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Kim N, Kim SS, Cho WK, Park W, Chang JH, Kim YB, Chang AR, Kim TH, Park J, Kim JH, Kim K, Lim YJ, Kim TG, Choi JH, Kwon J, Kim S, Shin KH, Kim H. Concurrent Versus Sequential Adjuvant Capecitabine-Based Chemoradiation in Residual Triple-Negative Breast Cancer After Neoadjuvant-Chemotherapy: A Multicenter Comparative Study. Int J Radiat Oncol Biol Phys 2025; 122:72-83. [PMID: 39672514 DOI: 10.1016/j.ijrobp.2024.11.109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/28/2024] [Accepted: 11/29/2024] [Indexed: 12/15/2024]
Abstract
PURPOSE Given the aggressive nature and poor prognosis of triple-negative breast cancer (TNBC), adjuvant capecitabine has been the standard therapy for residual disease after preoperative systemic therapy (PST). However, the optimal sequence of postoperative radiation therapy (RT) and capecitabine remains unclear. This study evaluated the efficacy and safety of concurrent RT and capecitabine (RT+CAP) versus sequential RT followed by capecitabine (RT→CAP) in patients with residual TNBC after PST. METHODS AND MATERIALS In this multicenter retrospective study, data from 491 patients treated at 14 tertiary hospitals were analyzed. The patients received either postoperative RT→CAP (n = 255) or RT+CAP (n = 236). Survival outcomes were analyzed using the Kaplan-Meier method, and multivariable Cox regression was used to adjust for potential confounders. RESULTS There were no significant differences in the baseline characteristics between the 2 groups. With a median follow-up of 41.8 months, the 4-year rates of disease-free survival (DFS) and overall survival (OS) were 68.8% and 82.4%, respectively. The RT+CAP group demonstrated improvements in DFS (74.6% vs 63.7%, P = .045) and OS (86.8% vs 78.3%, P = .006) compared with the RT→CAP group. Specifically, RT+CAP showed superior DFS and OS outcomes in patients with a low disease burden (ypT0-1, ypN0/axillar level I only, or Ki67 <15%). Additionally, the incidence of ≥grade 2 toxicities and discontinuation of capecitabine because of toxicity did not differ, indicating that RT+CAP was well tolerated. CONCLUSIONS RT+CAP offers improvements in oncologic outcomes without an increase in adverse events compared with RT→CAP, suggesting it is a promising treatment option for patients with residual TNBC after PST.
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Affiliation(s)
- Nalee Kim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Su Ssan Kim
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won Kyung Cho
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ji Hyun Chang
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong Bae Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ah Ram Chang
- Department of Radiation Oncology, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Tae Hyun Kim
- Proton Therapy Center, Research Institute and Hospital, National Cancer center, Gyeonggi-do, Republic of Korea
| | - Jongmoo Park
- Department of Radiation Oncology, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Jin Hee Kim
- Department of Radiation Oncology, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Kyubo Kim
- Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Yu Jin Lim
- Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Tae Gyu Kim
- Department of Radiation Oncology, Samsung Changwon Hospital, Changwon, Sungkyunkwan University School of Medicine, Republic of Korea
| | - Jin Hwa Choi
- Department of Radiation Oncology, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Jeanny Kwon
- Department of Radiation Oncology, Chungnam National University School of Medicine, Jung-gu, Daejeon, Republic of Korea
| | - Sungmin Kim
- Department of Radiation Oncology, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Kyung Hwan Shin
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Haeyoung Kim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Li J, Zhan S, Yang W, Zhang H, Ma X, Chen F, Li A, Tong P, Jiang F, Cao Z, Delahunty I, Wang J, Wu Y, Liu Z, Li Z, Teng Y, Xu L, Xie J. Radiation-induced ferroptosis via liposomal delivery of 7-Dehydrocholesterol. J Nanobiotechnology 2025; 23:249. [PMID: 40133959 PMCID: PMC11938788 DOI: 10.1186/s12951-025-03303-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 03/08/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Ferroptosis is an emerging cell death mechanism characterized by uncontrolled lipid peroxidation. However, selectively inducing ferroptosis in cancer cells remains a challenge. METHODS We explore an approach that enables ferroptosis induction through external radiation. The key component of this technology is 7-dehydrocholesterol (7DHC), a natural biosynthetic precursor of cholesterol. To facilitate delivery, we demonstrate that 7DHC, like cholesterol, can be incorporated into the lipid layer of liposomes. To enhance targeting, we also introduced NTSmut, a ligand for the neurotensin receptor 1 (NTSR1), which is overexpressed in multiple malignancies, into liposomes. RESULTS Under radiation, 7DHC reacts with radiation-induced reactive oxygen species (ROS), initiating a radical chain reaction with polyunsaturated fatty acids (PUFAs) in cell membranes. This process results in direct lipid peroxidation and subsequent ferroptotic cell death. In vivo studies demonstrate that NTSmut-conjugated, 7DHC-loaded liposomes (N-7DHC-lipos) effectively accumulate in tumors and significantly enhance the efficacy of radiation therapy. CONCLUSION While conventional radiosensitizers primarily target DNA and its repair mechanisms, our study introduces a strategy to enhance radiotherapy by specifically activating ferroptosis within the irradiated area, thereby minimizing systemic toxicity. Such a strategy of controlled activation of ferroptosis offers a favorable therapeutic index and potentially opens avenues for clinical application.
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Affiliation(s)
- Jianwen Li
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Shuyue Zhan
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Wei Yang
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - He Zhang
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Xinrui Ma
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Fanghui Chen
- Department of Hematology and Medical Oncology & Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Amy Li
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195, USA
| | - Pakteema Tong
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195, USA
| | - Fangchao Jiang
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Zhengwei Cao
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Ian Delahunty
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Jiayi Wang
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Yufei Wu
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Zhi Liu
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Zibo Li
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yong Teng
- Department of Hematology and Medical Oncology & Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Libin Xu
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195, USA
| | - Jin Xie
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA.
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Flörkemeier I, Hotze HL, Heyne AL, Hildebrandt J, Weimer JP, Hedemann N, Rogmans C, Holthaus D, Siebert FA, Hirt M, Polten R, Morgan M, Klapdor R, Schambach A, Dempfle A, Maass N, van Mackelenbergh MT, Clement B, Bauerschlag DO. Dual Topoisomerase Inhibitor Is Highly Potent and Improves Antitumor Response to Radiotherapy in Cervical Carcinoma. Int J Mol Sci 2025; 26:2829. [PMID: 40243435 PMCID: PMC11988843 DOI: 10.3390/ijms26072829] [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: 01/31/2025] [Revised: 03/11/2025] [Accepted: 03/13/2025] [Indexed: 04/18/2025] Open
Abstract
Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources and treatment limitations for cervical cancer. Thus, effective medicines that are simple to manufacture are needed. The newly developed dual topoisomerase inhibitor P8-D6, with its outstanding ability to induce apoptosis, could be a promising option. In this study, the efficacy of P8-D6 in combination with radiochemotherapy against cervical carcinoma was investigated in established cell lines and in a translational approach in ex vivo patient cells by measuring the cytotoxicity, cell viability and caspase activity in vitro in 2D and 3D cell cultures. Treatment with P8-D6 resulted in significantly greater cytotoxicity and apoptosis induction compared to standard therapeutic cisplatin in both 2D and 3D cell cultures. Specifically, a considerably stronger anti-proliferative effect was observed. The treatment also led to morphological changes and a loss of membrane integrity in the 3D spheroids. Radiotherapy also benefited greatly from P8-D6 treatment. In fact, P8-D6 was a more potent radiosensitizer than cisplatin. Simple synthesis, favorable physicochemical properties and high potency make P8-D6 a promising cervical cancer drug candidate.
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Affiliation(s)
- Inken Flörkemeier
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
- Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrecht University of Kiel, 24118 Kiel, Germany
- Priority Research Area Kiel Nano, Surface and Interface Sciences (KiNSIS), Kiel University, 24118 Kiel, Germany
| | - Hannah L. Hotze
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - Anna Lena Heyne
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
- Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrecht University of Kiel, 24118 Kiel, Germany
| | - Jonas Hildebrandt
- Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrecht University of Kiel, 24118 Kiel, Germany
| | - Jörg P. Weimer
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - Nina Hedemann
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - Christoph Rogmans
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - David Holthaus
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - Frank-André Siebert
- Clinic of Radiotherapy, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Markus Hirt
- Clinic of Radiotherapy, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Robert Polten
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
| | - Michael Morgan
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
| | - Rüdiger Klapdor
- Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany
- Department of Gynecology and Obstetrics, Albertinen Hospital Hamburg, 22457 Hamburg, Germany
| | - Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Astrid Dempfle
- Institute of Medical Informatics and Statistics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Nicolai Maass
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - Marion T. van Mackelenbergh
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
| | - Bernd Clement
- Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrecht University of Kiel, 24118 Kiel, Germany
| | - Dirk O. Bauerschlag
- Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (D.O.B.)
- Department of Gynecology, Jena University Hospital, 07747 Jena, Germany
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Hao JL, Li XY, Liu YT, Lang JX, Liu DJ, Zhang CD. Antibody-drug conjugates in gastric cancer: from molecular landscape to clinical strategies. Gastric Cancer 2024; 27:887-906. [PMID: 38963593 DOI: 10.1007/s10120-024-01529-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Antibody-drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics.
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Affiliation(s)
- Jia-Lin Hao
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Xin-Yun Li
- Clinical Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Yu-Tong Liu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110022, China
| | - Ji-Xuan Lang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Di-Jie Liu
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Chun-Dong Zhang
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
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Ramezani F, Takhshid MA, Abuei H, Farhadi A, Mosleh-Shirazi MA, Ramezani P. Combined Effects of Annexin A5 Overexpression, 5-Fluorouracil Treatment, and Irradiation on Cell Viability of Caski Cervical Cancer Cell Line. Reprod Sci 2024; 31:2654-2666. [PMID: 38811453 DOI: 10.1007/s43032-024-01575-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/22/2024] [Indexed: 05/31/2024]
Abstract
Cervical cancer is the fourth leading cause of cancer deaths in women globally. Combining gene therapy with chemo- and radiotherapy may improve cervical cancer treatment outcomes. This study evaluated the effects of Annexin A5(ANXA5) overexpression alongside 5-fluorouracil (5-FU) and irradiation on the viability of CaSki cervical squamous cell carcinoma (SCC) cells. pAdenoVator-CMV-ANXA5-IRES-GFP-plasmid and mock plasmid were transfected into CaSki cells using calcium-phosphate. Seventy-two hours post-transfection, GFP expression was quantified by fluorescence microscopy and flow cytometry to evaluate transfection efficiency. ANXA5 overexpression was confirmed via qPCR. Twenty-four hours post-transfection, cells received a single dose of 8 Gy and were treated with 1 and 2 µg/ml of 5-FU (IC50 = 2.783 µg/ml). Cell viability, apoptosis, cell cycle stage, and Bcl-2 and Bax gene expression were assessed via MTT, annexin V/7-AAD, PI staining, and qPCR assays, respectively. ANXA5 was overexpressed 31.5-fold compared to control (p < 0.0001). MTT assays showed ANXA5 overexpression dose-dependently reduced CaSki cell viability (p < 0.001). IC50 of 5-FU was reduced from 2.783 μg/mL to 1.794 μg/mL when combined with ANXA5 overexpression. Additive effects on cell death were observed for ANXA5 plus 5-FU or irradiation versus ANXA5 alone. Apoptosis assays indicated combinatorial treatment increased CaSki cell apoptosis over ANXA5 alone. Cell cycle analysis revealed ANXA5 arrested cell cycle at G1/S phases; the percentage of cells in the S phase further rose with combination treatment. Finally, combination therapy significantly decreased Bcl-2 expression and increased Bax versus control (p < 0.001). Altogether, ANXA5 overexpression alongside 5-FU and irradiation may improve cervical squamous cell carcinoma (SCC) treatment efficacy. Further, in vivo investigations are warranted to confirm these in vitro results.
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Affiliation(s)
- Faezeh Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali Takhshid
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
- School of Paramedical Sciences, Diagnostic Laboratory Sciences and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Haniyeh Abuei
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Farhadi
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
- School of Paramedical Sciences, Diagnostic Laboratory Sciences and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Amin Mosleh-Shirazi
- Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC), School of Paramedical Sciences, Shiraz University of Medical Sciences, Meshkinfam St, Shiraz, Iran
- Physics Unit, Department of Radio-Oncology, School of Medicine, Shiraz University of Medical Sciences, Namazi Teaching Hospital, Namazi Square, Shiraz, Iran
| | - Pouya Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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Mucignat G, Montanucci L, Elgendy R, Giantin M, Laganga P, Pauletto M, Mutinelli F, Vascellari M, Leone VF, Dacasto M, Granato A. A Whole-Transcriptomic Analysis of Canine Oral Melanoma: A Chance to Disclose the Radiotherapy Effect and Outcome-Associated Gene Signature. Genes (Basel) 2024; 15:1065. [PMID: 39202425 PMCID: PMC11353338 DOI: 10.3390/genes15081065] [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: 07/18/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 09/03/2024] Open
Abstract
Oral melanoma (OM) is the most common malignant oral tumour among dogs and shares similarities with human mucosal melanoma (HMM), validating the role of canine species as an immunocompetent model for cancer research. In both humans and dogs, the prognosis is poor and radiotherapy (RT) represents a cornerstone in the management of this tumour, either as an adjuvant or a palliative treatment. In this study, by means of RNA-seq, the effect of RT weekly fractionated in 9 Gray (Gy), up to a total dose of 36 Gy (4 weeks), was evaluated in eight dogs affected by OM. Furthermore, possible transcriptomic differences in blood and biopsies that might be associated with a longer overall survival (OS) were investigated. The immune response, glycosylation, cell adhesion, and cell cycle were the most affected pathways by RT, while tumour microenvironment (TME) composition and canonical and non-canonical WNT pathways appeared to be modulated in association with OS. Taking these results as a whole, this study improved our understanding of the local and systemic effect of RT, reinforcing the pivotal role of anti-tumour immunity in the control of canine oral melanoma (COM).
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Affiliation(s)
- Greta Mucignat
- Department of Comparative Biomedicine and Food Science, University of Padua, Agripolis Legnaro, 35020 Padua, Italy; (G.M.); (M.G.); (M.P.)
| | - Ludovica Montanucci
- McGovern Medical School and Center for Neurogenomics, UTHealth, University of Texas Houston, Houston, TX 77030, USA;
| | - Ramy Elgendy
- Discovery Sciences, Centre for Genomics Research, AstraZeneca, 411 10 Gothenburg, Sweden;
| | - Mery Giantin
- Department of Comparative Biomedicine and Food Science, University of Padua, Agripolis Legnaro, 35020 Padua, Italy; (G.M.); (M.G.); (M.P.)
| | - Paola Laganga
- Anicura—Centro Oncologico Veterinario, Sasso Marconi, 40037 Bologna, Italy; (P.L.); (V.F.L.)
| | - Marianna Pauletto
- Department of Comparative Biomedicine and Food Science, University of Padua, Agripolis Legnaro, 35020 Padua, Italy; (G.M.); (M.G.); (M.P.)
| | - Franco Mutinelli
- Veterinary and Public Health Institute, Legnaro, 35020 Padua, Italy; (F.M.); (M.V.)
| | - Marta Vascellari
- Veterinary and Public Health Institute, Legnaro, 35020 Padua, Italy; (F.M.); (M.V.)
| | - Vito Ferdinando Leone
- Anicura—Centro Oncologico Veterinario, Sasso Marconi, 40037 Bologna, Italy; (P.L.); (V.F.L.)
| | - Mauro Dacasto
- Department of Comparative Biomedicine and Food Science, University of Padua, Agripolis Legnaro, 35020 Padua, Italy; (G.M.); (M.G.); (M.P.)
| | - Anna Granato
- Veterinary and Public Health Institute, Legnaro, 35020 Padua, Italy; (F.M.); (M.V.)
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Luo T, Jiang X, Fan Y, Yuan E, Li J, Tillman L, Lin W. STING agonist-conjugated metal-organic framework induces artificial leukocytoid structures and immune hotspots for systemic antitumor responses. Natl Sci Rev 2024; 11:nwae167. [PMID: 38887543 PMCID: PMC11182667 DOI: 10.1093/nsr/nwae167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/15/2024] [Accepted: 04/23/2024] [Indexed: 06/20/2024] Open
Abstract
Radiotherapy is widely used for cancer treatment, but its clinical utility is limited by radioresistance and its inability to target metastases. Nanoscale metal-organic frameworks (MOFs) have shown promise as high-Z nanoradiosensitizers to enhance radiotherapy and induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics to synergize with radiotherapy for enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer, GA-MOF, by conjugating a STING agonist, 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), on MOFs for synergistic radiosensitization and STING activation. GA-MOF demonstrated strong anticancer efficacy by forming immune-cell-rich nodules (artificial leukocytoid structures) and transforming them into immunostimulatory hotspots with radiotherapy. Further combination with an immune checkpoint blockade suppressed distant tumors through systemic immune activation. Our work not only demonstrates the potent radiosensitization of GA-MOF, but also provides detailed mechanisms regarding MOF distribution, immune regulatory pathways and long-term immune effects.
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Affiliation(s)
- Taokun Luo
- Department of Chemistry, University of Chicago, Chicago 60637, USA
| | - Xiaomin Jiang
- Department of Chemistry, University of Chicago, Chicago 60637, USA
| | - Yingjie Fan
- Department of Chemistry, University of Chicago, Chicago 60637, USA
| | - Eric Yuan
- Department of Chemistry, University of Chicago, Chicago 60637, USA
| | - Jinhong Li
- Department of Chemistry, University of Chicago, Chicago 60637, USA
| | - Langston Tillman
- Department of Chemistry, University of Chicago, Chicago 60637, USA
| | - Wenbin Lin
- Department of Chemistry, University of Chicago, Chicago 60637, USA
- Department of Radiation and Cellular Oncology and the Ludwig Center for Metastasis Research, University of Chicago, Chicago 60637, USA
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Johnson HR, Gunder LC, Gillette A, Sleiman H, Rademacher BL, Meske LM, Culberson WS, Micka JA, Favreau P, Yao E, Matkowskyj KA, Skala MC, Carchman EH. Preclinical Models of Anal Cancer Combined-Modality Therapy. J Surg Res 2024; 294:82-92. [PMID: 37864962 DOI: 10.1016/j.jss.2023.09.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/15/2023] [Accepted: 09/19/2023] [Indexed: 10/23/2023]
Abstract
INTRODUCTION There have been no significant changes in anal cancer treatment options in 4 decades. In this study, we highlight two preclinical models designed to assess anal cancer treatments. MATERIALS AND METHODS Transgenic K14E6/E7 mice were treated with 7, 12-dimethylbenz(a)anthracene until anal tumors developed. Mice were treated with localized radiation in addition to chemotherapy (combined-modality therapy [CMT]) and compared to no treatment control (NTC). K14E6/E7 mouse anal spheroids with and without Pik3ca mutations were isolated and treated with vehicle, LY3023414 (LY3) (a drug previously shown to be effective in cancer prevention), CMT, or CMT + LY3. RESULTS In the in vivo model, there was a significant increase in survival in the CMT group compared to the NTC group (P = 0.0392). In the ex vivo model, there was a significant decrease in the mean diameter of CMT and CMT + LY3-treated spheroids compared to vehicle (P ≤ 0.0001). For LY3 alone compared to vehicle, there was a statistically significant decrease in spheroid size in the K14E6/E7 group without mutation (P = 0.0004). CONCLUSIONS We have provided proof of concept for two preclinical anal cancer treatment models that allow for the future testing of novel therapies for anal cancer.
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Affiliation(s)
- Hillary R Johnson
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin
| | - Laura C Gunder
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin
| | | | - Hana Sleiman
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin
| | - Brooks L Rademacher
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin
| | - Louise M Meske
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin
| | - Wesley S Culberson
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin
| | - John A Micka
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin
| | - Peter Favreau
- Morgridge Institute for Research, Madison, Wisconsin
| | - Evan Yao
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin
| | - Kristina A Matkowskyj
- Department of Pathology and Laboratory Medicine, University of Wisconsin Madison, Madison, Wisconsin; Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, Wisconsin; William S. Middleton Memorial Veterans, Madison, Wisconsin
| | - Melissa C Skala
- Morgridge Institute for Research, Madison, Wisconsin; Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, Wisconsin
| | - Evie H Carchman
- Department of Surgery, University of Wisconsin - Madison, Madison, Wisconsin; Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin; William S. Middleton Memorial Veterans, Madison, Wisconsin.
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9
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Beduk Esen CS, Gedik ME, Canpinar H, Yedekci FY, Yildiz F, Gunaydin G, Gultekin M. Radiosensitising Effects of Metformin Added to Concomitant Chemoradiotherapy with Cisplatin in Cervical Cancer. Clin Oncol (R Coll Radiol) 2023; 35:744-755. [PMID: 37679230 DOI: 10.1016/j.clon.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/13/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023]
Abstract
AIMS The role of metformin on the radiosensitising effect of cisplatin is not clear. Here we investigated the radiosensitising effect of metformin alone and combined with cisplatin in HeLa cells, as well as the implications of the adenosine monophosphate-activated protein kinase (AMPK) pathway on the radiosensitising effect. MATERIALS AND METHODS HeLa cells were treated with ionising radiation, metformin, cisplatin, A769662 (AMPK activator) and dorsomorphin (AMPK inhibitor) or in combination. A cell proliferation assay, Western blot and flow cytometry were carried out. RESULTS Metformin potentiated cisplatin cytotoxicity when administered 4 h before ionising radiation. Although the radiosensitising effects of metformin and cisplatin alone were observed, which is more apparent at high ionising radiation doses, the metformin-cisplatin combination did not increase the radiosensitivity of cisplatin at any ionising radiation dose. Dorsomorphin alone significantly decreased cell proliferation and potentiated the radiosensitising effects of cisplatin with ionising radiation. Administration of A769662 24 h prior to cisplatin treatment resulted in an increased AMPK level that yielded resistance to cisplatin, but this effect was not observed in HeLa cells concomitantly treated with A769662 and cisplatin. CONCLUSIONS Modulation of AMPK may have a role in cervical cancer treatment. Increased AMPK levels result in higher sensitivity to ionising radiation but causes resistance to cisplatin. Dorsomorphin is proven to be a potent radiosensitising agent. The use of metformin alone may be an option as a radiosensitiser during high-dose ionising radiation (e.g. intracavitary brachytherapy).
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Affiliation(s)
- C S Beduk Esen
- Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey.
| | - M E Gedik
- Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey.
| | - H Canpinar
- Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey.
| | - F Y Yedekci
- Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey.
| | - F Yildiz
- Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey.
| | - G Gunaydin
- Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey; Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey.
| | - M Gultekin
- Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey.
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10
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Fang X, Sun P, Dong Y, Huang Y, Lu JJ, Kong L. In vitro evaluation of photon and carbon ion radiotherapy in combination with cisplatin in head and neck squamous cell carcinoma cell lines. Front Oncol 2023; 13:896142. [PMID: 37081974 PMCID: PMC10110960 DOI: 10.3389/fonc.2023.896142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
BackgroundHeavy ion radiotherapy, such as carbon ion radiotherapy (CIRT), has multiple advantages over conventional photon therapy. Cisplatin, as a classic anti-tumor drugs, has been tested and discovered as a photon radiosensitizer in several cell lines, including head and neck squamous cell carcinoma (HNSCC). Hence, the aim of our study is to evaluate whether cisplatin can sensitize CIRT towards HNSCC cell lines in vitro.MethodsHuman nasopharyngeal carcinoma cell line CNE-2, human tongue squamous carcinoma cell line TCA 8113 and human hypopharynx squamous carcinoma cell line FADU were all irradiated with photon beam of 2, 4, 6, 8 Gy (physical dose) and carbon ion beam of 1, 2, 3, 4 Gy (physical dose) and treated with cisplatin. Cell survival was assessed by clonogenic survival assay.ResultsCIRT showed significantly stronger cytotoxic effect than standard photon radiotherapy. The relative biological effectiveness (RBE) of carbon ion beam at 10% survival (RBE10) was calculated 3.07 for CNE-2, 2.33 for TCA 8113 and 2.36 for FADU. Chemoradiotherapy (both photon radiotherapy and CIRT) was more effective than radiotherapy alone. In vitro sensitizer enhancement ratios (SERs) of cisplatin in CNE-2, TCA 8113 and FA DU cell lines after photon irradiation were 1.33, 1.14 and 1.21, while after carbon ion irradiation were 1.02, 1.00 and 0.96, showed that cisplatin sensitized photon irradiation but showed no sensitization effect in carbon ion irradiation in all tested cell lines.ConclusionsIn conclusion, high linear energy transfer (LET) CIRT was more effective than photon irradiation to prevent the proliferation of HNSCC cell lines. Additional treatment with cisplatin could sensitize photon irradiation but showed no effect on carbon ion irradiation.
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Affiliation(s)
- Xumeng Fang
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Pian Sun
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Yuanli Dong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Yangle Huang
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Jiade Jay Lu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
- *Correspondence: Jiade Jay Lu, ; Lin Kong,
| | - Lin Kong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
- *Correspondence: Jiade Jay Lu, ; Lin Kong,
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11
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Geurts YM, Shakir R, Ntentas G, Roberti S, Aznar MC, John KM, Ramroth J, Janus CPM, Krol ADG, Roesink JM, van der Maazen RWM, Zijlstra JM, Darby SC, Aleman BMP, van Leeuwen FE, Cutter DJ, Schaapveld M. Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma. JAMA Oncol 2023; 9:481-489. [PMID: 36729438 PMCID: PMC9896374 DOI: 10.1001/jamaoncol.2022.7153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Importance Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear. Objective To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors. Design, Setting, and Participants A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022. Exposures Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets. Main Outcomes and Measures Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored. Results The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose. Conclusions and Relevance This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.
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Affiliation(s)
- Yvonne M. Geurts
- Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Rebecca Shakir
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Georgios Ntentas
- Nuffield Department of Population Health, University of Oxford, Oxford, UK,Department of Medical Physics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK,School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK
| | - Sander Roberti
- Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marianne C. Aznar
- Division of Cancer Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK
| | - Katinka M. John
- Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Johanna Ramroth
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Cécile P. M. Janus
- Department of Radiotherapy, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Augustinus D. G. Krol
- Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Judith M. Roesink
- Department of Radiotherapy, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Josée M. Zijlstra
- Department of Hematology, Amsterdam University Medical Center, Vrije Universiteit, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Sarah C. Darby
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Berthe M. P. Aleman
- Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Flora E. van Leeuwen
- Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - David J. Cutter
- Nuffield Department of Population Health, University of Oxford, Oxford, UK,Oxford Cancer and Hematology Center, Oxford University Hospitals National Health Service Foundation Trust, Churchill Hospital, Oxford, UK
| | - Michael Schaapveld
- Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
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Targeting PI3K/AKT/mTOR Signaling Pathway as a Radiosensitization in Head and Neck Squamous Cell Carcinomas. Int J Mol Sci 2022; 23:ijms232415749. [PMID: 36555391 PMCID: PMC9778923 DOI: 10.3390/ijms232415749] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/24/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway.
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13
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Effect of cisplatin on oral ulcer-induced nociception in rats. Arch Oral Biol 2022; 144:105572. [DOI: 10.1016/j.archoralbio.2022.105572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/29/2022] [Accepted: 10/12/2022] [Indexed: 11/19/2022]
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14
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Zheng R, Wang B, Liang F, Xu B. Systemic therapy‐based split‐course stereotactic body radiation therapy. PRECISION RADIATION ONCOLOGY 2022. [DOI: 10.1002/pro6.1176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Affiliation(s)
- Rong Zheng
- Department of Radiation Oncology Fujian Medical University Union Hospital Fuzhou Fujian China
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors (Fujian Medical University) Fuzhou Fujian China
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies) Fuzhou Fujian China
| | - Bisi Wang
- Department of Radiation Oncology Fujian Medical University Union Hospital Fuzhou Fujian China
| | - Feihong Liang
- Department of Radiation Oncology Fujian Medical University Union Hospital Fuzhou Fujian China
| | - Benhua Xu
- Department of Radiation Oncology Fujian Medical University Union Hospital Fuzhou Fujian China
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors (Fujian Medical University) Fuzhou Fujian China
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies) Fuzhou Fujian China
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15
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Zhu L, Zhao Y, Liu T, Chen M, Qian WP, Jiang B, Barwick BG, Zhang L, Styblo TM, Li X, Yang L. Inhibition of NADPH Oxidase-ROS Signal using Hyaluronic Acid Nanoparticles for Overcoming Radioresistance in Cancer Therapy. ACS NANO 2022; 16:18708-18728. [PMID: 36256454 PMCID: PMC9764083 DOI: 10.1021/acsnano.2c07440] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Upregulation of NADPH oxidases (NOXs) in cancer cells leads to chronic increase in intracellular reactive oxygen species (ROS) and adaptation to a high ROS level for cell survival and, thereby, low sensitivity to radiotherapy. To overcome resistance to radiotherapy, we have developed a bioactive and CD44 targeted hyaluronic acid nanoparticle encapsulated with an NOX inhibitor, GKT831 (HANP/GKT831). We found that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 alone in cancer cells. Systemic delivery of HANP/GKT831 led to the targeted accumulation in breast cancer patient derived xenograft (PDX) tumors in nude mice. Importantly, the combination of systemic delivery of HANP/GKT831 with a low dose of local radiotherapy significantly enhanced tumor growth inhibition in breast cancer PDX models. Our results showed that HANP/GKT831 primed tumor cells to radiation-induced DNA damage and cell death by downregulation of DNA repair function and oncogenic signal pathways.
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Affiliation(s)
- Lei Zhu
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
| | - Yi Zhao
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
- Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
| | - Tongrui Liu
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
| | - Minglong Chen
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
- Department of Nuclear Medicine, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Wei Ping Qian
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
| | - Binghua Jiang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia 19107, Pennsylvania, United States
| | - Benjamin G Barwick
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta 30322, Georgia, United States
| | - Lumeng Zhang
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
- Department of Nuclear Medicine, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Toncred M Styblo
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
| | - Xiaoxian Li
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta 30322, Georgia, United States
| | - Lily Yang
- Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta 30322, Georgia, United States
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16
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Zhu J, Li L, Duan Y, Wu Y, Wang X. Prognostic role of pre-treatment serum ALB in Patients with oropharyngeal cancer: A retrospective cohort study. Front Oncol 2022; 12:924210. [PMID: 36531036 PMCID: PMC9756847 DOI: 10.3389/fonc.2022.924210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 09/27/2022] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The morbidity of oropharyngeal cancer (OPC) is continuing to rise in numerous developed countries. An accurate prognostic assessment is needed to evaluate the malignant degree or risk classification to optimize treatment. Albumin (ALB) as an independent prognostic indicator of cancer survival has been established in previous studies. This study investigated the prognostic value of pre-treatment serum ALB in OPC patients. METHODS The clinicopathological data of 246 patients diagnosed with OPC from 2010 to 2019 were analyzed retrospectively. Analyze the relationship between ALB and clinicopathological characteristics of patients. The optimal cut-off values for ALB were determined via Cutoff Finder (Method for cutoff determination: Survival: significance (log-rank test)). To determine the independent prognostic factors, the Cox proportional hazards model was used to perform univariate and multivariate analyses of the serum ALB levels related to overall survival (OS) and disease-free survival (DFS). RESULTS The optimal cut-off point for ALB was 39.15 g/L determined via Cutoff Finder. Serum ALB levels were significantly associated with age (P=0.047), Presence of comorbidity (P=0.009), Charlson score index (P=0.007), Hemoglobin (P<0.001), Neutrophil to Lymphocyte Ratio (P=0.002), Albumin-To-Alkaline Phosphatase Ratio (P<0.001), Alkaline phosphatase (P=0.005), T stage (P=0.016), and HPV status (P=0.002). In the univariate and multivariate analyses, ALB was found to be an independent prognostic indicator for DFS (HR =0.39, 95% CI:0.23-0.66, P=0.000) and OS (HR =0.46, 95% CI: 0.25-0.83, P=0.01) in OPC patients. CONCLUSIONS Pre-treatment serum ALB could serve as a valuable prognostic biomarker for the prognostic stratification of OPC patients.
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Affiliation(s)
- Jiajia Zhu
- Department of Maxillofacial and Otorhinolaryngology Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China
| | - Liang Li
- Department of Maxillofacial and Otorhinolaryngology Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China
- Department of Otolaryngology, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, China
| | - Yuansheng Duan
- Department of Maxillofacial and Otorhinolaryngology Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China
| | - Yansheng Wu
- Department of Maxillofacial and Otorhinolaryngology Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngology Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China
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Matsui JK, Perlow HK, Ritter AR, Upadhyay R, Raval RR, Thomas EM, Beyer SJ, Pillainayagam C, Goranovich J, Ong S, Giglio P, Palmer JD. Small Molecules and Immunotherapy Agents for Enhancing Radiotherapy in Glioblastoma. Biomedicines 2022; 10:biomedicines10071763. [PMID: 35885067 PMCID: PMC9313399 DOI: 10.3390/biomedicines10071763] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/13/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor that is associated with a poor prognosis and quality of life. The standard of care has changed minimally over the past two decades and currently consists of surgery followed by radiotherapy (RT), concomitant and adjuvant temozolomide, and tumor treating fields (TTF). Factors such as tumor hypoxia and the presence of glioma stem cells contribute to the radioresistant nature of GBM. In this review, we discuss the current treatment modalities, mechanisms of radioresistance, and studies that have evaluated promising radiosensitizers. Specifically, we highlight small molecules and immunotherapy agents that have been studied in conjunction with RT in clinical trials. Recent preclinical studies involving GBM radiosensitizers are also discussed.
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Affiliation(s)
- Jennifer K. Matsui
- College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
| | - Haley K. Perlow
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
| | - Alex R. Ritter
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
| | - Rituraj Upadhyay
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
| | - Raju R. Raval
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
| | - Evan M. Thomas
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
| | - Sasha J. Beyer
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
| | - Clement Pillainayagam
- Department of Neuro-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (C.P.); (J.G.); (S.O.); (P.G.)
| | - Justin Goranovich
- Department of Neuro-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (C.P.); (J.G.); (S.O.); (P.G.)
| | - Shirley Ong
- Department of Neuro-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (C.P.); (J.G.); (S.O.); (P.G.)
| | - Pierre Giglio
- Department of Neuro-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (C.P.); (J.G.); (S.O.); (P.G.)
| | - Joshua D. Palmer
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (H.K.P.); (A.R.R.); (R.U.); (R.R.R.); (E.M.T.); (S.J.B.)
- Correspondence:
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Bejar FG, Oaknin A, Williamson C, Mayadev J, Peters PN, Secord AA, Wield AM, Coffman LG. Novel Therapies in Gynecologic Cancer. Am Soc Clin Oncol Educ Book 2022; 42:1-17. [PMID: 35594502 DOI: 10.1200/edbk_351294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
During the past decade, considerable strides have been made in the understanding and treatment of gynecologic cancers. The advent of PARP inhibitors, antiangiogenic therapies, immunotherapy combinations, and targeted agents have altered the standard of care in ovarian, endometrial, and cervical cancers. However, continued advancement in the treatment of gynecologic cancers is critical. Fortunately, exciting work defining new therapeutic targets and novel treatment strategies is on the horizon. Here, we discuss emerging treatments for gynecologic cancers, including endometrial, cervical, ovarian, and rare gynecologic cancers. We highlight research that has deepened our understanding of the unique biology and molecular underpinnings of these cancers and is being translated into powerful new treatment approaches. We particularly highlight the advent of immunotherapy in endometrial cancer; radiosensitizers in cervical, vaginal, and vulvar cancers; targeted therapies in ovarian cancer; and molecularly driven approaches to treat rare gynecologic cancers. Continued basic, translational, and clinical research holds the promise to change the landscape of gynecologic cancer and improve the lives of all women impacted by these diseases.
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Affiliation(s)
- Francisco Grau Bejar
- Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Ana Oaknin
- Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Casey Williamson
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA
| | - Jyoti Mayadev
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA
| | - Pamela N Peters
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Angeles Alvarez Secord
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Alyssa M Wield
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Hospital, Pittsburgh, PA
| | - Lan G Coffman
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Hospital, Pittsburgh, PA.,Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, PA
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19
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The dogma of Cetuximab and Radiotherapy in head and neck cancer – A dawn to dusk journey. Clin Transl Radiat Oncol 2022; 34:75-81. [PMID: 35356388 PMCID: PMC8958314 DOI: 10.1016/j.ctro.2022.03.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/16/2022] [Accepted: 03/19/2022] [Indexed: 11/21/2022] Open
Abstract
Cetuximab is routinely used in the radical treatment of head and neck cancers. Results of many important studies are out now and are not encouraging. Routine use of Cetuximab in this setting has to be re-evaluated again. Since the introduction of Cetuximab as a biological molecule against Epidermal Growth Factor Receptor (EGFR), its use in the cancers of head and neck region is widely explored. With the recognition that EGFR expression is associated with radioresistance and poor prognosis, incorporation of an anti-EGFR agent along with Radiotherapy (RT) is a logical and attractive option. Cetuximab in combination with RT as Bio-Radiotherapy (BRT) is considered one of the standard treatment modalities in Locally Advanced Head and Neck Squamous Cell Cancers (LA-HNSCC). Many important phase-III clinical trials were undertaken simultaneously, where the use of Cetuximab BRT was tested in various clinical scenarios with different hypothesis. With the studies still ongoing and the results awaited, its use was continued in clinical practice. Today the results are out and definitely not encouraging. After the initial success, Cetuximab has miserably failed to win over cisplatin based chemoradiation which is the current standard of care in LA-HNSCC. Hence, it is the need of the hour to re-evaluate and define the present role of Cetuximab in the definitive management of LA-HNSCC in the light of the latest clinical evidence..
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20
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Marcu LG. Gender and Sex-Related Differences in Normal Tissue Effects Induced by Platinum Compounds. Pharmaceuticals (Basel) 2022; 15:255. [PMID: 35215367 PMCID: PMC8876358 DOI: 10.3390/ph15020255] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 12/18/2022] Open
Abstract
Gender medicine in the field of oncology is an under-researched area, despite the existing evidence towards gender-dependent response to therapy and treatment-induced adverse effects. Oncological treatment aims to fulfil its main goal of achieving high tumour control by also protecting normal tissue from acute or chronic damage. Chemotherapy is an important component of cancer treatment, with a large number of drugs being currently in clinical use. Cisplatin is one of the most commonly employed chemotherapeutic agents, used either as a sole drug or in combination with other agents. Cisplatin-induced toxicities are well documented, and they include nephrotoxicity, neurotoxicity, gastrointestinal toxicity, ototoxicity, just to name the most frequent ones. Some of these toxicities have short-term sequelae, while others are irreversible. Furthermore, research showed that there is a strong gender-dependent aspect of side effects caused by the administration of cisplatin. While evidence towards sex differences in animal models is substantial, clinical studies considering sex/gender as a variable factor are limited. This work summarises the current knowledge on sex/gender-related side effects induced by platinum compounds and highlights the gaps in research that require more attention to open new therapeutic possibilities and preventative measures to alleviate normal tissue toxicity and increase patients' quality of life in both males and females.
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Affiliation(s)
- Loredana G. Marcu
- Faculty of Informatics & Science, Department of Physics, University of Oradea, 410087 Oradea, Romania;
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
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21
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Karlsson H, Fryknäs M, Senkowski W, Larsson R, Nygren P. Selective radiosensitization by nitazoxanide of quiescent clonogenic colon cancer tumour cells. Oncol Lett 2022; 23:123. [PMID: 35261637 PMCID: PMC8867181 DOI: 10.3892/ol.2022.13243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/31/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Henning Karlsson
- Department of Medical Sciences, Genetics and Pathology, Uppsala University, Uppsala S‑751 85, Sweden
| | - Mårten Fryknäs
- Department of Medical Sciences, Genetics and Pathology, Uppsala University, Uppsala S‑751 85, Sweden
| | - Wojciech Senkowski
- Department of Medical Sciences, Genetics and Pathology, Uppsala University, Uppsala S‑751 85, Sweden
| | - Rolf Larsson
- Department of Medical Sciences, Genetics and Pathology, Uppsala University, Uppsala S‑751 85, Sweden
| | - Peter Nygren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala S‑751 85, Sweden
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22
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Charalampakis N, Tsakatikas S, Schizas D, Kykalos S, Tolia M, Fioretzaki R, Papageorgiou G, Katsaros I, Abdelhakeem AAF, Sewastjanow-Silva M, Rogers JE, Ajani JA. Trimodality treatment in gastric and gastroesophageal junction cancers: Current approach and future perspectives. World J Gastrointest Oncol 2022; 14:181-202. [PMID: 35116110 PMCID: PMC8790425 DOI: 10.4251/wjgo.v14.i1.181] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/28/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric and gastroesophageal junction (GEJ) cancers represent an aggressive group of malignancies with poor prognosis even when diagnosed in relatively early stage, with an increasing incidence both in Asia and in Western countries. These cancers are characterized by heterogeneity as a result of different pathogenetic mechanisms as shown in recent molecular analyses. Accordingly, the understanding of phenotypic and genotypic correlations/classifications has been improved. Current therapeutic strategies have also advanced and moved beyond surgical extirpation alone, with the incorporation of other treatment modalities, such as radiation and chemotherapy (including biologics). Chemoradiotherapy has been used as postoperative treatment after suboptimal gastrectomy to ensure local disease control but also improvement in survival. Preoperative chemoradiotherapy/chemotherapy has been employed to increase the chance of a successful R0 resection and pathologic complete response rate, which is associated with improved long-term outcomes. Several studies have defined various chemotherapy regimens to accompany radiation (before and after surgery). Recently, addition of immunotherapy after trimodality of gastroesophageal cancer has produced an advantage in disease-free interval. Targeted agents used in the metastatic setting are being investigated in the early setting with mixed results. The aim of this review is to summarize the existing data on trimodality approaches for gastric and GEJ cancers, highlight the remaining questions and present the current research effort addressing them.
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Affiliation(s)
- Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Dimitrios Schizas
- TheFirst Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Stylianos Kykalos
- TheSecond Propedeutic Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, Heraklion 71110, Greece
| | - Rodanthi Fioretzaki
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Georgios Papageorgiou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Ioannis Katsaros
- Department of General Surgery, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Ahmed Adel Fouad Abdelhakeem
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Matheus Sewastjanow-Silva
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Jane E Rogers
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
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Gomes ER, Franco MS. Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy. Pharmaceutics 2022; 14:pharmaceutics14010105. [PMID: 35057001 PMCID: PMC8781448 DOI: 10.3390/pharmaceutics14010105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is responsible for a significant proportion of death all over the world. Therefore, strategies to improve its treatment are highly desired. The use of nanocarriers to deliver anticancer treatments has been extensively investigated and improved since the approval of the first liposomal formulation for cancer treatment in 1995. Radiotherapy (RT) is present in the disease management strategy of around 50% of cancer patients. In the present review, we bring the state-of-the-art information on the combination of nanocarrier-assisted delivery of molecules and RT. We start with formulations designed to encapsulate single or multiple molecules that, once delivered to the tumor site, act directly on the cells to improve the effects of RT. Then, we describe formulations designed to modulate the tumor microenvironment by delivering oxygen or to boost the abscopal effect. Finally, we present how RT can be employed to trigger molecule delivery from nanocarriers or to modulate the EPR effect.
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Affiliation(s)
- Eliza Rocha Gomes
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil;
| | - Marina Santiago Franco
- Department of Radiation Sciences (DRS), Institute of Radiation Medicine (IRM), 85764 München, Germany
- Correspondence: ; Tel.: +49-89-3187-48767
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24
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Xu HG, Reshetnikov V, Wondrak M, Eckhardt L, Kunz-Schughart LA, Janko C, Tietze R, Alexiou C, Borchardt H, Aigner A, Gong W, Schmitt M, Sellner L, Daum S, Özkan HG, Mokhir A. Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers. Cancers (Basel) 2021; 14:208. [PMID: 35008371 PMCID: PMC8750417 DOI: 10.3390/cancers14010208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5-7.1 µM in human ovarian carcinoma, Burkitt's lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers.
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Affiliation(s)
- Hong-Gui Xu
- Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany; (H.-G.X.); (V.R.); (S.D.); (H.G.Ö.)
| | - Viktor Reshetnikov
- Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany; (H.-G.X.); (V.R.); (S.D.); (H.G.Ö.)
| | - Marit Wondrak
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden—Rossendorf, 01307 Dresden, Germany; (M.W.); (L.E.); (L.A.K.-S.)
| | - Lisa Eckhardt
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden—Rossendorf, 01307 Dresden, Germany; (M.W.); (L.E.); (L.A.K.-S.)
| | - Leoni A. Kunz-Schughart
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden—Rossendorf, 01307 Dresden, Germany; (M.W.); (L.E.); (L.A.K.-S.)
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany
| | - Christina Janko
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universitätsklinikum Erlangen, 91054 Erlangen, Germany; (C.J.); (R.T.); (C.A.)
| | - Rainer Tietze
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universitätsklinikum Erlangen, 91054 Erlangen, Germany; (C.J.); (R.T.); (C.A.)
| | - Christoph Alexiou
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universitätsklinikum Erlangen, 91054 Erlangen, Germany; (C.J.); (R.T.); (C.A.)
| | - Hannes Borchardt
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany; (H.B.); (A.A.)
| | - Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany; (H.B.); (A.A.)
| | - Wenjie Gong
- Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany; (W.G.); (M.S.); (L.S.)
- Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Michael Schmitt
- Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany; (W.G.); (M.S.); (L.S.)
| | - Leopold Sellner
- Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany; (W.G.); (M.S.); (L.S.)
- Takeda Pharmaceuticals, Cambridge, MA 02139, USA
| | - Steffen Daum
- Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany; (H.-G.X.); (V.R.); (S.D.); (H.G.Ö.)
- Merck, Im Laternenacker 5, 8200 Schaffhausen, Switzerland
| | - Hülya Gizem Özkan
- Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany; (H.-G.X.); (V.R.); (S.D.); (H.G.Ö.)
| | - Andriy Mokhir
- Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany; (H.-G.X.); (V.R.); (S.D.); (H.G.Ö.)
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Parmar A, Macluskey M, Mc Goldrick N, Conway DI, Glenny AM, Clarkson JE, Worthington HV, Chan KK. Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy. Cochrane Database Syst Rev 2021; 12:CD006386. [PMID: 34929047 PMCID: PMC8687638 DOI: 10.1002/14651858.cd006386.pub4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Oral cavity and oropharyngeal cancers are the most common cancers arising in the head and neck. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients. This review updates one last published in 2011. OBJECTIVES To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal squamous cell carcinoma results in improved overall survival, improved disease-free survival and/or improved locoregional control, when incorporated as either induction therapy given prior to locoregional treatment (i.e. radiotherapy or surgery), concurrent with radiotherapy or in the adjuvant (i.e. after locoregional treatment with radiotherapy or surgery) setting. SEARCH METHODS An information specialist searched 4 bibliographic databases up to 15 September 2021 and used additional search methods to identify published, unpublished and ongoing studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and that evaluated the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration. DATA COLLECTION AND ANALYSIS For this update, we assessed the new included trials for their risk of bias and at least two authors extracted data from them. Our primary outcome was overall survival (time to death from any cause). Secondary outcomes were disease-free survival (time to disease recurrence or death from any cause) and locoregional control (response to primary treatment). We contacted trial authors for additional information or clarification when necessary. MAIN RESULTS We included 100 studies with 18,813 participants. None of the included trials were at low risk of bias. For induction chemotherapy, we reported the results for contemporary regimens that will be of interest to clinicians and people being treated for oral cavity and oropharyngeal cancers. Overall, there is insufficient evidence to clearly demonstrate a survival benefit from induction chemotherapy with platinum plus 5-fluorouracil prior to radiotherapy (hazard ratio (HR) for death 0.85, 95% confidence interval (CI) 0.70 to 1.04, P = 0.11; 7427 participants, 5 studies; moderate-certainty evidence), prior to surgery (HR for death 1.06, 95% CI 0.71 to 1.60, P = 0.77; 198 participants, 1 study; low-certainty evidence) or prior to concurrent chemoradiation (CRT) with cisplatin (HR for death 0.71, 95% CI 0.37 to 1.35, P = 0.30; 389 participants, 2 studies; low-certainty evidence). There is insufficient evidence to support the use of an induction chemotherapy regimen with cisplatin plus 5-fluorouracil plus docetaxel prior to CRT with cisplatin (HR for death 1.08, 95% CI 0.80 to 1.44, P = 0.63; 760 participants, 3 studies; low-certainty evidence). There is insufficient evidence to support the use of adjuvant chemotherapy over observation only following surgery (HR for death 0.95, 95% CI 0.73 to 1.22, P = 0.67; 353 participants, 5 studies; moderate-certainty evidence). Among studies that compared post-surgical adjuvant CRT, as compared to post-surgical RT, adjuvant CRT showed a survival benefit (HR 0.84, 95% CI 0.72 to 0.98, P = 0.03; 1097 participants, 4 studies; moderate-certainty evidence). Primary treatment with CRT, as compared to radiotherapy alone, was associated with a reduction in the risk of death (HR for death 0.74, 95% CI 0.67 to 0.83, P < 0.00001; 2852 participants, 24 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: The results of this review demonstrate that chemotherapy in the curative-intent treatment of oral cavity and oropharyngeal cancers only seems to be of benefit when used in specific circumstances together with locoregional treatment. The evidence does not show a clear survival benefit from the use of induction chemotherapy prior to radiotherapy, surgery or CRT. Adjuvant CRT reduces the risk of death by 16%, as compared to radiotherapy alone. Concurrent chemoradiation as compared to radiation alone is associated with a greater than 20% improvement in overall survival; however, additional research is required to inform how the specific chemotherapy regimen may influence this benefit.
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Affiliation(s)
- Ambika Parmar
- Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Canada
| | | | | | - David I Conway
- Glasgow Dental School, University of Glasgow, Glasgow, UK
| | - Anne-Marie Glenny
- Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Janet E Clarkson
- Division of Oral Health Sciences, School of Dentistry, University of Dundee, Dundee, UK
| | - Helen V Worthington
- Cochrane Oral Health, Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Kelvin Kw Chan
- Sunnybrook Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada
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26
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Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol 2021; 18:751-772. [PMID: 34326502 DOI: 10.1038/s41571-021-00539-4] [Citation(s) in RCA: 249] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.
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Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy. Int J Mol Sci 2021; 22:ijms222212603. [PMID: 34830482 PMCID: PMC8622791 DOI: 10.3390/ijms222212603] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 01/07/2023] Open
Abstract
Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy.
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28
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Commander CW, Mauro DM. Current Approach to Planning Angiography and MAA Administration. Semin Intervent Radiol 2021; 38:397-404. [PMID: 34629705 DOI: 10.1055/s-0041-1735616] [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: 10/20/2022]
Abstract
Transarterial radioembolization of primary and secondary hepatic malignancies utilizing yttrium-90 microspheres is a commonly performed treatment by interventional radiologists. Traditionally performed as a two-part procedure, a diagnostic angiography is performed 1 to 3 weeks prior to treatment with the injection of technetium-99m-macroaggregated albumin followed by planar scintigraphy in the nuclear medicine department. Careful attention must be paid to the details during the diagnostic angiography to ensure the delivery of a safe and optimal dose to the diseased liver and to minimize radiation-induced damage to both unaffected liver and adjacent structures. In this article, we will review the steps and considerations that must be made during the angiography planning and discuss current and future areas of research.
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Affiliation(s)
- Clayton W Commander
- Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - David M Mauro
- Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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29
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McDonald J, Chuang CY, Hicks JK, Berry DK, Imanirad I, Rishi A, Frakes JM, Hoffe SE, Felder S. FANCD2 Mutation in a Patient With Early Rectal Cancer Receiving Definitive Chemoradiation. Adv Radiat Oncol 2021; 6:100717. [PMID: 34258475 PMCID: PMC8260782 DOI: 10.1016/j.adro.2021.100717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/13/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Affiliation(s)
| | | | | | | | | | | | | | | | - Seth Felder
- Surgical Oncology, Moffitt Cancer Center, Tampa, Florida
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Mariam NBG, Song YP, Joseph N, Hoskin P, Reeves K, Porta N, James N, Choudhury A. Hypofractionation: less is more? Oncotarget 2021; 12:1729-1733. [PMID: 34434502 PMCID: PMC8378765 DOI: 10.18632/oncotarget.28023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 12/03/2022] Open
Abstract
One third of patients with bladder cancer present with muscle invasive bladder cancer (MIBC) which has a poor prognosis. International guidelines for the management of MIBC recommend radical cystectomy or bladder-preserving treatment based on radical radiotherapy with a form of radiosensitisation. In the UK, both conventional fractionation with 64 Gy in 32 fractions and hypofractionation with 55 Gy in 20 fractions are standard of care options with the choice varying between centres. A meta-analysis of individual patients with locally advanced bladder cancer from two UK multicentre phase 3 trials was published recently. This study evaluated the non-inferiority of a hypofractionated schedule compared to a conventional regime. This analysis confirmed the non-inferiority of the hypofractionated regimen, and noted superior locoregional control. We discuss the relevance of these findings to current practice while considering the radiobiology of hypofractionation, the role of systemic therapies and radiosensitisation, as well as the socioeconomic benefits.
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Affiliation(s)
| | - Yee Pei Song
- Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | | | - Peter Hoskin
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Mount Vernon Cancer Centre, Northwood, UK
| | - Kimberley Reeves
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Nuria Porta
- Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK
| | - Nicholas James
- Prostate and Bladder Cancer Research Team, The Institute of Cancer Research, London, UK
| | - Ananya Choudhury
- Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Rim CH, Park S, Shin IS, Yoon WS. Is the Concurrent Use of Sorafenib and External Radiotherapy Feasible for Advanced Hepatocellular Carcinoma? A Meta-Analysis. Cancers (Basel) 2021; 13:2912. [PMID: 34200809 PMCID: PMC8230463 DOI: 10.3390/cancers13122912] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 02/07/2023] Open
Abstract
We evaluate the feasibility of a concurrent application of sorafenib and external beam radiation therapy (EBRT) for advanced hepatocellular carcinoma (HCC). PubMed, Embase, Medline, and Cochrane Library were searched up to 9 April 2021. The primary endpoint was grade ≥3 complications, and the secondary endpoint was overall survival (OS). Subgroup analyses were performed for studies with the EBRT targets, intrahepatic vs. non-intrahepatic lesions (e.g., extrahepatic metastases or malignant vessel involvement only). Eleven studies involving 512 patients were included in this meta-analysis. Pooled rates of gastrointestinal, hepatologic, hematologic, and dermatologic grade ≥3 toxicities were 8.1% (95% confidence interval (CI): 4.8-13.5, I2 = ~0%), 12.9% (95% CI: 7.1-22.1, I2 = 22.4%), 9.1% (95% CI: 3.8-20.3, I2 = 51.3%), and 6.8% (95% CI: 3.8-11.7, I2 = ~0%), respectively. Pooled grade ≥3 hepatologic and hematologic toxicity rates were lower in studies targeting non-intrahepatic lesions than those targeting intrahepatic lesions (hepatologic: 3.3% vs. 17.1%, p = 0.041; hematologic: 3.3% vs. 16.0%, p = 0.078). Gastrointestinal and dermatologic grade ≥3 complications were not significantly different between the subgroups. Regarding OS, concurrent treatment was more beneficial than non-concurrent treatment (odds ratio: 3.3, 95% CI: 1.3-8.59, p = 0.015). One study reported a case of lethal toxicity due to tumor rupture and gastrointestinal bleeding. Concurrent treatment can be considered and applied to target metastatic lesions or local vessel involvement. Intrahepatic lesions should be treated cautiously by considering the target size and hepatic reserve.
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Affiliation(s)
- Chai Hong Rim
- Department of Radiation Oncology, Ansan Hospital, Korea University Medical College, Ansan 15355, Korea; (S.P.); (W.S.Y.)
| | - Sunmin Park
- Department of Radiation Oncology, Ansan Hospital, Korea University Medical College, Ansan 15355, Korea; (S.P.); (W.S.Y.)
| | - In-Soo Shin
- Graduate School of Education, Dongguk University, Seoul 04620, Korea;
| | - Won Sup Yoon
- Department of Radiation Oncology, Ansan Hospital, Korea University Medical College, Ansan 15355, Korea; (S.P.); (W.S.Y.)
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Ke CC, Li JJ, Wu HP, Kuo WW, Chen YA, Lu CH, Wang HE, Hsu SM, Hsieh YJ, Liu RS. Enhancement of IUdR Radiosensitization in Cancer Therapy by Low-Energy Transmission X Ray Irradiation. J Med Biol Eng 2021. [DOI: 10.1007/s40846-021-00616-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Sarkar RR, Hatamipour A, Panjwani N, Courtney PT, Cherry DR, Salans MA, Yip AT, Rose BS, Simpson DR, Banegas MP, Murphy JD. Impact of Radiation on Cardiovascular Outcomes in Older Resectable Esophageal Cancer Patients With Medicare. Am J Clin Oncol 2021; 44:275-282. [PMID: 33782335 PMCID: PMC8141011 DOI: 10.1097/coc.0000000000000815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Preoperative radiotherapy improves outcomes for operable esophageal cancer patients, though the proximity of the heart to the esophagus puts patients at risk of radiation-induced cardiovascular disease. This study characterizes the impact of radiotherapy and different radiation techniques on cardiovascular morbidity among a cohort of esophageal cancer patients. MATERIALS AND METHODS We identified 1125 patients aged 65 and older diagnosed between 2000 and 2011 with esophageal cancer who received surgery alone, or surgery preceded by either preoperative chemotherapy or preoperative chemoradiation from the Surveillance Epidemiology and End Results (SEER)-Medicare database. We used Medicare claims to identify severe perioperative and late cardiovascular events. Multivariable logistic regression and Fine-Gray models were used to determine the effect of presurgery treatment on the risk of perioperative and late cardiovascular disease. RESULTS Preoperative chemotherapy or chemoradiation did not significantly increase the risk of perioperative cardiovascular complications compared with surgery alone. Patients treated with preoperative chemoradiation had a 36% increased risk of having a late cardiovascular event compared with patients treated with surgery alone (subdistribution hazard ratio [SDHR]: 1.36; P=0.035). There was no significant increase in late cardiovascular events among patients treated with preoperative chemotherapy (SDHR: 1.18; P=0.40). Among patients treated with preoperative chemoradiation, those receiving intensity modulated radiotherapy had a 68% decreased risk of having a late cardiovascular event compared with patients receiving conventional radiation (SDHR: 0.32; P=0.007). CONCLUSIONS This study demonstrates an increased risk of cardiovascular complications among operative esophageal cancer patients treated with preoperative chemoradiation, though these risks might be reduced with more cardioprotective radiation techniques such as intensity modulated radiotherapy.
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Affiliation(s)
- Reith R Sarkar
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Ahmadreza Hatamipour
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Neil Panjwani
- Department of Radiation Oncology, Stanford University, Stanford, CA
| | - P Travis Courtney
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Daniel R Cherry
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Mia A Salans
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Anthony T Yip
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Brent S Rose
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Daniel R Simpson
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
| | - Matthew P Banegas
- Center for Health Research, Kaiser Permanente Northwest, Portland, OR
| | - James D Murphy
- University of California San Diego School of Medicine
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla
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Manoharan D, Chang LC, Wang LC, Shan YS, Lin FC, Wu LC, Sheu HS, Su WP, Yeh CS. Synchronization of Nanoparticle Sensitization and Radiosensitizing Chemotherapy through Cell Cycle Arrest Achieving Ultralow X-ray Dose Delivery to Pancreatic Tumors. ACS NANO 2021; 15:9084-9100. [PMID: 33974409 DOI: 10.1021/acsnano.1c02283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Pancreatic cancer is among the leading causes of cancer-related death and remains a formidable therapeutic challenge. To date, surgical resection and chemotherapy have been the standards of care. Methotrexate (MTX), which is recognized as a refractory drug for pancreatic cells, was conjugated to the surface of LiYF4:Ce3+ nanoparticles (NP-MTX) through a photocleavable linker molecule. When LiYF4:Ce3+ NPs are stimulated by X-rays, they emit light, which induces the photocleavage of the photolabile linker molecule to release MTX. MTX can target pancreatic tumors, which overexpress folic acid (FA) receptors and are internalized into the cell through receptor-mediated endocytosis. The synergistic effect of the NP-MTX treatment initiated by X-ray irradiation occurs due to the combination of nanoparticle sensitization and the radiosensitizing chemotherapy of the photocleaved MTX molecule. This dual sensitization effect mediated by NP-MTX enabled 40% dose enhancement, which corresponded with an increase in the generation of cytotoxic cellular reactive oxygen species (ROS) and enhanced S phase arrest within the cell cycle. The delivery of an ultralow radiation dose of 0.1 Gy resulted in the photocleavage of MTX from NP-MTX, and this strategy demonstrated in vivo efficacy against AsPC-1 and PANC-1 xenografted pancreatic tumors.
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Affiliation(s)
- Divinah Manoharan
- Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
| | - Li-Chan Chang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Liu-Chun Wang
- Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Forn-Chia Lin
- Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Lai-Chin Wu
- National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan
| | - Hwo-Shuenn Sheu
- National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan
| | - Wen-Pin Su
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Departments of Oncology and Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Chen-Sheng Yeh
- Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Yedekci Y, Gedik E, Evis Z, Dogan L, Özyigit G, Gürkaynak M. Radiosensitization induced by zinc‐doped hydroxyapatite nanoparticles in breast cancer cells. INTERNATIONAL JOURNAL OF APPLIED CERAMIC TECHNOLOGY 2021; 18:563-572. [DOI: 10.1111/ijac.13707] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 12/22/2020] [Indexed: 04/07/2025]
Abstract
AbstractZinc‐doped hydroxyapatite (HA) nanoparticles were synthesized by microwave assisted method and used with ionizing radiation for inhibition of proliferation of breast cancer cells. Zinc‐doped HAs were produced in four different compositions in order to determine the best doping rate in terms of physical and biological properties. Nanoparticle characterizations were performed with X‐ray diffractometer, Fourier transform infrared spectroscopy, scanning electron microscopy, and inductively coupled plasma‐mass spectrometry. Viability of MDA‐MB‐231(isolated at M D Anderson from a pleural effusion of a patient with invasive ductal carcinoma) cells treated with nano‐HA particles and radiation were assessed by MTT assay. Caspase‐7 and Poly (ADP‐ribose) polymerase protein expressions in samples were examined by the Western blot. X‐ray diffraction patterns of our samples were found to be in good correlation with the reference HA peaks. Notably, increasing zinc amount resulted in elevated percentage of β‐tricalcium phosphate, phases. All formulations including pure HA particles were non‐cytotoxic in MDA MB 231 cells. On the other hand, low rate Zn‐doped HA particles showed significant anti‐proliferation effect during irradiation. The combination of irradiation with Zn‐doped HA particles also induced apoptosis, demonstrated as cleavage of caspase‐7 and PARP proteins. In conclusion, low rate Zn‐doped HA enhanced the radiation effect on breast cancer cells.
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Affiliation(s)
- Yagiz Yedekci
- Department of Radiation Oncology Faculty of Medicine Hacettepe University Ankara Turkey
| | - Emre Gedik
- Department of Basic Oncology Cancer Institute Hacettepe University Ankara Turkey
| | - Zafer Evis
- Department of Engineering Sciences Middle East Technical University Ankara Turkey
| | - Lale Dogan
- Department of Basic Oncology Cancer Institute Hacettepe University Ankara Turkey
| | - Gökhan Özyigit
- Department of Radiation Oncology Faculty of Medicine Hacettepe University Ankara Turkey
| | - Murat Gürkaynak
- Department of Radiation Oncology Faculty of Medicine Hacettepe University Ankara Turkey
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Witt JS, Wisinski KB, Anderson BM. Concurrent Radiation and Modern Systemic Therapies for Breast Cancer: An Ever-Expanding Frontier. Clin Breast Cancer 2021; 21:120-127. [PMID: 34030859 DOI: 10.1016/j.clbc.2020.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/28/2020] [Indexed: 11/29/2022]
Abstract
Radiotherapy is a critical tool for reducing locoregional recurrence, extending survival, and palliating symptoms in patients with breast cancer. With an ever-expanding armamentarium of systemic agents available, and an increasing trend toward the use of hypofractionated radiation regimens, it can be difficult to determine the safety of concurrent therapy. In particular, new targeted agents in both the adjuvant and metastatic setting have limited prospective or long-term data demonstrating safety when delivered concurrently with radiotherapy. Other systemic agents, including chemotherapy and endocrine therapy, are also important components of the overall treatment strategy for localized and metastatic breast cancer, and are often delivered concurrently with radiation in certain clinical scenarios. This review explores the safety, efficacy, and pitfalls of delivering radiation in conjunction with systemic therapies for breast cancer.
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Affiliation(s)
- Jacob S Witt
- Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Kari B Wisinski
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Carbone Cancer Center, University of Wisconsin, Madison, WI
| | - Bethany M Anderson
- Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI; Carbone Cancer Center, University of Wisconsin, Madison, WI.
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Combining Gold Nanoparticles with Other Radiosensitizing Agents for Unlocking the Full Potential of Cancer Radiotherapy. Pharmaceutics 2021; 13:pharmaceutics13040442. [PMID: 33805917 PMCID: PMC8064393 DOI: 10.3390/pharmaceutics13040442] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 11/29/2022] Open
Abstract
About half of cancer patients (50%) receive radiotherapy (RT) for the treatment of local tumors. However, one of the main obstacles in RT is the close proximity of adjacent organs at risk, resulting in treatment doses being limited by significant tissue toxicity, hence preventing the necessary dose escalation that would guarantee local control. Effective local cancer therapy is needed to avoid progression of tumors and to decrease the development of systemic metastases which may further increase the possibility of resection. In an effort to do so, radiosensitizing agents are introduced to further increase damage to the tumor while minimizing normal tissue toxicity. Cisplatin and docetaxel (DTX) are currently being used as radiation dose enhancers in RT. Recent research shows the potential of gold nanoparticles (GNPs) as a radiosensitizing agent. GNPs are biocompatible and have been tested in phase I clinical trials. The focus will be on exploring the effects of adding other radiosensitizing agents such as DTX and cisplatin to the GNP-RT platform. Therefore, a combined use of local radiosensitizing agents, such as GNPs, with currently available radiosensitizing drugs could make a significant impact in future RT. The ultimate goal is to develop treatments that have limited or nonexistent side effects to improve the quality of life of all cancer patients.
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38
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Why Concurrent CDDP and Radiotherapy Has Synergistic Antitumor Effects: A Review of In Vitro Experimental and Clinical-Based Studies. Int J Mol Sci 2021; 22:ijms22063140. [PMID: 33808722 PMCID: PMC8003508 DOI: 10.3390/ijms22063140] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/08/2021] [Accepted: 03/17/2021] [Indexed: 01/17/2023] Open
Abstract
Chemo-radiotherapy, which combines chemotherapy with radiotherapy, has been clinically practiced since the 1970s, and various anticancer drugs have been shown to have a synergistic effect when used in combination with radiotherapy. In particular, cisplatin (CDDP), which is often the cornerstone of multi-drug combination cancer therapies, is highly versatile and frequently used in combination with radiotherapy for the treatment of many cancers. Therefore, the mechanisms underlying the synergistic effect of CDDP and radiotherapy have been widely investigated, although no definitive conclusions have been reached. We present a review of the combined use of CDDP and radiotherapy, including the latest findings, and propose a mechanism that could explain their synergistic effects. Our hypothesis involves the concepts of overlap and complementation. “Overlap” refers to the overlapping reactions of CDDP and radiation-induced excessive oxidative loading, which lead to accumulating damage to cell components, mostly within the cytoplasm. “Complementation” refers to the complementary functions of CDDP and radiation that lead to DNA damage, primarily in the nucleus. In fact, the two concepts are inseparable, but conceptualizing them separately will help us understand the mechanism underlying the synergism between radiation therapy and other anticancer drugs, and help us to design future radiosensitizers.
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Chuang FC, Wang CC, Chen JH, Hwang TZ, Yeh SA, Su YC. PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy. PLoS One 2021; 16:e0245715. [PMID: 33471836 PMCID: PMC7817006 DOI: 10.1371/journal.pone.0245715] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 01/04/2021] [Indexed: 11/26/2022] Open
Abstract
Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC.
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Affiliation(s)
- Fu-Cheng Chuang
- Department of Radiation Oncology, E-Da Hospital, Kaohsiung, Taiwan
- Department of Medicine, School of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chih-Chun Wang
- Department of Medicine, School of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Otolaryngology, E-Da Hospital, Kaohsiung, Taiwan
| | - Jian-Han Chen
- Department of Medicine, School of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of General Surgery, E-Da Hospital, Kaohsiung, Taiwan
| | - Tzer-Zen Hwang
- Department of Medicine, School of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Otolaryngology, E-Da Hospital, Kaohsiung, Taiwan
| | - Shyh-An Yeh
- Department of Radiation Oncology, E-Da Hospital, Kaohsiung, Taiwan
- Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung City, Taiwan
| | - Yu-Chieh Su
- Department of Medicine, School of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Hematology-Oncology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
- * E-mail:
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40
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Hiraki M, Tanaka T, Hiraki Y, Watanabe T, Sato H, Aibe H, Kitahara K. Short-term outcomes of preoperative chemoradiotherapy with S-1 for locally advanced rectal cancer. Mol Clin Oncol 2020; 14:4. [PMID: 33235732 DOI: 10.3892/mco.2020.2166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 09/09/2020] [Indexed: 01/01/2023] Open
Abstract
The purpose of the present study was to evaluate the short-term results of preoperative chemoradiation therapy with S-1 for locally advanced rectal cancer. A total of 32 patients with advanced rectal cancer who had been treated with preoperative chemoradiotherapy with S-1 and underwent surgical resection between May 2012 and December 2019 were analyzed. Advanced rectal cancer of clinical stage II and III was diagnosed in 13 (41%) and 19 (59%) patients, respectively. Therapeutic toxicities of anemia (24 patients; 75%), anal pain (22 patients; 69%) and skin and subcutaneous tissue disorders (19 patients; 59%) were frequently observed in all grades. Grade ≥3 leukopenia, anemia, neutrophil count reduction, platelet count reduction and diarrhea were identified in 2 (6%), 1 (3%), 1 (3%), 1 (3%) and 1 (3%) patients, respectively. A total of 29 patients (91%) completed this therapy without any change to the protocol or dosage. R0 resection was performed in 100% of the patients, and no postoperative mortality was observed. Pathological complete response was observed in 9 cases (28.1%). This therapy can be considered for cases of locally advanced rectal cancer due to its acceptable toxicity and relatively high antitumor effect.
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Affiliation(s)
- Masatsugu Hiraki
- Department of Surgery, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
| | - Toshiya Tanaka
- Department of Surgery, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
| | - Yoshiki Hiraki
- Department of Radiology, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
| | - Tetsuo Watanabe
- Department of Radiology, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
| | - Hirofumi Sato
- Department of Surgery, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
| | - Hitoshi Aibe
- Department of Radiology, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
| | - Kenji Kitahara
- Department of Surgery, Saga Medical Center Koseikan, Kasemachi, Saga 840-8571, Japan
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Bartoli M, Jagdale P, Tagliaferro A. A Short Review on Biomedical Applications of Nanostructured Bismuth Oxide and Related Nanomaterials. MATERIALS (BASEL, SWITZERLAND) 2020; 13:E5234. [PMID: 33228140 PMCID: PMC7699380 DOI: 10.3390/ma13225234] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022]
Abstract
In this review, we reported the main achievements reached by using bismuth oxides and related materials for biological applications. We overviewed the complex chemical behavior of bismuth during the transformation of its compounds to oxide and bismuth oxide phase transitions. Afterward, we summarized the more relevant studies regrouped into three categories based on the use of bismuth species: (i) active drugs, (ii) diagnostic and (iii) theragnostic. We hope to provide a complete overview of the great potential of bismuth oxides in biological environments.
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Affiliation(s)
- Mattia Bartoli
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy;
- Italian Institute of Technology, Via Livorno 60, 10144 Torino, Italy
| | - Pravin Jagdale
- Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), Via G. Giusti 9, 50121 Florence, Italy;
| | - Alberto Tagliaferro
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy;
- Italian Institute of Technology, Via Livorno 60, 10144 Torino, Italy
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Park M, Kwon J, Shin HJ, Moon SM, Kim SB, Shin US, Han YH, Kim Y. Butyrate enhances the efficacy of radiotherapy via FOXO3A in colorectal cancer patient‑derived organoids. Int J Oncol 2020; 57:1307-1318. [PMID: 33173975 PMCID: PMC7646587 DOI: 10.3892/ijo.2020.5132] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/22/2020] [Indexed: 12/19/2022] Open
Abstract
Enhancing the radioresponsiveness of colorectal cancer (CRC) is essential for local control and prognosis. However, consequent damage to surrounding healthy cells can lead to treatment failure. We hypothesized that short‑chain fatty acids (SCFAs) could act as radiosensitizers for cancer cells, allowing the administration of a lower and safer dose of radiation. To test this hypothesis, the responses of three‑dimensional‑cultured organoids, derived from CRC patients, to radiotherapy, as well as the effects of combined radiotherapy with the SCFAs butyrate, propionate and acetate as candidate radiosensitizers, were evaluated via reverse transcription‑quantitative polymerase chain reaction, immunohistochemistry and organoid viability assay. Of the three SCFAs tested, only butyrate suppressed the proliferation of the organoids. Moreover, butyrate significantly enhanced radiation‑induced cell death and enhanced treatment effects compared with administration of radiation alone. The radiation‑butyrate combination reduced the proportion of Ki‑67 (proliferation marker)‑positive cells and decreased the number of S phase cells via FOXO3A. Meanwhile, 3/8 CRC organoids were found to be non‑responsive to butyrate with lower expression levels of FOXO3A compared with the responsive cases. Notably, butyrate did not increase radiation‑induced cell death and improved regeneration capacity after irradiation in normal organoids. These results suggest that butyrate could enhance the efficacy of radiotherapy while protecting the normal mucosa, thus highlighting a potential strategy for minimizing the associated toxicity of radiotherapy.
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Affiliation(s)
- Misun Park
- Department of Radiological and Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Junhye Kwon
- Department of Radiological and Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Hye-Jin Shin
- Department of Radiological and Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Sun Mi Moon
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Sang Bum Kim
- Department of Radiological and Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Ui Sup Shin
- Department of Radiological and Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Young-Hoon Han
- Department of Radiological and Medico‑Oncological Sciences, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Younjoo Kim
- Department of Radiological and Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
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Kim KH, Kim HS, Kim SC, Kim D, Kim YB, Chung HC, Rha SY. Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells. Front Oncol 2020; 10:562284. [PMID: 33042843 PMCID: PMC7517358 DOI: 10.3389/fonc.2020.562284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/18/2020] [Indexed: 12/24/2022] Open
Abstract
Background Despite the important role of radiotherapy in cancer treatment, a subset of patients responds poorly to treatment majorly due to radioresistance. Particularly the role of radiotherapy has not been established in gastric cancer (GC). Herein, we aimed to identify a radiosensitivity gene signature and to discover relevant targets to enhance radiosensitivity in GC cells. Methods An oligonucleotide microarray (containing 22,740 probes) was performed in 12 GC cell lines prior to radiation. A clonogenic assay was performed to evaluate the survival fraction at 2 Gy (SF2) as a surrogate marker for radiosensitivity. Genes differentially expressed (fold change > 6, q-value < 0.025) were identified between radiosensitive and radioresistant cell lines, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for validation. Gene set and pathway analyses were performed using Ingenuity Pathway Analysis (IPA). Results Radiosensitive (SF2 < 0.4) and radioresistant cell lines (SF2 ≥ 0.6) exhibited a marked difference in gene expression. We identified 68 genes that are differentially expressed between radiosensitive and radioresistant cell lines. The identified genes showed interactions via AKT, HIF1A, TGFB1, and TP53, and their functions were associated with the genetic networks associated with cellular growth and proliferation, cellular movement, and cell cycle. The Akt signaling pathway exhibited the highest association with radiosensitivity. Combinatorial treatment with MK-2206, an allosteric Akt inhibitor, and radiotherapy significantly increased cell death compared with radiotherapy alone in two radioresistant cell lines (YCC-2 and YCC-16). Conclusion We identified a GC-specific radiosensitivity gene signature and suggest that the Akt signaling pathway could serve as a therapeutic target for GC radiosensitization.
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Affiliation(s)
- Kyung Hwan Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Sang Cheol Kim
- Division of Biomedical Informatics, Center for Genome Science, National Institute of Health, KCDC, Cheongju, South Korea
| | - DooA Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong Bae Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyun Cheol Chung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Sun Young Rha
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
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Long-term analysis of multimodality treatment outcomes and prognosis of esthesioneuroblastomas: a single center results of 138 patients. Radiat Oncol 2020; 15:219. [PMID: 32948223 PMCID: PMC7501706 DOI: 10.1186/s13014-020-01667-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
Background The aim of this study is to evaluate the efficacy of different treatment strategies and the potential prognostic factors of esthesioneuroblastoma (ENB). Materials and methods Between April 1984 and December 2018, 138 patients with non-metastatic ENB were retrospectively analyzed. The treatment modalities mainly included surgery alone (n = 7), radiotherapy alone (n = 33), concurrent chemoradiotherapy (n = 17), surgery combined with current chemoradiotherapy (n = 32), and surgery plus radiotherapy (n = 49). Results The median follow-up time for the entire cohort was 61 months (range, 4–231 months). The 5-year overall survival (OS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) rate were 69.6, 78.0 and 73.9%, respectively. Surgery combined with radiotherapy elicited superior survival results, and the combination of surgery and current chemoradiotherapy achieved the best prognoses for all patients, patients with advanced Kadish disease, patients receiving intensity modulated radiation therapy and those with positive surgical margin. Univariate analysis identified orbital invasion and treatment modalities were predictors for OS, LRFFS and DMFS. Lymph node metastasis was associated with OS and DMFS, but not LRFFS. Intracranial invasion, advanced Kadish stage and not receiving concurrent chemotherapy were also predictive of lower OS. Multivariate analyses indicated that lymph node metastasis was an independent prognostic factor affecting DMFS, whereas treatment modalities was independent prognostic factors for OS and LRFFS. Conclusion Orbital invasion, intracranial invasion, lymph node metastasis and advanced Kadish disease at initial diagnosis were significantly associated with inferior prognosis. Regarding the treatment modality, the optimal strategy remined surgery with radiotherapy-based multimodality treatment. The concurrent chemoradiotherapy may play a more beneficial role.
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Ali MY, Oliva CR, Noman ASM, Allen BG, Goswami PC, Zakharia Y, Monga V, Spitz DR, Buatti JM, Griguer CE. Radioresistance in Glioblastoma and the Development of Radiosensitizers. Cancers (Basel) 2020; 12:E2511. [PMID: 32899427 PMCID: PMC7564557 DOI: 10.3390/cancers12092511] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/24/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
Ionizing radiation is a common and effective therapeutic option for the treatment of glioblastoma (GBM). Unfortunately, some GBMs are relatively radioresistant and patients have worse outcomes after radiation treatment. The mechanisms underlying intrinsic radioresistance in GBM has been rigorously investigated over the past several years, but the complex interaction of the cellular molecules and signaling pathways involved in radioresistance remains incompletely defined. A clinically effective radiosensitizer that overcomes radioresistance has yet to be identified. In this review, we discuss the current status of radiation treatment in GBM, including advances in imaging techniques that have facilitated more accurate diagnosis, and the identified mechanisms of GBM radioresistance. In addition, we provide a summary of the candidate GBM radiosensitizers being investigated, including an update of subjects enrolled in clinical trials. Overall, this review highlights the importance of understanding the mechanisms of GBM radioresistance to facilitate the development of effective radiosensitizers.
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Affiliation(s)
- Md Yousuf Ali
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA;
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; (C.R.O.); (B.G.A.); (P.C.G.); (D.R.S.)
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Claudia R. Oliva
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; (C.R.O.); (B.G.A.); (P.C.G.); (D.R.S.)
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Abu Shadat M. Noman
- Department of Biochemistry and Molecular Biology, The University of Chittagong, Chittagong 4331, Bangladesh;
- Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Bryan G. Allen
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; (C.R.O.); (B.G.A.); (P.C.G.); (D.R.S.)
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Prabhat C. Goswami
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; (C.R.O.); (B.G.A.); (P.C.G.); (D.R.S.)
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Yousef Zakharia
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA; (Y.Z.); (V.M.)
| | - Varun Monga
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA; (Y.Z.); (V.M.)
| | - Douglas R. Spitz
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; (C.R.O.); (B.G.A.); (P.C.G.); (D.R.S.)
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - John M. Buatti
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Corinne E. Griguer
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; (C.R.O.); (B.G.A.); (P.C.G.); (D.R.S.)
- Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
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Zhang X, Wang F, Zeng Y, Zhu X, Peng L, Zhang L, Gu J, Han H, Yi X, Shi J. Salicylate sensitizes oral squamous cell carcinoma to chemotherapy through targeting mTOR pathway. Oral Dis 2020; 26:1131-1140. [PMID: 32267053 DOI: 10.1111/odi.13345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 11/30/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is an extremely aggressive neoplasm, which is usually diagnosed in the advanced stage of the disease. Extensive studies have shown a link between chronic inflammation and various types of cancer, including OSCC. Salicylate is a biotransformation product of aspirin, with similar anti-inflammatory ability to aspirin but lacks aspirin's inhibitory effect on the isolated cyclooxygenase activity. Our study indicates that salicylate sensitizes OSCC to anti-cancer drugs, but the mechanisms of its action are unclear. Here, OSCC cells were used to evaluate the cytotoxicity of salicylate alone or in combination with cisplatin (CDDP). RPPA proteomic array and Western blotting were employed to determine the signaling pathways affected by salicylate. Salicylate decreased cell survival rate and induced cell apoptosis in OSCC cells but not human normal oral mucosal epithelial cells (hTERT-OME). The use of sodium salicylate (SS) dramatically sensitized OSCC cells to CDDP. RPPA array showed that SS reduced many oncogenes such as PI3K/mTOR signaling and cancer stem cell (CSC)-related genes versus control. Western and transcriptional analyses substantiated that salicylate down-regulated these CSC-associated genes and the mTOR pathway dose dependently. Salicylate preferentially repressed the ability of sorted ALDH1+ cells to form tumor spheres. Finally, salicylate suppressed tumor growth in vivo, and the combination of salicylate and CDDP further synergistically reduced the growth of tumors. Salicylate hinders OSCC cell growth and sensitizes OSCC cells to CDDP through targeting CSCs and the mTOR signaling pathway. We propose that salicylate is beneficial for OSCC patients, and salicylate may be combined with chemotherapies to effectively treat OSCC patients.
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Affiliation(s)
- Xu Zhang
- Department of Stomatology, Wuchang Hospital, Wuhan City, China
| | - Fei Wang
- Department of Neurosurgery, Tongji Hospital, Tongji University, Shanghai, China
| | - Yu Zeng
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Xuyou Zhu
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Lin Peng
- Department of Dermatology, Tongji Hospital, Tongji University, Shanghai, China
| | - Long Zhang
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Jun Gu
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Hongxiu Han
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Xianghua Yi
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Juanhong Shi
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
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Tabei M, Zeinizade E, Beik J, Kamrava SK, Nasiri Z, Ghaznavi H, Shakeri-Zadeh A. Insights into Nano-Photo-Thermal Therapy of Cancer: The Kinetics of Cell Death and Effect on Cell Cycle. Anticancer Agents Med Chem 2020; 20:612-621. [DOI: 10.2174/1871520620666200129111332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 10/31/2019] [Accepted: 11/12/2019] [Indexed: 11/22/2022]
Abstract
Background:
Despite considerable advances in nano-photo-thermal therapy (NPTT), there have been
a few studies reporting in-depth kinetics of cell death triggered by such a new modality of cancer treatment.
Objective:
In this study, we aimed to (1) investigate the cell death pathways regulating the apoptotic responses
to NPTT; and (2) ascertain the effect of NPTT on cell cycle progression.
Methods:
Folate conjugated gold nanoparticle (F-AuNP) was firstly synthesized, characterized and then assessed
to determine its potentials in targeted NPTT. The experiments were conducted on KB nasopharyngeal
cancer cells overexpressing folate receptors (FRs), as the model, and L929 normal fibroblast cells with a low
level of FRs, as the control. Cytotoxicity was evaluated by MTT assay and the cell death mode (i.e., necrosis or
apoptosis) was determined through AnnexinV/FITC-propidium iodide staining. Next, the gene expression profiles
of some key apoptotic factors involved in the mitochondrial signaling pathway were investigated using
RT-qPCR. Finally, cell cycle phase distribution was investigated at different time points post NPTT using flow
cytometric analysis.
Results:
The obtained results showed that KB cell death following targeted NPTT was greater than that observed
for L929 cells. The majority of KB cell death following NPTT was related to apoptosis. RT-qPCR analysis
indicated that the elevated expression of Bax along with the depressed expression of Bcl-xL, Survivin and
XIAP may involve in the regulation of apoptosis in response to NPTT. Flow cytometric analysis manifested that
16-24 hours after NPTT, the major proportion of KB cells was in the most radiosensitive phases of the cell cycle
(G2/M).
Conclusion:
This study extended the understanding of the signaling pathway involved in the apoptotic response
to NPTT. Moreover, the potential effect of NPTT on sensitizing cancer cells to subsequent radiation therapy was
highlighted.
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Affiliation(s)
- Mousa Tabei
- Medical Physics Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Elham Zeinizade
- Medical Physics Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Jaber Beik
- Medical Physics Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - S. Kamran Kamrava
- ENT and Head & Neck Research Center and Department, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Zahra Nasiri
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Habib Ghaznavi
- Department of Pharmaceutical Research Centre, Zahedan University of Medical Sciences (ZaUMS), Zahedan, Iran
| | - Ali Shakeri-Zadeh
- Medical Physics Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
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Zhang Q, Kong Y, Yang Z, Liu Y, Liu R, Geng Y, Luo H, Zhang H, Li H, Feng S, Wang X. Preliminary study on radiosensitivity to carbon ions in human breast cancer. JOURNAL OF RADIATION RESEARCH 2020; 61:399-409. [PMID: 32239160 PMCID: PMC7299270 DOI: 10.1093/jrr/rraa017] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 09/24/2019] [Accepted: 03/10/2020] [Indexed: 05/11/2023]
Abstract
The aim of the study was to investigate the various effects of high linear energy transfer (LET) carbon ion (12C6+) and low LET X-ray radiation on MDA-MB-231 and MCF-7 human breast cancer cells and to explore the underlying mechanisms of radiation sensitivity. Cell proliferation, cell colony formation, cell cycle distribution, cell apoptosis and protein expression levels [double-strand break marker γ-H2AX, cell cycle-related protein cyclin B1, apoptosis-related proteins Bax and Bcl-2, and the Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase B1 (p70S6K) pathway] were detected after irradiation with carbon ions or X-rays at doses of 0, 2, 4 and 8 Gy. Our results showed that the inhibition of cell proliferation and cell colony formation and the induction of G2/M phase arrest, DNA lesions and cell apoptosis/necrosis elicited by carbon ion irradiation were more potent than the effects elicited by X-ray radiation at the same dose. Simultaneously, compared with X-ray radiation, carbon ion radiation induced a marked increase in Bax and prominent decreases in cyclin B1 and Bcl-2 in a dose-dependent manner. Furthermore, the Akt/mTOR/p70S6K pathway was significantly inhibited by carbon ion radiation in both breast cancer cell lines. These results indicate that carbon ion radiation kills MDA-MB-231 and MCF-7 breast cancer cells more effectively than X-ray radiation, which might result from the inhibition of the Akt/mTOR/p70S6K pathway.
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Affiliation(s)
- Qiuning Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
- Lanzhou Heavy Ion Hospital, Lanzhou 730030, China
| | - Yarong Kong
- The Life Sciences College of Lanzhou University, Lanzhou 730000, China
| | - Zhen Yang
- Basic Medical College of Lanzhou University, Lanzhou 730000, China
- Lanzhou Heavy Ion Hospital, Lanzhou 730030, China
| | - Yang Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
| | - Ruifeng Liu
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
- Gansu Provincial Cancer Hospital, Lanzhou 730050, China
| | - Yichao Geng
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
| | - Hongtao Luo
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
- Gansu Provincial Cancer Hospital, Lanzhou 730050, China
| | - Hong Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
| | - Hongyan Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
| | - Shuangwu Feng
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
| | - Xiaohu Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
- The Life Sciences College of Lanzhou University, Lanzhou 730000, China
- Basic Medical College of Lanzhou University, Lanzhou 730000, China
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
- Gansu Provincial Cancer Hospital, Lanzhou 730050, China
- Lanzhou Heavy Ion Hospital, Lanzhou 730030, China
- Corresponding author. Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China. Tel: 86-931-2302995;
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Pizzuti VJ, Misra R, Lee J, Torregrosa-Allen SE, Currie MP, Clark SR, Patel AP, Schorr CR, Jones-Hall Y, Childress MO, Plantenga JM, Rancilio NJ, Elzey BD, Won YY. Folic Acid-Conjugated Radioluminescent Calcium Tungstate Nanoparticles as Radio-Sensitizers for Cancer Radiotherapy. ACS Biomater Sci Eng 2019; 5:4776-4789. [PMID: 33448820 DOI: 10.1021/acsbiomaterials.9b00773] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Radiation therapy is a primary treatment modality for many forms of cancer. Normally, the highest tolerable dose of ionizing radiation is used to treat tumors, but limitations imposed by normal tissue complications present challenges for local tumor control. In light of this, a class of compounds called radio-sensitizers have been developed to enhance the effectiveness of radiation. Many of these are small molecule drugs found to interact favorably with radiation therapy, but recent advances have been made using nanoparticles as radio-sensitizers. Herein, we report the utilization of radio-luminescent calcium tungstate nanoparticles that emit photoelectrons, UV-A, and visible light during X-ray irradiation, acting as effective radio-sensitizers ("Radio Luminescence Therapy"). In addition, a folic acid-functionalized form of these nanoparticles was shown to enhance radio-sensitization in vitro and in murine models of head and neck cancer. Folic acid-functionalized particles were found to decrease UV-A-induced clonogenic cell survival relative to nonfunctionalized particles. Several possible mechanisms were explored, and the folic acid-functionalized particles were found to mediate this increase in efficacy likely by activating pro-proliferative signaling through folate's innate mitogenic activity, leading to decreased repair of UV-A-induced DNA lesions. Finally, a clinical case study of a canine sarcoma patient demonstrated the initial safety and feasibility of translating these folic acid-functionalized particles into the clinic as radio-sensitizers in the treatment of spontaneous tumors.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Nicholas J Rancilio
- Department of Veterinary Clinical Sciences, Auburn University, 1010 Wire Road, Auburn, Alabama 36849, United States
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Song YP, McWilliam A, Hoskin PJ, Choudhury A. Organ preservation in bladder cancer: an opportunity for truly personalized treatment. Nat Rev Urol 2019; 16:511-522. [PMID: 31197260 DOI: 10.1038/s41585-019-0199-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2019] [Indexed: 02/07/2023]
Abstract
Radical treatment of many solid tumours has moved from surgery to multimodal organ preservation strategies combining systemic and local treatments. Trimodality bladder-preserving treatment (TMT) comprises maximal transurethral resection of the bladder tumour followed by radiotherapy and concurrent radiosensitizing treatment, thereby sparing the urinary bladder. From the patient's perspective, the choice of maintaining quality of life without a negative effect on the chances of cure and long-term survival is attractive. In muscle-invasive bladder cancer (MIBC), the evidence shows comparable clinical outcomes between patients undergoing radical cystectomy and TMT. Despite this evidence, many patients continue to be offered radical surgery as the standard-of-care treatment. Improvements in radiotherapy techniques with adaptive radiotherapy and advances in imaging translate to increases in the accuracy of treatment delivery and reductions in long-term toxicities. With the advent of novel biomarkers promising improved prediction of treatment response, stratification of patients for different treatments on the basis of tumour biology could soon be a reality. The future of oncological treatment lies in personalized medicine with the combination of technological and biological advances leading to truly bespoke management for patients with MIBC.
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Affiliation(s)
- Yee Pei Song
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK. .,Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK.
| | - Alan McWilliam
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.,Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK
| | - Peter J Hoskin
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.,Mount Vernon Cancer Centre, Northwood, Middlesex, United Kingdom
| | - Ananya Choudhury
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.,Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK
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