harold Ting
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, United States
| | - Gagan Deep
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, United States; University of Colorado Cancer Center, University of Colorado, Aurora, CO, United States
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, United States; University of Colorado Cancer Center, University of Colorado, Aurora, CO, United States
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, United States; University of Colorado Cancer Center, University of Colorado, Aurora, CO, United States.
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A mathematical model of HiF-1α-mediated response to hypoxia on the G1/S transition. Math Biosci 2013; 248:31-9. [PMID: 24345497 DOI: 10.1016/j.mbs.2013.11.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Revised: 11/22/2013] [Accepted: 11/25/2013] [Indexed: 12/28/2022]
Abstract
Hypoxia is known to influence the cell cycle by increasing the G1 phase duration or by inducing a quiescent state (arrest of cell proliferation). This entry into quiescence is a mean for the cell to escape from hypoxia-induced apoptosis. It is suggested that some cancer cells have gain the advantage over normal cells to easily enter into quiescence when environmental conditions, such as oxygen pressure, are unfavorable [43,1]. This ability contributes in the appearance of highly resistant and aggressive tumor phenotypes [2]. The HiF-1α factor is the key actor of the intracellular hypoxia pathway. As tumor cells undergo chronic hypoxic conditions, HiF-1α is present in higher level in cancer than in normal cells. Besides, it was shown that genetic mutations promoting overstabilization of HiF-1α are a feature of various types of cancers [7]. Finally, it is suggested that the intracellular level of HiF-1α can be related to the aggressiveness of the tumors [53,24,4,10]. However, up to now, mathematical models describing the G1/S transition under hypoxia, did not take into account the HiF-1α factor in the hypoxia pathway. Therefore, we propose a mathematical model of the G1/S transition under hypoxia, which explicitly integrates the HiF-1α pathway. The model reproduces the slowing down of G1 phase under moderate hypoxia, and the entry into quiescence of proliferating cells under severe hypoxia. We show how the inhibition of cyclin D by HiF-1α can induce quiescence; this result provides a theoretical explanation to the experimental observations of Wen et al. (2010) [50]. Thus, our model confirms that hypoxia-induced chemoresistance can be linked, for a part, to the negative regulation of cyclin D by HiF-1α.
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Simvastatin enhances the chemotherapeutic efficacy of S-1 against bile duct cancer. Anticancer Drugs 2013; 24:1020-9. [DOI: 10.1097/cad.0b013e328364f935] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Statin use and incident prostate cancer risk: does the statin brand matter? A population-based cohort study. Prostate Cancer Prostatic Dis 2013; 17:6-9. [PMID: 24061633 DOI: 10.1038/pcan.2013.34] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 07/28/2013] [Accepted: 07/30/2013] [Indexed: 01/14/2023]
Abstract
BACKGROUND Statins have known anticarcinogenic effects; evidence for long-term statin use as effective chemoprevention for prostate cancer is inconsistent. METHODS We conducted a population-based cohort study to examine the association between statin use and risk of prostate cancer using the Database of Clalit Health Services. A total of 66,741 eligible participants were identified at 1 January 2001 and followed through to 31 December 2009. Cox proportional hazard models were used to compute hazard ratios (HRs) of incident prostate cancer associated with statin therapy controling for patients' clinical and sociodemographic characteristics. RESULTS A total of 1813 cases of prostate cancer were diagnosed. Statin use was associated with a decreased incidence of prostate cancer, the association was stronger with increasing total dose, hydrophobic statins use and longer periods of treatment. When comparing statin use of over 6 months, this association was strongest for simvastatin (HR 0.51, 95% confidence interval (CI) 0.47-0.56), atorvostatin (HR 0.48, 95% CI 0.33-0.68) and rosuvastatin (HR 0.22, 95% CI 0.08-0.75). CONCLUSIONS Our findings suggest that prolonged statin use is associated with a reduced risk of prostate cancer; however, this was not true for all types of statin.
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Fernandes NV, Yeganehjoo H, Katuru R, DeBose-Boyd RA, Morris LL, Michon R, Yu ZL, Mo H. Geranylgeraniol suppresses the viability of human DU145 prostate carcinoma cells and the level of HMG CoA reductase. Exp Biol Med (Maywood) 2013; 238:1265-74. [PMID: 24006306 DOI: 10.1177/1535370213492693] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor receptors. The diterpene geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50=80±18 µmol/L, n=5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, geranylgeraniol may have potential in the chemoprevention and/or therapy of human prostate cancer.
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Affiliation(s)
- Nicolle V Fernandes
- Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX 76204, USA
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Nölting S, Garcia E, Alusi G, Giubellino A, Pacak K, Korbonits M, Grossman AB. Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. J Mol Endocrinol 2012; 49:79-96. [PMID: 22715163 PMCID: PMC4714579 DOI: 10.1530/jme-12-0028] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line - both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses below 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs.
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Affiliation(s)
- Svenja Nölting
- Department of Endocrinology, William Harvey Research Institute and Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
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Kwok SCM, Samuel SP, Handal J. Atorvastatin activates heme oxygenase-1 at the stress response elements. J Cell Mol Med 2012; 16:394-400. [PMID: 21447045 PMCID: PMC3823302 DOI: 10.1111/j.1582-4934.2011.01324.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Statins are known to inhibit growth of a number of cancer cells, but their mechanism of action is not well established. In this study, human prostate adenocarcinoma PC-3 and breast adenocarcinoma MCF-7 cell lines were used as models to investigate the mechanism of action of atorvastatin, one of the statins. Atorvastatin was found to induce apoptosis in PC-3 cells at a concentration of 1 μM, and in MCF-7 cells at 50 μM. Initial survey of possible pathway using various pathway-specific luciferase reporter assays showed that atorvastatin-activated antioxidant response element (ARE), suggesting oxidative stress pathway may play a role in atorvastatin-induced apoptosis in both cell lines. Among the antioxidant response genes, heme oxygenase-1 (HO-1) was significantly up-regulated by atorvastatin. Pre-incubation of the cells with geranylgeranyl pyrophosphate blocked atorvastatin-induced apoptosis, but not up-regulation of HO-1, suggesting that atorvastatin-induced apoptosis is dependent on GTPase activity and up-regulation of HO-1 gene is not. Six ARE-like elements (designated StRE1 [stress response element] through StRE6) are present in the HO-1 promoter. Atorvastatin was able to activate all of the elements. Because these StRE sites are present in clusters in HO-1 promoter, up-regulation of HO-1 by atorvastatin may involve multiple StRE sites. The role of HO-1 in atorvastatin-induced apoptosis in PC-3 and MCF-7 remains to be studied.
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Affiliation(s)
- Simon C M Kwok
- ORTD, Albert Einstein Medical Center, Philadelphia, PA 19141-3098, USA.
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Lovastatin Causes Diminished PSA Secretion by Inhibiting AR Expression and Function in LNCaP Prostate Cancer Cells. Urology 2011; 77:1508.e1-7. [DOI: 10.1016/j.urology.2010.12.074] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 11/25/2010] [Accepted: 12/29/2010] [Indexed: 11/22/2022]
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Cellular and molecular effects of the liposomal mTHPC derivative Foslipos in prostate carcinoma cells in vitro. Photodiagnosis Photodyn Ther 2011; 8:86-96. [DOI: 10.1016/j.pdpdt.2011.02.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 02/23/2011] [Accepted: 02/25/2011] [Indexed: 12/20/2022]
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Tan N, Klein EA, Li J, Moussa AS, Jones JS. Statin use and risk of prostate cancer in a population of men who underwent biopsy. J Urol 2011; 186:86-90. [PMID: 21571344 DOI: 10.1016/j.juro.2011.03.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Indexed: 01/28/2023]
Abstract
PURPOSE We determined the association between statin use and prostate cancer in men who underwent prostate biopsy. MATERIALS AND METHODS We performed a retrospective cohort study of men who underwent prostate biopsy from 2000 to 2007 at Cleveland Clinic. Statin use was determined using outpatient pharmacy records, and clinical and pathological outcomes were obtained. Multivariate logistic regression analysis to determine the effects of statins (and duration of use) was performed after adjusting for age, body mass index, African-American race, number of cores taken and prostate volume. RESULTS We analyzed data from 4,204 patients, and we identified 3,182 (75.7%) not on statins and 1,022 on statins. Men diagnosed with prostate cancer on statins compared to those not taking statins were less likely to have digital rectal examination positivity (5.3% vs 8.9%, OR 0.7, p <0.01), Gleason score 7 or greater prostate cancer (61.4% vs 72.4%, OR 0.78, p = 0.02) and high volume prostate cancer (27.2 vs 31.4, p <0.01). Moreover statin users had lower prostate specific antigen compared to nonstatin users (5.13 vs 5.98, p = 0.03). Multivariate analysis adjusted risk ratios for prostate cancer diagnosis, high grade prostate cancer (Gleason score 7 or greater) and 3 or more cores positive in statin users were 0.92 (95% CI 0.85-0.98), 0.76 (95% CI 0.67-0.85) and 0.86 (95% CI 0.75-0.97) and only high grade prostate cancer persisted with length of use. CONCLUSIONS Statin use was associated with a decreased risk of prostate cancer, less frequent high grade prostate cancer and lower volume of prostate cancer, suggesting that statin use has a protective effect against prostate cancer.
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Affiliation(s)
- Nelly Tan
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.
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29
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Katuru R, Fernandes NV, Elfakhani M, Dutta D, Mills N, Hynds DL, King C, Mo H. Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells. Exp Biol Med (Maywood) 2011; 236:604-13. [PMID: 21540247 DOI: 10.1258/ebm.2011.010379] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The diterpene geranylgeraniol (all trans-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol) suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell growth (IC(50) = 55 ± 13 µmol/L) following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 phase, manifested by a geranylgeraniol-induced increase in the G1/S ratio and decreased expression of cyclin D1 and cyclin-dependent kinase 4, apoptosis detected by Guava Nexin™ assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, and cell differentiation shown by increased alkaline phosphatase activity, contributed to the growth suppression. Murine 3T3-L1 fibroblasts were 10-fold more resistant than B16 cells to geranylgeraniol-mediated growth suppression. Geranylgeraniol at near IC(50) concentration (60 µmol/L) suppressed the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by 50%. The impact of geranylgeraniol on B16 cell growth, cell cycle arrest and apoptosis were attenuated by supplemental mevalonate, the product of HMG-CoA reductase that is essential for cell growth. Geranylgeraniol and d-δ-tocotrienol, a down-regulator of HMG-CoA reductase, additively suppressed the growth of B16 cells. These results support our hypothesis that mevalonate depletion mediates the tumor-specific growth-suppressive impact of geranylgeraniol. Geranylgeraniol may have potential in cancer chemoprevention and/or therapy.
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Affiliation(s)
- Rajasekhar Katuru
- Department of Nutrition and Food Sciences, Texas Woman’s University, Denton, 76204, USA
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Lee J, Lee I, Han B, Park JO, Jang J, Park C, Kang WK. Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 2011; 103:674-88. [PMID: 21398618 DOI: 10.1093/jnci/djr070] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to treatment with cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor. Statins have reported antitumor activity, but it is unknown whether simvastatin can reverse cetuximab resistance in KRAS mutant CRC. METHODS Human CRC cell lines with KRAS mutations (LS153, LS174T, DLD1, LoVo, SW403, SW480, SNU175, and LS1034) or with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations (DiFi, SW48, HT29, and RKO) were used to test the effect of cetuximab, simvastatin, and cetuximab plus simvastatin on cell proliferation and apoptosis in vitro. Because BRAF(V600E) mutant may be responsible for cetuximab resistance in KRAS wild-type cells, we measured the growth of xenograft tumors originating from KRAS mutant and BRAF mutant cells in mice treated with cetuximab alone or plus simvastatin (n = 5 mice per treatment group). We used immunoblot assays to study RAS-regulated activation of BRAF protein after simvastatin treatment. All statistical tests were two-sided. RESULTS Addition of simvastatin (0.2 μM) to cetuximab (0.03-1.0 μM) reduced cell proliferation of KRAS mutant (P < .001) but not of BRAF mutant CRC cells in vitro. Treatment of KRAS mutant cells with simvastatin reduced BRAF activity and induced apoptosis. Treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (eg, for tumors originating from DLD1 cells, cetuximab vs cetuximab + simvastatin, mean tumor volume = 49.4 vs 20.2 cm(3), mean difference = 29.2 cm(3), 95% confidence interval = 19.7 to 38.5, P < .001); treatment with cetuximab alone or in combination with simvastatin had no effect on the growth of BRAF mutant tumors. CONCLUSION Simvastatin may overcome cetuximab resistance in colon cancer cells with KRAS mutations by modulating BRAF activity and inducing apoptosis.
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Affiliation(s)
- Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea
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Papadopoulos G, Delakas D, Nakopoulou L, Kassimatis T. Statins and prostate cancer: molecular and clinical aspects. Eur J Cancer 2011; 47:819-30. [PMID: 21354784 DOI: 10.1016/j.ejca.2011.01.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2010] [Revised: 12/18/2010] [Accepted: 01/19/2011] [Indexed: 01/05/2023]
Abstract
The field of the potential applications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) beyond their unambiguous cardiovascular beneficial effects is steadily increasing. In this regard, statins have also been shown to possess anti-inflammatory, immunomodulatory, antioxidant and growth inhibitory properties. Regarding their role in carcinogenesis, both preclinical and clinical studies report conflicting results. Intriguingly, accumulating evidence suggests that statins may relate to decreased prostate cancer incidence and recurrence risk. However, data from clinical studies seem to be still weak and are confounded by several factors. Nonetheless, preclinical data suggest that statins might exert a chemopreventive role against prostate cancer by inhibiting the proliferation and inducing apoptosis of prostate cancer cells and also inhibiting angiogenesis, inflammation and metastasis. Cholesterol lowering as well as statin pleiotropy through inhibition of the synthesis of isoprenoids have both been implicated in their anticancer properties. In this review, we discuss the preclinical and clinical evidence supporting the preventive or potentially harmful effects of statins on prostate tumourigenesis and conclude that statins should not be recommended for the prevention of prostate cancer development or progression based on the current data.
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Chang SL, Harshman LC, Presti JC. Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J Clin Oncol 2010; 28:3951-7. [PMID: 20679596 DOI: 10.1200/jco.2009.27.9406] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
PURPOSE Previous studies suggest that some common medications alter prostate-specific antigen (PSA) levels. It remains unclear whether these reported medication effects are due to clinicodemographic factors or concurrent use of other medications. We investigated the impact of individual and combinations of common medications on PSA in a large cross-sectional study of the United States population. PATIENTS AND METHODS The study included men > or = 40 years old without prostate cancer from the 2003 to 2004 and 2005 to 2006 cycles of the National Health and Nutrition Examination Survey (NHANES). Men with recent prostate manipulation, prostatitis, and those on hormone therapy were excluded. Weighted multivariate linear regression was performed on log-transformed total PSA to determine the effect of the 10 most commonly prescribed medication classes, adjusting for potential confounders including demographics, clinical characteristics, physical examination, laboratory studies, and duration of medication use. RESULTS In total, 1,864 men met inclusion criteria. Nonsteroidal anti-inflammatory drug (NSAID; P = .03), statin (P = .01), and thiazide diuretic (P = .025) intake was inversely related to PSA levels. Five years of NSAID, statin, and thiazide diuretic use was associated with PSA levels lower by 6%, 13%, and 26%, respectively. The combination of statins and thiazide diuretics showed the greatest reduction in PSA levels: 36% after 5 years. Concurrent calcium channel blocker use minimizes or negates the inverse relationship of statin use and PSA level. CONCLUSION We found that men using NSAIDs, statins, and thiazide diuretics have reduced PSA levels by clinically relevant amounts. The impact of regularly consuming these common medications on prostate cancer screening is unknown.
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Affiliation(s)
- Steven L Chang
- Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Kollmeier MA, Katz MS, Mak K, Yamada Y, Feder DJ, Zhang Z, Jia X, Shi W, Zelefsky MJ. Improved biochemical outcomes with statin use in patients with high-risk localized prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2010; 79:713-8. [PMID: 20452139 DOI: 10.1016/j.ijrobp.2009.12.006] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 11/20/2009] [Accepted: 12/03/2009] [Indexed: 10/19/2022]
Abstract
PURPOSE To investigate the association between 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and biochemical and survival outcomes after high-dose radiotherapy (RT) for prostate cancer. METHODS AND MATERIALS A total of 1711 men with clinical stage T1-T3 prostate cancer were treated with conformal RT to a median dose of 81 Gy during 1995-2007. Preradiotherapy medication data were available for 1681 patients. Three hundred eighty-two patients (23%) were taking a statin medication at diagnosis and throughout RT. Nine hundred forty-seven patients received a short-course of neoadjuvant and concurrent androgen-deprivation therapy (ADT) with RT. The median follow-up was 5.9 years. RESULTS The 5- and 8-year PSA relapse-free survival (PRFS) rates for statin patients were 89% and 80%, compared with 83% and 74% for those not taking statins (p=0.002). In a multivariate analysis, statin use (hazard ratio [HR] 0.69, p=0.03), National Comprehensive Cancer Network (NCCN) low-risk group, and ADT use were associated with improved PRFS. Only high-risk patients in the statin group demonstrated improvement in PRFS (HR 0.52, p=0.02). Across all groups, statin use was not associated with improved distant metastasis-free survival (DMFS) (p=0.51). On multivariate analysis, lower NCCN risk group (p=0.01) and ADT use (p=0.005) predicted improved DMFS. CONCLUSIONS Statin use during high-dose RT for clinically localized prostate cancer was associated with a significant improvement in PRFS in high-risk patients. These data suggest that statins have anticancer activity and possibly provide radiosensitization when used in conjunction with RT in the treatment of prostate cancer.
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Affiliation(s)
- Marisa A Kollmeier
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Nam E, Park C. Maspin suppresses survival of lung cancer cells through modulation of Akt pathway. Cancer Res Treat 2010; 42:42-7. [PMID: 20369051 DOI: 10.4143/crt.2010.42.1.42] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Accepted: 10/07/2009] [Indexed: 01/15/2023] Open
Abstract
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.
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Affiliation(s)
- Eunsook Nam
- Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Murtola TJ, Pennanen P, Syvälä H, Bläuer M, Ylikomi T, Tammela TLJ. Effects of simvastatin, acetylsalicylic acid, and rosiglitazone on proliferation of normal and cancerous prostate epithelial cells at therapeutic concentrations. Prostate 2009; 69:1017-23. [PMID: 19301305 DOI: 10.1002/pros.20951] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Non-steroidal anti-inflammatory drugs and cholesterol-lowering statins have been reported to inhibit prostate cancer cell growth suggesting their chemopreventive potential within the prostate. However, the effect has been demonstrated only with advanced prostate cancer cell lines and with drug concentrations above the clinical therapeutic range. In this study we compared the effect of therapeutic concentrations of acetylsalicylic acid, simvastatin and rosiglitazone on the growth of a set of prostatic primary cultures and various prostate epithelial cell lines. METHODS Two primary epithelial cell lines isolated from surgical resecates of normal prostate tissue (P96E, P97E), a primary cell line isolated from untreated prostate carcinoma (ESTO1), two transformed prostate epithelial cell lines (PWR1-E, RWPE-1) and advanced cancer cell lines LNCaP and VCaP were used in the study. Cells were treated for seven days with therapeutic concentrations of acetylsalisylic acid, simvastatin, rosiglitazone or their combination. Cellular growth rate was measured by crystal violet staining method. RESULTS Acetylsalicylic acid (0.5 mM) and simvastatin (10 nM) inhibited the growth of prostate epithelial cells of normal and primary cancer origin, whereas advanced cancer cell lines were resistant to the effect. Rosiglitazone at the therapeutic level of 1 microM did not reduce the growth of any cell type studied. CONCLUSIONS Our results demonstrate that acetylsalicylic acid and simvastatin inhibit prostate epithelial cell growth at clinically relevant doses. This should be acknowledged when designing possible prostate cancer chemopreventive trials.
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Affiliation(s)
- Teemu J Murtola
- School of Public Health, University of Tampere, Tampere, Finland.
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Abstract
While the beneficial effects of hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on cardiovascular disease are well established, much uncertainty remains about their effects on cancer. The statins inhibit the rate-limiting step in the mevalonate pathway, leading to reduced levels of cholesterol and other molecules of importance for critical cellular processes. A growing body of preclinical data indicates that statins may have antineoplastic properties, but some studies raise the possibility that statins may possess a carcinogenic potential. Clinical and observational studies of the association between statin use and cancer have been inconclusive with regard to any chemopreventive or therapeutic effect, but they do provide reassuring evidence that statins do not appear to be carcinogenic. The reasons for the varying results are unclear but they may relate to methodological issues. Additional studies, including Phase II randomized trials and epidemiological studies with accurate measures of statin use and comprehensive control for confounding factors, are needed to determine the potentially beneficially effects of statins on cancer development and progression.
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Affiliation(s)
- Søren Friis
- Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
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Colli JL, Amling CL. High cholesterol levels are associated with reduced prostate cancer mortality rates during periods of high but not low statin use in the United States. Urol Oncol 2009; 27:170-3. [DOI: 10.1016/j.urolonc.2007.11.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2007] [Revised: 11/08/2007] [Accepted: 11/08/2007] [Indexed: 10/22/2022]
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Colli JL, Amling CL. Exploring causes for declining prostate cancer mortality rates in the United States. Urol Oncol 2008; 26:627-33. [PMID: 18367111 DOI: 10.1016/j.urolonc.2007.05.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2007] [Accepted: 05/15/2007] [Indexed: 12/01/2022]
Abstract
OBJECTIVES Prostate cancer mortality rates in the U.S.A. increased in the late 1980s and declined from 1993 until 2003. The purpose of this study is to compare declining prostate cancer mortality rates among states with independent variables that may have an association to explore causes for the decline. METHODS AND MATERIALS Annual rates of prostate cancer mortality for men over 50 were obtained from the National Vital Statistic System public use data file for states for individual years from 1993 to 2003. The annual rate of prostate cancer mortality decline for each state was calculated by the Joinpoint Regression Program (Statistical Research and Applications Branch of NCI). Annual rates of prostate cancer decline were cross-correlated to state levels of PSA screening, health insurance coverage, obesity, physical inactivity, diabetes, and high cholesterol for males from 45 to 64. RESULTS Declining prostate cancer mortality rates for white males correlated with high cholesterol levels (R = -0.42, P = 0.002) and PSA screening levels (R = -0.28, P = 0.05). Declining prostate cancer mortality rates for black males correlated with health insurance coverage (R = -0.43, P = 0.03). CONCLUSIONS Declining prostate cancer mortality rates are weakly associated with increased PSA screening for white males but there was no association for black males, possibly because blacks have less access to medical care. The strong inverse correlation between declining prostate cancer mortality rates and levels of white males with high cholesterol levels was unexpected but may be associated with the widespread use of cholesterol reducing medications (statins), which are hypothesized to reduce prostate cancer risk.
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Affiliation(s)
- Janet L Colli
- Department of Urology, University of Alabama, Birmingham, AL 35294, USA; Birmingham VA Medical Center (VMAC), Birmingham, AL 35294, USA.
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Simvastatin inducing PC3 prostate cancer cell necrosis mediated by calcineurin and mitochondrial dysfunction. J Bioenerg Biomembr 2008; 40:307-14. [DOI: 10.1007/s10863-008-9155-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2008] [Accepted: 07/02/2008] [Indexed: 01/22/2023]
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Murtola TJ, Visakorpi T, Lahtela J, Syvälä H, Tammela TL. Statins and prostate cancer prevention: where we are now, and future directions. ACTA ACUST UNITED AC 2008; 5:376-87. [PMID: 18542103 DOI: 10.1038/ncpuro1146] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2007] [Accepted: 04/22/2008] [Indexed: 12/31/2022]
Abstract
Statins are cholesterol-lowering drugs that are widely used to prevent and treat atherosclerotic cardiovascular disease. Recent research from both in vitro and in vivo studies suggests that there is an association between the use of statins and a reduction in the incidence of and mortality from prostate cancer. Several mechanisms of action that might bring about these beneficial effects of statins have been proposed, most of which include direct effects of statins on intracellular signaling. In this Review we discuss the current knowledge on the use of statins to prevent prostate cancer. We will also look at future directions for clinical research on this topic.
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Affiliation(s)
- Teemu J Murtola
- Department of Epidemiology, School of Public Health, University of Tampere, Tampere, Finland.
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Tan SH, Nevalainen MT. Signal transducer and activator of transcription 5A/B in prostate and breast cancers. Endocr Relat Cancer 2008; 15:367-90. [PMID: 18508994 PMCID: PMC6036917 DOI: 10.1677/erc-08-0013] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Protein kinase signaling pathways, such as Janus kinase 2-Signal transducer and activator of transcription 5A/B (JAK2-STAT5A/B), are of significant interest in the search for new therapeutic strategies in both breast and prostate cancers. In prostate cancer, the components of the JAK2-STAT5A/B signaling pathway provide molecular targets for small-molecule inhibition of survival and growth signals of the cells. At the same time, new evidence suggests that the STAT5A/B signaling pathway is involved in the transition of organ-confined prostate cancer to hormone-refractory disease. This implies that the active JAK2-STAT5A/B signaling pathway potentially provides the means for pharmacological intervention of clinical prostate cancer progression. In addition, active STAT5A/B may serve as a prognostic marker for identification of those primary prostate cancers that are likely to progress to aggressive disease. In breast cancer, the role of STAT5A/B is more complex. STAT5A/B may have a dual role in the regulation of malignant mammary epithelium. Data accumulated from mouse models of breast cancer suggest that in early stages of breast cancer STAT5A/B may promote malignant transformation and enhance growth of the tumor. This is in contrast to established breast cancer, where STAT5A/B may mediate the critical cues for maintaining the differentiation of mammary epithelium. In addition, present data suggest that activation of STAT5A/B in breast cancer predicts favorable clinical outcome. The dual nature of STAT5A/B action in breast cancer makes the therapeutic use of STAT5 A/B more complex.
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Affiliation(s)
- Shyh-Han Tan
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, BLSB 309, Philadelphia, Pennsylvania 19107, USA
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In Vitro Mechanisms of Lovastatin on Lung Cancer Cell Lines as a Potential Chemopreventive Agent. Lung 2007; 186:45-54. [DOI: 10.1007/s00408-007-9053-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2007] [Accepted: 10/09/2007] [Indexed: 12/20/2022]
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Saunus JM, Edwards SL, French JD, Smart CE, Brown MA. Regulation ofBRCA1messenger RNA stability in human epithelial cell lines and during cell cycle progression. FEBS Lett 2007; 581:3435-42. [PMID: 17612526 DOI: 10.1016/j.febslet.2007.06.046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2007] [Revised: 06/18/2007] [Accepted: 06/19/2007] [Indexed: 11/21/2022]
Abstract
The mechanisms regulating expression of breast cancer 1 (BRCA1) are not fully characterised. By studying regulation of endogenous BRCA1 in human epithelial cell lines and during cell cycle progression, we provide evidence to suggest BRCA1 is regulated post-transcriptionally at the level of messenger RNA stability. We also show that RNA-binding proteins associate with an AU-rich, cis-active sequence of the BRCA1 3' untranslated region in a cell cycle-dependent manner. Our data identify a new post-transcriptional regulatory axis and a novel mechanism for modulating the levels of BRCA1 protein, with possible implications for understanding the mechanisms underlying BRCA1 repression in breast cancer.
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Affiliation(s)
- Jodi M Saunus
- School of Molecular and Microbial Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia
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Bismar TA, Demichelis F, Riva A, Kim R, Varambally S, He L, Kutok J, Aster JC, Tang J, Kuefer R, Hofer MD, Febbo PG, Chinnaiyan AM, Rubin MA. Defining aggressive prostate cancer using a 12-gene model. Neoplasia 2006; 8:59-68. [PMID: 16533427 PMCID: PMC1584291 DOI: 10.1593/neo.05664] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015). This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process.
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Affiliation(s)
- Tarek A Bismar
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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Eitsuka T, Nakagawa K, Miyazawa T. Down-regulation of telomerase activity in DLD-1 human colorectal adenocarcinoma cells by tocotrienol. Biochem Biophys Res Commun 2006; 348:170-5. [PMID: 16875674 DOI: 10.1016/j.bbrc.2006.07.029] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2006] [Accepted: 07/10/2006] [Indexed: 11/16/2022]
Abstract
As high telomerase activity is detected in most cancer cells, inhibition of telomerase by drug or dietary food components is a new strategy for cancer prevention. Here, we investigated the inhibitory effect of vitamin E, with particular emphasis on tocotrienol (unsaturated vitamin E), on human telomerase in cell-culture study. As results, tocotrienol inhibited telomerase activity of DLD-1 human colorectal adenocarcinoma cells in time- and dose-dependent manner, interestingly, with delta-tocotrienol exhibiting the highest inhibitory activity. Tocotrienol inhibited protein kinase C activity, resulting in down-regulation of c-myc and human telomerase reverse transcriptase (hTERT) expression, thereby reducing telomerase activity. In contrast to tocotrienol, tocopherol showed very weak telomerase inhibition. These results provide novel evidence for the first time indicating that tocotrienol acts as a potent candidate regulator of telomerase and supporting the anti-proliferative function of tocotrienol.
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Affiliation(s)
- Takahiro Eitsuka
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan
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Abstract
This study emphasizes the importance of Rho/ROCK pathway in lovastatin-induced apoptosis as replenishment with exogenous isoprenoid, geranylgeranylpyrophosphate (GGPP), resulted in inhibition of apoptosis in cultured tumor cells. Treatment of C6 glioma cells with Toxin B and exoenzyme C3 resulted in cell death suggesting the role of geranylgeranylated protein(s) in the survival of glioma cells. Relative apoptotic death observed in cells transfected with dominant negative constructs of RhoA, Rac, and cdc42 imply Rho A as playing the major role in cell survival. Furthermore, the inhibition of Rho A kinase (ROCK), a direct downstream effector of Rho A, by Y-27632 or dominant negative of ROCK, induced apoptosis in glioma cells. These findings indicate that RhoA/ROCK pathway is involved negatively in the regulation of glioma cell death pathway. Moreover, in vivo studies of lovastatin treatment in animals implanted with C6 glioma cell tumors also resulted in smaller tumor size and induced apoptosis in the tumor tissue. The implantation of stably transfected C6 glioma cells with expression vector of C3 exoenzyme, dominant negative of RhoA and ROCK, resulted in significant smaller tumor mass, further establishing the importance of geranylgeranylated proteins, specifically RhoA and its downstream effecter ROCK, in cell survival and tumor genesis.
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Affiliation(s)
- R Rattan
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Lee J, Lee I, Park C, Kang WK. Lovastatin-induced RhoA modulation and its effect on senescence in prostate cancer cells. Biochem Biophys Res Commun 2006; 339:748-54. [PMID: 16316623 DOI: 10.1016/j.bbrc.2005.11.075] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2005] [Accepted: 11/02/2005] [Indexed: 11/22/2022]
Abstract
Lovastatin inhibits a 3-hydroxy 3-methylglutaryl coenzyme A reductase and prevents the synthesis of cholesterol precursors, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), responsible for important cell signaling in cell proliferation and migration. Recently, the anti-cancer effect of lovastatin has been suggested in various tumor types. In this study, we showed that a low dose lovastatin induced senescence and G1 cell cycle arrest in human prostate cancer cells. Addition of GGPP or mevalonate, but not FPP, prevented the lovastatin-induced G1 phase cell cycle arrest and cell senescence. We found that constitutively active RhoA (caRhoA) reversed lovastatin-induced senescence in caRhoA-transfected PC-3 cells. Thus, we postulate that modulation of RhoA may be critical in lovastatin-induced senescence in PC-3 cells.
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Affiliation(s)
- Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Abstract
Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.
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Affiliation(s)
- Marie-France Demierre
- Department of Dermatology, Boston University School of Medicine, 720 Harrison Avenue DOB 801A, Boston, MA 02118, USA
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Kang WK, Lee I, Park C. Characterization of RhoA-mediated chemoresistance in gastric cancer cells. Cancer Res Treat 2005; 37:251-6. [PMID: 19956523 DOI: 10.4143/crt.2005.37.4.251] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2005] [Accepted: 07/06/2005] [Indexed: 12/28/2022] Open
Abstract
PURPOSE RhoA is a critical transducer of extracellular signals, which leads to organization of actin cytoskeleton, motility, adhesion and gene regulation. The present study aimed to explore whether RhoA influences the susceptibility of gastric cancer cells to chemotherapeutic drugs. MATERIALS AND METHODS SNU638 cells were transfected with a mock vector (pcDNA3.1), RhoA (pcDNA/RhoA), or constitutively active RhoA (pcDNA/caRhoA). MTT assay and Western blot analysis were performed to study the growth response to several chemotherapeutic drugs in the gastric cancer cell line, SNU638, with different RhoA levels. RESULTS RhoA significantly enhanced the resistance to lovastatin, 5-FU, taxol and vincristine, but did not affect the sensitivity to cisplatin or etoposide in SNU638. In the Western blot analysis, RhoA decreased the PARP cleavage, which was accompanied by a concurrent reduction in cell death. The gene expression profile after a cDNA microarray analysis demonstrated that RhoA was associated with the differential expression of 19 genes, including those involved in anti-oxidant defense, glucose metabolism, anti-apoptosis and protein turnover. CONCLUSION Gastric cancer cells with a high expression of RhoA could be resistant to chemotherapeutic drugs, such as taxol or vincristine, implying that treatment strategies aimed at inactivation of RhoA might be promising for improving the efficacy of these chemotherapeutic drugs.
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Affiliation(s)
- Won Ki Kang
- Cancer Center, Samsung Medical Center, and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
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Yao CJ, Lai GM, Chan CF, Cheng AL, Yang YY, Chuang SE. Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. Int J Cancer 2005; 118:773-9. [PMID: 16094629 DOI: 10.1002/ijc.21361] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Lovastatin (an HMG-CoA reductase inhibitor) and troglitazone (a PPAR-gamma agonist) have been intensively studied prospectively for their application in cancer treatment. However, clinical trials of lovastatin or troglitazone in cancer treatment resulted in only limited responses. To improve their efficacy, lovastatin and troglitazone have, respectively, been tried to combine with other anticancer agents with varied outcomes. In our study, we found a dramatic synergism between lovastatin and troglitazone in anticancer at clinically achievable concentrations. This synergism was found in far majority of cell lines tested including DBTRG 05 MG (glioblastoma) and CL1-0 (lung). This amazing synergism was accompanied by synergistic modulation of E2F-1 and p27(Kip1), which were reported to mediate the anticancer activities of lovastatin and troglitazone, respectively, and other cell cycle regulating proteins such as CDK2, cyclin A and RB phosphorylation status. With this dramatic combination effect of lovastatin and troglitazone, a promising regimen of cancer therapy may be materialized in the future.
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Affiliation(s)
- Chih-Jung Yao
- Division of Cancer Research, National Health Research Institutes, Taipei, Taiwan
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