|
1
|
Sharma S, Rana R, Prakash P, Ganguly NK. Drug target therapy and emerging clinical relevance of exosomes in meningeal tumors. Mol Cell Biochem 2024; 479:127-170. [PMID: 37016182 PMCID: PMC10072821 DOI: 10.1007/s11010-023-04715-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 03/17/2023] [Indexed: 04/06/2023]
Abstract
Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma.
Collapse
Affiliation(s)
- Swati Sharma
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060 India
| | - Rashmi Rana
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060 India
| | - Prem Prakash
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, 110062 India
| | | |
Collapse
|
|
2
|
Azab MA, Cole K, Earl E, Cutler C, Mendez J, Karsy M. Medical Management of Meningiomas. Neurosurg Clin N Am 2023; 34:319-333. [PMID: 37210123 DOI: 10.1016/j.nec.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Meningiomas represent the most common type of benign tumor of the extra-axial compartment. Although most meningiomas are benign World Health Organization (WHO) grade 1 lesions, the increasingly prevalent of WHO grade 2 lesion and occasional grade 3 lesions show worsened recurrence rates and morbidity. Multiple medical treatments have been evaluated but show limited efficacy. We review the status of medical management in meningiomas, highlighting successes and failures of various treatment options. We also explore newer studies evaluating the use of immunotherapy in management.
Collapse
Affiliation(s)
- Mohammed A Azab
- Biomolecular Sciences Graduate Program, Boise State University, 1910 University Drive, Boise, ID 83725, USA
| | - Kyril Cole
- School of Medicine, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA
| | - Emma Earl
- School of Medicine, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA
| | - Chris Cutler
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 N Green Bay Rd., North Chicago, IL 60064, USA
| | - Joe Mendez
- Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr., Salt Lake City, UT 84112, USA
| | - Michael Karsy
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 North Medical Drive East, Salt Lake City, UT 84132, USA.
| |
Collapse
|
|
3
|
Phan NN, Wang CY, Chen CF, Sun Z, Lai MD, Lin YC. Voltage-gated calcium channels: Novel targets for cancer therapy. Oncol Lett 2017; 14:2059-2074. [PMID: 28781648 PMCID: PMC5530219 DOI: 10.3892/ol.2017.6457] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 04/13/2017] [Indexed: 01/11/2023] Open
Abstract
Voltage-gated calcium channels (VGCCs) comprise five subtypes: The L-type; R-type; N-type; P/Q-type; and T-type, which are encoded by α1 subunit genes. Calcium ion channels also have confirmed roles in cellular functions, including mitogenesis, proliferation, differentiation, apoptosis and metastasis. An association between VGCCs, a reduction in proliferation and an increase in apoptosis in prostate cancer cells has also been reported. Therefore, in the present study, the online clinical database Oncomine was used to identify the alterations in the mRNA expression level of VGCCs in 19 cancer subtypes. Overall, VGCC family genes exhibited under-expression in numerous types of cancer, including brain, breast, kidney and lung cancers. Notably, the majority of VGCC family members (CACNA1C, CACNA1D, CACNA1A, CACNA1B, CACNA1E, CACNA1H and CACNA1I) exhibited low expression in brain tumors, with mRNA expression levels in the top 1–9% of downregulated gene rankings. A total of 5 VGCC family members (CACNA1A, CACNA1B, CACNA1E, CACNA1G and CACNA1I) were under-expressed in breast cancer, with a gene ranking in the top 1–10% of the low-expressed genes compared with normal tissue. In kidney and lung cancers, CACNA1S, CACNA1C, CACNA1D, CACNA1A and CACNA1H exhibited low expression, with gene rankings in the top 1–8% of downregulated genes. In conclusion, the present findings may contribute to the development of new cancer treatment approaches by identifying target genes involved in specific types of cancer.
Collapse
Affiliation(s)
- Nam Nhut Phan
- Faculty of Applied Sciences, Ton Duc Thang University, Tan Phong Ward, Ho Chi Minh 700000, Vietnam
| | - Chih-Yang Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.,Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.,Department of Anatomy, University of California, San Francisco, CA 94143, USA
| | - Chien-Fu Chen
- School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung 84001, Taiwan, R.O.C
| | - Zhengda Sun
- Department of Radiology, University of California, San Francisco, CA 94143, USA
| | - Ming-Derg Lai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.,Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C
| | - Yen-Chang Lin
- Graduate Institute of Biotechnology, Chinese Culture University, Taipei 1114, Taiwan, R.O.C
| |
Collapse
|
|
4
|
Zhao L, Zhao Y, Schwarz B, Mysliwietz J, Hartig R, Camaj P, Bao Q, Jauch KW, Guba M, Ellwart JW, Nelson PJ, Bruns CJ. Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells. Int J Oncol 2016; 49:99-110. [PMID: 27177126 PMCID: PMC4902079 DOI: 10.3892/ijo.2016.3512] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 03/28/2016] [Indexed: 01/22/2023] Open
Abstract
Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multi-drug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density.
Collapse
Affiliation(s)
- Lu Zhao
- Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Yue Zhao
- Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Bettina Schwarz
- Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany
| | - Josef Mysliwietz
- Institute of Molecular Immunology, Helmholtz Center for Environment and Health, Munich, Germany
| | - Roland Hartig
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Peter Camaj
- Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Qi Bao
- Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany
| | - Karl-Walter Jauch
- Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany
| | - Makus Guba
- Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany
| | - Joachim Walter Ellwart
- Institute of Molecular Immunology, Helmholtz Center for Environment and Health, Munich, Germany
| | - Peter Jon Nelson
- Clinical Biochemistry Group, Medical Clinic and Policlinic IV, Munich Medical Center, Campus Innenstadt, LMU, Munich, Germany
| | | |
Collapse
|
|
5
|
Karsy M, Guan J, Cohen A, Colman H, Jensen RL. Medical Management of Meningiomas: Current Status, Failed Treatments, and Promising Horizons. Neurosurg Clin N Am 2016; 27:249-60. [PMID: 27012389 DOI: 10.1016/j.nec.2015.11.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Meningiomas are benign tumors of the central nervous system, with low recurrence risk for World Health Organization (WHO) grade I lesions but a high risk for WHO grade II and III lesions. Current standard treatments include maximum safe surgical resection when indicated and radiation. Only three systemic therapies alpha-interferon, somatostatin receptor agonists, and vascular endothelial growth factor inhibitors are currently recommended by the National Comprehensive Cancer Network for treatment of recurrent meningioma. This paper aims to review medical approaches in the treatment of meningiomas.
Collapse
Affiliation(s)
- Michael Karsy
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT 84132, USA
| | - Jian Guan
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT 84132, USA
| | - Adam Cohen
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
| | - Howard Colman
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT 84132, USA; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
| | - Randy L Jensen
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT 84132, USA; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA; Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
| |
Collapse
|
|
6
|
Karsy M, Hoang N, Barth T, Burt L, Dunson W, Gillespie DL, Jensen RL. Combined Hydroxyurea and Verapamil in the Clinical Treatment of Refractory Meningioma: Human and Orthotopic Xenograft Studies. World Neurosurg 2016; 86:210-9. [DOI: 10.1016/j.wneu.2015.09.060] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 09/16/2015] [Accepted: 09/19/2015] [Indexed: 11/26/2022]
|
|
7
|
Iglesias Gómez JC, Mosquera Orgueira A. An integrative analysis of meningioma tumors reveals the determinant genes and pathways of malignant transformation. Front Oncol 2014; 4:147. [PMID: 25003081 PMCID: PMC4066933 DOI: 10.3389/fonc.2014.00147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 05/28/2014] [Indexed: 01/18/2023] Open
Abstract
Meningiomas are frequent central nervous system neoplasms, which despite their predominant benignity, show sporadically malignant behavior. Type 2 neurofibromatosis and polymorphisms in several genes have been associated with meningioma risk and are probably involved in its pathogenesis. Although GWAS studies have found loci related to meningioma risk, little is known about the factors determining malignant transformation. Thus, this study is aimed to identify the genomic and transcriptomic factors influencing evolution from benignity toward aggressive phenotypes. By applying an integrative bioinformatics pipeline combining public information on a wealth of biological layers of complexity (from genetic polymorphisms to protein interactions), this study identified a module of co-expressed genes highly correlated with tumor stage and statistically linked to several genomic regions (module Quantitative Trait Loci, mQTLs). Ontology analysis of the transcription hub genes identified microtubule-associated cell-cycle processes as key drivers of such network. mQTLs and single nucleotide polymorphisms associated with meningioma stage were replicated in an alternative meningioma cohort, and integration of these results with up-to-date scientific literature and several databases retrieved a list of genes and pathways with a potentially important role in meningioma malignancy. As a result, cytoskeleton and cell-cell adhesion pathways, calcium-channels and glutamate receptors, as well as oxidoreductase and endoplasmic reticulum-associated degradation pathways were found to be the most important and redundant findings associated to meningioma progression. This study presents an integrated view of the pathways involved in meningioma malignant conversion and paves the way for the development of new research lines that will improve our understanding of meningioma biology.
Collapse
|
|
8
|
Moazzam AA, Wagle N, Zada G. Recent developments in chemotherapy for meningiomas: a review. Neurosurg Focus 2013; 35:E18. [DOI: 10.3171/2013.10.focus13341] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Object
Currently, few medical options exist for refractory and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. The authors review these recent developments, with an emphasis on emerging avenues for therapy, clinical efficacy, and adverse effects.
Methods
A review of the literature was performed to identify any studies exploring recent medical and chemotherapeutic agents that have been or are currently being tested for meningiomas. Results from included preclinical and human clinical trials were reviewed and summarized.
Results
Current guidelines recommend only 3 drugs that can be used to treat patients with refractory and highgrade meningiomas: hydroxyurea, interferon-α 2B, and Sandostatin long-acting release. Recent developments in the medical treatment of meningiomas have been made across a variety of pharmacological classes, including cytotoxic agents, hormonal agents, immunomodulators, and targeted agents toward a variety of growth factors and their signaling cascades. Promising avenues of therapy that are being evaluated for efficacy and safety include antagonists of platelet-derived growth factor receptor, epidermal growth factor receptor, vascular endothelial growth factor receptor, and mammalian target of rapamycin. Because malignant transformation in meningiomas is likely to be mediated by numerous processes interacting via a complex matrix of signals, combination therapies affecting multiple molecular targets are currently being explored and hold significant promise as adjuvant therapy options.
Conclusions
Improved understanding of the molecular mechanisms driving meningioma tumorigenesis and malignant transformation has resulted in the targeted development of more specific agents for chemotherapeutic intervention in patients with nonresectable, aggressive, and malignant meningiomas.
Collapse
Affiliation(s)
| | | | - Gabriel Zada
- 3Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| |
Collapse
|
|
9
|
Jagannathan J, Oskouian RJ, Yeoh HK, Saulle D, Dumont AS. Molecular biology of unreresectable meningiomas: implications for new treatments and review of the literature. Skull Base 2011; 18:173-87. [PMID: 18978964 DOI: 10.1055/s-2007-1003925] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Even though meningiomas are most often benign tumors, they can be locally invasive and can develop in locations that prevent surgical treatment. The molecular and biologic factors underlying meningioma development are only now beginning to be understood. Genetic factors such as mutations in the neurofibromatosis-2 gene and in chromosomes 1, 9, and 10 play important roles in meningioma development and may be responsible for atypical tumors in some cases. Cellular factors such as telomerase activation and tyrosine kinase receptor mutations may also play an important role. Finally, autocrine and paracrine factors including epidermal growth factor receptor, platelet-derived growth factor-1, and fibroblast growth factor have been implicated in the development of some tumors. Although the relationship between the various factors implicated in tumor development is unknown, understanding these factors will be critical in the treatment of malignant or surgically inaccessible tumors.
Collapse
Affiliation(s)
- Jay Jagannathan
- Department of Neurosurgery, University of Virginia Health Sciences Center, Charlottesville, Virginia
| | | | | | | | | |
Collapse
|
|
10
|
Aberrant signaling pathways in meningiomas. J Neurooncol 2010; 99:315-24. [DOI: 10.1007/s11060-010-0381-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 08/20/2010] [Indexed: 12/24/2022]
|
|
11
|
Chemotherapy, hormonal therapy, and immunotherapy for recurrent meningiomas. J Neurooncol 2008; 92:1-6. [DOI: 10.1007/s11060-008-9734-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2008] [Accepted: 11/03/2008] [Indexed: 11/26/2022]
|
|
12
|
Dueñas-González A, García-López P, Herrera LA, Medina-Franco JL, González-Fierro A, Candelaria M. The prince and the pauper. A tale of anticancer targeted agents. Mol Cancer 2008; 7:82. [PMID: 18947424 PMCID: PMC2615789 DOI: 10.1186/1476-4598-7-82] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2008] [Accepted: 10/23/2008] [Indexed: 02/07/2023] Open
Abstract
Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.
Collapse
Affiliation(s)
- Alfonso Dueñas-González
- Unidad de Investigacion Biomédica en Cáncer, Instituto de Investigaciones Biomedicas, UNAM/Instituto Nacional de Cancerologia, Mexico City, Mexico.
| | | | | | | | | | | |
Collapse
|
|
13
|
Chen J, Zhang H, Wang H. Experimental study on the inhibitory effects of verapamil on the proliferation of meningiomas cells. ACTA ACUST UNITED AC 2008; 27:88-90. [PMID: 17393119 DOI: 10.1007/s11596-007-0125-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2005] [Indexed: 11/26/2022]
Abstract
In order to investigate the effects of verapamil on the proliferation of meningiomas cells in vitro and in vivo, the cultured meningiomas cells were cultured with verapamil at different concentrations for 24 h and the inhibitory effects of verapamil on cell proliferation were observed by MTT method. The meningiomas model was established by implanting the newly removed tumor fragments into the nude mice subcutaneously. The nude mice with tumors were divided into two groups: verapamil-treated group and control group. Tumor volumes were measured and after 12 weeks the tumors were taken out and examined histologically. The expression of proliferating cell nuclear antigen (PCNA) in the tumors was detected by using immunohistochemistry. It was found that verapamil could inhibit the growth of cultured meningiomas cells in a concentration-dependant manner. The inhibitory effect could be observed in the concentration of 1 micromol/L verapamil and the most obvious effects appeared in the concentration of 100 micromol/L. Tumor volume in the verapamiltreated group was obviously smaller than that in the control group (211.40+/-5.50 vs 163.94+/-3.62, P<0.01) and the expression of PCNA was also lower (1.52+/-0.24 vs 2.86+/-0.53, P<0.05). Tumor inhibition rate was about 22.45%. It was suggested that verapamil could inhibit the proliferation and growth of meningiomas cells in vitro and in vivo.
Collapse
Affiliation(s)
- Jian Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | | | | |
Collapse
|
|
14
|
Abstract
✓ Meningiomas are slow growing, extraaxial tumors that derive from the arachnoidal cap cells of the meninges. Resection remains the main modality of treatment and can be curative in some cases. External-beam radiotherapy and radiosurgery can benefit selected patients. The role of chemotherapy continues to be defined, but should be considered for patients with inoperable or frequently recurring meningiomas. Hydroxyurea, an inhibitor of ribonucleotide reductase, is one of the most active agents and is known to induce apoptosis in meningioma cells in vitro and in mouse xenografts. Results of preliminary clinical studies suggest that hydroxyurea has modest activity against recurrent and inoperable meningiomas, and can induce long term stabilization in some patients. However, the results are conflicting and a few clinical trials did not show positive results. Further clinical trials with larger patient cohorts and longer follow-up periods will be necessary to confirm the activity of hydroxyurea.
Collapse
|
|
15
|
Ragel BT, Couldwell WT, Wurster RD, Jensen RL. Chronic suppressive therapy with calcium channel antagonists for refractory meningiomas. Neurosurg Focus 2007; 23:E10. [DOI: 10.3171/foc-07/10/e10] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
✓In this article, the authors review the research supporting the use of calcium channel antagonists (CCAs) in the treatment of recurrent or unresectable meningiomas. Calcium channel antagonists (for example, diltiazem and verapamil) are known to augment the effects of chemotherapy drugs (for example, vincristine) in multiple cancers. Although it was initially thought that this occurred by interference with calcium-dependent secondary messenger systems, it appears that other mechanisms account for this effect. The authors' initial work in this field was based on the then-emerging data that meningiomas are receptor positive for growth factor receptors (for example, platelet-derived growth factor [PDGF]), which are known to trigger calcium-dependent secondary messenger pathways. In fact, they were able to show that CCAs block the growth stimulatory effects of multiple growth factors, including PDGF, in vitro and augment the growth inhibitory effects of hydroxyurea and RU486 (mifepristone). The authors have shown similar in vivo growth inhibition by these agents. In addition, diltiazem- and verapamil-treated meningiomas are less vascular and smaller, with decreased cell proliferation and increased apoptosis. The use of CCAs is attractive as an adjunct treatment for unresectable or recurrent meningiomas because they are safe drugs with well-known side effect profiles that lend themselves to long-term chronic therapy.
Collapse
Affiliation(s)
- Brian T. Ragel
- 1Department of Neurosurgery, University of Utah
- 2Huntsman Cancer Institute, Salt Lake City, Utah; and
| | - William T. Couldwell
- 1Department of Neurosurgery, University of Utah
- 2Huntsman Cancer Institute, Salt Lake City, Utah; and
| | - Robert D. Wurster
- 3Department of Neurosurgery, Loyola University of Chicago, Stritch School of Medicine, Chicago, Illinois
| | - Randy L. Jensen
- 1Department of Neurosurgery, University of Utah
- 2Huntsman Cancer Institute, Salt Lake City, Utah; and
| |
Collapse
|
|
16
|
Bazargan L, Fouladdel S, Shafiee A, Amini M, Ghaffari SM, Azizi E. Evaluation of anticancer effects of newly synthesized dihydropyridine derivatives in comparison to verapamil and doxorubicin on T47D parental and resistant cell lines in vitro. Cell Biol Toxicol 2007; 24:165-74. [PMID: 17805981 DOI: 10.1007/s10565-007-9026-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2006] [Accepted: 05/24/2007] [Indexed: 12/20/2022]
Abstract
Failure of current anticancer drugs mandates screening for new compounds of synthetic or biological origin to be used in cancer therapy. Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. Efflux of cytotoxic agents mediated by P-glycoprotein (P-gp or MDR1) is believed to be an important mechanism of multidrug resistance. Therefore, we decided to investigate the antiproliferative effects of seven newly synthesized 1,4-dihydropyridine (DHP) derivatives in comparison to verapamil (VP) and doxorubicin (DOX) on human breast cancer T47D cells and its MDR1 overexpressed and moderately resistant cells (RS cells) using MTT cytotoxicity assay. We also examined the effects of these compounds on cytotoxicity of DOX in these two cell types. The cytotoxicity assays using MTT showed that most of the tested new DHP derivatives and VP at 10 microM concentration had varying levels of toxicity on both T47D and RS cells. The toxicity was mostly in the range of 10-25%. However, the cytotoxicity of these DHP derivatives, similar to VP, was significantly less than DOX when comparing IC(50) values. Furthermore, these compounds in general had relatively more cytotoxicity on T47D vs RS cells at 10-microM concentration. Among new DHPs, compounds 7a (3,5-dibenzoyl-4-(2-methylthiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine) and 7d (3,5-diacetyl-4-[2-(2-chlorophenyl)thiazol-4-yl)]-1,4-dihydro-2,6-dimethylpyridine) showed noticeable potentiation of DOX cytotoxicity (reduction of DOX IC(50)) compared to DOX alone in both cells, particularly in RS cells. This effect was similar to that of VP, a known prototype of MDR1 reversal agent. In other words, compounds 7a and 7d resensitized RS cells to DOX or reversed their resistance. Results indicate that compound 7d exerts highest effect on RS cells. Therefore, these two newly synthesized DHP derivatives, compounds 7a and 7d, are promising as potential new MDR1 reversal agents and should be further studied on other highly resistant cells due to MDR1 overexpression and with further molecular investigation.
Collapse
Affiliation(s)
- L Bazargan
- Molecular Research Laboratory, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical Sciences, University of Tehran, Tehran, Iran
| | | | | | | | | | | |
Collapse
|
|
17
|
Yoshida J, Ishibashi T, Nishio M. G1 cell cycle arrest by amlodipine, a dihydropyridine Ca2+ channel blocker, in human epidermoid carcinoma A431 cells. Biochem Pharmacol 2006; 73:943-53. [PMID: 17217918 DOI: 10.1016/j.bcp.2006.12.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2006] [Revised: 11/20/2006] [Accepted: 12/11/2006] [Indexed: 01/27/2023]
Abstract
We demonstrated previously that amlodipine, a dihydropyridine Ca(2+) channel blocker, exhibits antitumor effects on human epidermoid carcinoma A431 cells both in vitro and in vivo, in part through inhibition of capacitative Ca(2+) entry. In this study, we examined the effects of amlodipine on cell cycle distribution and cell cycle regulatory molecules in A431 cells, since a rise in intracellular Ca(2+) is required at several points during cell cycle progression. Flow cytometric analysis revealed that treatment with amlodipine (20-30muM, for 24h) induced G1 phase cell accumulation. The amlodipine-induced G1 arrest was associated with a decrease in phosphorylation of retinoblastoma protein (pRB), a regulator of G1 to S phase transition, reduction of protein levels of cyclin D1 and cyclin dependent kinase 4 (CDK4), G1 specific cell cycle proteins, and increased expression of p21(Waf1/Cip1), an inhibitory protein of CDK/cyclin complexes. In vitro kinase assay revealed that amlodipine significantly decreased CDK2-, CDK4-, and their partners cyclin E- and cyclin D1-associated kinase activities. The amlodipine-induced reductions in cyclin D1 protein expression and in CDK2 kinase activity were reproduced by a dihydropyridine derivative, nicardipine, having an inhibitory effect on A431 cell growth, but not by nifedipine, lacking the antiproliferative activity. Our results demonstrate that amlodipine caused G1 cell cycle arrest and growth inhibition in A431 cells through induction of p21(Waf1/Cip1) expression, inhibition of CDK/cyclin-associated kinase activities, and reduced phosphorylation of pRB.
Collapse
Affiliation(s)
- Junko Yoshida
- Department of Pharmacology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Ishikawa 920-0293, Japan.
| | | | | |
Collapse
|
|
18
|
Ragel BT, Gillespie DL, Kushnir V, Polevaya N, Kelly D, Jensen RL. Calcium Channel Antagonists Augment Hydroxyurea- And Ru486-Induced Inhibition Of Meningioma Growth In Vivo And In Vitro. Neurosurgery 2006; 59:1109-20; discussion 1120-1. [PMID: 17143245 DOI: 10.1227/01.neu.0000245597.46581.fb] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Although the chemotherapy drug hydroxyurea (HU) and the antiprogesterone mifepristone (RU486) have been used to treat meningiomas for which surgical and radiation therapies have failed, results have been disappointing. The addition of calcium channel antagonists (CCAs) to chemotherapeutic drugs enhances tumor growth inhibition in other tumor types, and the authors demonstrated that CCAs can block meningioma growth in vitro and in vivo. The purpose of this study was to test the effects of the addition of a CCA to HU or RU486 on meningioma growth. METHODS Primary and malignant (IOMM-Lee) meningioma cell lines were treated with HU, RU486, or either of these plus diltiazem or verapamil. Assays for cell growth, apoptosis, and fluorescent-activated cell sorting were performed on in vitro cultures. Similar cell lines were implanted into nude mice and were treated with HU or RU486, in combination with a CCA. Tumors were analyzed by light microscopy, MIB-1, and factor VIII immunohistochemical staining studies. RESULTS The addition of diltiazem or verapamil to HU or RU486 augmented meningioma growth inhibition by 20 to 60% in vitro. In vivo, tumors treated with combination drugs were smaller; and immunohistochemical analysis of the IOMM-Lee tumors showed a 10% decrease in the MIB-1 ratio (from 0.41 to 0.30) and an approximate 75% decrease in microvascular density. CONCLUSION The addition of diltiazem or verapamil to HU or RU486 augments meningioma growth inhibition in vitro by inducing apoptosis and G1 cell-cycle arrest. The combination of HU and diltiazem inhibited the growth of meningiomas in vivo by decreasing proliferation and microvascular density. These results suggest a possible role for these drugs as an additional adjuvant therapy for recurrent or unresectable meningiomas.
Collapse
Affiliation(s)
- Brian T Ragel
- Department of Neurosurgery, University of Utah, 30 North 1900 East, Suite 3B409, Salt Lake City, UT 84132, USA
| | | | | | | | | | | |
Collapse
|
|
19
|
Abstract
AIM: To investigate the effects and mechanisms of Verapamil on cultured human colonic tumor (HCT) cells.
METHODS: HCT cells were treated with different concentrations of Verapamil, and their proliferation was examined by MTT assay. The areas of sub-diploid peak were measured by flow cytometry, and the DNA ladder was found by agarose gel electrophoresis. The characteristic changes in morphology were observed under light microscopy. The cell nuclei (propidium iodide labeled, PI-labeled) and cellular distribution and concentration of calcium (Fluo-3-labeled) were studied by using laser confocal scanning microscope.
RESULTS: The proliferation of HCT cells was inhibited by different concentrations of Verapamil. With the increase in concentration of Verapamil, the percent of G0-G1 phase cells in HCT cells increased and that of S phase cells decreased. After treating with different concentrations of Verapamil, flow cytometry showed that HCT cells were enlarged in areas of sub-diploid in a dose-dependent manner. Gel electrophoresis results displayed a typical DNA ladder. On staining with Wrights-Giemsa, the typical cellular apoptosis morphologic changes were also observed. PI-labeled cell nuclei were found markedly changed. In addition, we inspected that the 100 μmol/L Verapamil could increase the intracellular calcium ion concentration [Ca2+]i in HCT cells.
CONCLUSION: Verapamil can inhibit proliferation of HCT cells via inducing cell apoptosis.
Collapse
Affiliation(s)
- Qi-Zhen Cao
- Department of Pharmacology, Peking University Health Science Center, Peking University, Beijing 100083, China
| | | | | |
Collapse
|
|
20
|
Abstract
BACKGROUND Meningiomas are biologically complex and clinically and surgically challenging. These features, combined with the rewarding potential for cure, make them of great interest to neurologists, neurosurgeons, and neuroscientists alike. REVIEW SUMMARY Initially, we review the clinical context of meningiomas, particularly recent changes in histopathological classification, diagnosis, and neuroimaging. Secondly, the underlying basic science as it has evolved over the last decades is summarized. The status of areas recently of intense interest, such as steroid hormone receptors and oncogenic viruses is described. Additionally, emerging areas of great promise, such as cytogenetics and molecular biology are presented. Lastly, we describe recent advances in management. In particular, skull-base surgery, image-guided surgery, and advances in radiotherapy are emphasized. The possible impact of basic research on management and outcome is also outlined. CONCLUSIONS Although usually benign and amenable to cure, meningiomas still present significant diagnostic and treatment challenges. Advances in basic science, surgery, and adjuvant therapy are widening the potential for safe, effective, evidence-based management leading to even better outcomes
Collapse
Affiliation(s)
- Katharine J Drummond
- Department of Neurosurgery, The Brigham and Women's Hospital, Boston, Massachusetts, USA.
| | | | | |
Collapse
|
|
21
|
Yoshida J, Ishibashi T, Nishio M. Antitumor effects of amlodipine, a Ca 2+ channel blocker, on human epidermoid carcinoma A431 cells in vitro and in vivo. Eur J Pharmacol 2004; 492:103-12. [PMID: 15178352 DOI: 10.1016/j.ejphar.2004.04.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2004] [Revised: 03/24/2004] [Accepted: 04/01/2004] [Indexed: 11/26/2022]
Abstract
Amlodipine, a dihydropyridine Ca(2+) channel blocker, is reported to inhibit proliferation of human epidermoid carcinoma A431 cells, and specifically attenuates Ca(2+) responses evoked by thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPases. In this study, we further examined the possible mechanism of the antiproliferative action of amlodipine and its antitumor effect on A431 xenografts in nude mice. Amlodipine reduced BrdU incorporation into nucleic acids in serum-starved A431 cells, and the reduction was diminished by uridine 5'-triphosphate (UTP), a phospholipase C (PLC)-linked agonist. Fluorometric measurement of intracellular free Ca(2+) concentration revealed that amlodipine blunted the UTP-induced Ca(2+) release from the internal Ca(2+) stores and consequently Ca(2+) influx through Ca(2+)-permeable channels on the plasma membrane. Although amlodipine alone caused Ca(2+) release from thapsigargin-sensitive Ca(2+) stores, such an effect was not reproduced by other dihydropyridine Ca(2+) channel blockers, including nicardipine and nimodipine, despite their antiproliferative effects in the cells. Daily intraperitoneal administration of amlodipine (10 mg/kg) for 20 days into mice bearing A431 xenografts retarded tumor growth and prolonged the survival of mice. Our results suggest a potential antitumor action for amlodipine in vitro and in vivo, which may be in part mediated by inhibiting Ca(2+) influx evoked by the passive depletion of internal Ca(2+) stores and by PLC-linked agonist stimulation.
Collapse
Affiliation(s)
- Junko Yoshida
- Department of Pharmacology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
| | | | | |
Collapse
|
|
22
|
Yoshida J, Ishibashi T, Nishio M. Antiproliferative effect of Ca2+ channel blockers on human epidermoid carcinoma A431 cells. Eur J Pharmacol 2003; 472:23-31. [PMID: 12860469 DOI: 10.1016/s0014-2999(03)01831-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The effects of Ca(2+) channel blockers on the proliferation of human epidermoid carcinoma A431 cells were investigated by microtiter tetrazolium (MTT) proliferation assay and bromodeoxyuridine (BrdU) incorporation assay. Dihydropyridine derivatives, such as amlodipine, nicardipine, and nimodipine inhibited A431 cell growth and the incorporation of BrdU into cells with IC(50) values of 20-30 microM, while verapamil, diltiazem and dihydropyridine nifedipine inhibited neither the cell growth nor BrdU incorporation at the same concentration. Though extracellular Ca(2+) is indispensable to the cell growth, an L-type Ca(2+) channel agonist, 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl]pyridine-3-carboxylic acid methyl ester (200 nM), did not affect the antiproliferative action of amlodipine. Thapsigargin, an inhibitor of Ca(2+)-ATPase of the endoplasmic reticulum, inhibited itself the growth of A431 cells and also showed a synergistic effect with the antiproliferative action of amlodipine. In the fluorimetric measurement of intracellular free Ca(2+) concentration in fura-2 or fluo-3 loaded A431 cells, amlodipine blunted the thapsigargin- or cyclopiazonic acid-induced Ca(2+) release from endoplasmic reticulum and the ensuing Ca(2+) influx through Ca(2+)-permeable channels. The effect on the thapsigargin-induced Ca(2+) responses could be reproduced by nicardipine and nimodipine but not by nifedipine or verapamil, lacking antiproliferative potency. These findings suggest that the intracellular Ca(2+) control system responsible for thapsigargin- and cyclopiazonic acid-sensitive endoplasmic reticulum, but not L-type Ca(2+) channels, may be modulated by amlodipine, which results in the inhibition of A431 cell growth.
Collapse
Affiliation(s)
- Junko Yoshida
- Department of Pharmacology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
| | | | | |
Collapse
|
|
23
|
Affiliation(s)
- Brian Ragel
- Department of Neurosurgery, University of Utah, Salt Lake City 84132, USA
| | | |
Collapse
|
|
24
|
Jensen RL, Wurster RD. Calcium channel antagonists inhibit growth of subcutaneous xenograft meningiomas in nude mice. SURGICAL NEUROLOGY 2001; 55:275-83. [PMID: 11516467 DOI: 10.1016/s0090-3019(01)00444-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND We have previously shown that calcium channel antagonists inhibit in vitro meningioma growth. This study examines the effect of calcium channel antagonists on in vivo xenograft meningioma growth. METHODS Meningioma cells taken from human patients were mixed with Matrigel and injected into the subcutaneous space in the flank of nude mice. These animals were treated with calcium channel antagonists in their drinking water. Tumor volumes were measured over time; comparison was made between control and treatment groups. Daily weights, average daily water consumption, and serum calcium channel antagonist levels were determined. Comparison of histology and proliferation index was made between control and treatment groups. RESULTS Diltiazem treatment decreased tumor growth over time compared to control groups. Increased tumor growth inhibition was seen with increasing doses (p > 0.05). Treatment with verapamil had similar effects; however, there are no statistically significant dose dependent decreases in growth with increasing verapamil doses. There were no tumor "cures" or spontaneous regression of tumor in any group including the control groups. Animal daily weight and average daily water consumption was unaffected by increasing calcium channel antagonist doses compared to control groups. Mouse serum drug levels increased with increasing doses of drug in the drinking water of treatment groups (p > 0.05). Histology and proliferative index of treatment groups were similar to control groups. CONCLUSION Calcium channel antagonists decrease but do not completely inhibit the growth of meningiomas in nude mice. Clinical correlations and potential applications are discussed.
Collapse
Affiliation(s)
- R L Jensen
- Department of Neurosurgery, University of Utah, Salt Lake City, Utah 84112, USA
| | | |
Collapse
|