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Ke R, Kumar S, Singh SK, Rana A, Rana B. Molecular insights into the role of mixed lineage kinase 3 in cancer hallmarks. Biochim Biophys Acta Rev Cancer 2024; 1879:189157. [PMID: 39032538 DOI: 10.1016/j.bbcan.2024.189157] [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: 12/22/2023] [Revised: 07/14/2024] [Accepted: 07/17/2024] [Indexed: 07/23/2024]
Abstract
Mixed-lineage kinase 3 (MLK3) is a serine/threonine kinase of the MAPK Kinase kinase (MAP3K) family that plays critical roles in various biological processes, including cancer. Upon activation, MLK3 differentially activates downstream MAPKs, such as JNK, p38, and ERK. In addition, it regulates various non-canonical signaling pathways, such as β-catenin, AMPK, Pin1, and PAK1, to regulate cell proliferation, apoptosis, invasion, and metastasis. Recent studies have also uncovered other potentially diverse roles of MLK3 in malignancy, which include metabolic reprogramming, cancer-associated inflammation, and evasion of cancer-related immune surveillance. The role of MLK3 in cancer is complex and cancer-specific, and an understanding of its function at the molecular level aligned specifically with the cancer hallmarks will have profound therapeutic implications for diagnosing and treating MLK3-dependent cancers. This review summarizes the current knowledge about the effect of MLK3 on the hallmarks of cancer, providing insights into its potential as a promising anticancer drug target.
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Affiliation(s)
- Rong Ke
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Sandeep Kumar
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Sunil Kumar Singh
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Basabi Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
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Kejík Z, Hajduch J, Abramenko N, Vellieux F, Veselá K, Fialová JL, Petrláková K, Kučnirová K, Kaplánek R, Tatar A, Skaličková M, Masařík M, Babula P, Dytrych P, Hoskovec D, Martásek P, Jakubek M. Cyanine dyes in the mitochondria-targeting photodynamic and photothermal therapy. Commun Chem 2024; 7:180. [PMID: 39138299 PMCID: PMC11322665 DOI: 10.1038/s42004-024-01256-6] [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: 02/08/2024] [Accepted: 07/26/2024] [Indexed: 08/15/2024] Open
Abstract
Mitochondrial dysregulation plays a significant role in the carcinogenesis. On the other hand, its destabilization strongly represses the viability and metastatic potential of cancer cells. Photodynamic and photothermal therapies (PDT and PTT) target mitochondria effectively, providing innovative and non-invasive anticancer therapeutic modalities. Cyanine dyes, with strong mitochondrial selectivity, show significant potential in enhancing PDT and PTT. The potential and limitations of cyanine dyes for mitochondrial PDT and PTT are discussed, along with their applications in combination therapies, theranostic techniques, and optimal delivery systems. Additionally, novel approaches for sonodynamic therapy using photoactive cyanine dyes are presented, highlighting advances in cancer treatment.
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Affiliation(s)
- Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic.
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic.
| | - Jan Hajduch
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Nikita Abramenko
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Frédéric Vellieux
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Kateřina Veselá
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | | | - Kateřina Petrláková
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
| | - Kateřina Kučnirová
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Ameneh Tatar
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Markéta Skaličková
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
| | - Michal Masařík
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
| | - Petr Babula
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
| | - Petr Dytrych
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 121 08, Prague, Czech Republic
| | - David Hoskovec
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 121 08, Prague, Czech Republic
| | - Pavel Martásek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic.
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Prague, Czech Republic.
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00, Prague, Czech Republic.
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Chelakkot C, Chelakkot VS, Shin Y, Song K. Modulating Glycolysis to Improve Cancer Therapy. Int J Mol Sci 2023; 24:2606. [PMID: 36768924 PMCID: PMC9916680 DOI: 10.3390/ijms24032606] [Citation(s) in RCA: 144] [Impact Index Per Article: 72.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/31/2023] Open
Abstract
Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
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Affiliation(s)
| | - Vipin Shankar Chelakkot
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Youngkee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyoung Song
- College of Pharmacy, Duksung Women’s University, Seoul 01366, Republic of Korea
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Mendes MIP, Arnaut LG. Redaporfin Development for Photodynamic Therapy and its Combination with Glycolysis Inhibitors. Photochem Photobiol 2022; 99:769-776. [PMID: 36564949 DOI: 10.1111/php.13770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/13/2022] [Indexed: 12/25/2022]
Abstract
Photodynamic therapy (PDT) remains an underutilized treatment modality in oncology. Many efforts have been dedicated to the development of better photosensitizers, better formulations and delivery methods, rigorous planning of light dose distribution in tissues, mechanistic insight, improvement of treatment protocols and combinations with other therapeutic agents. Hopefully, progress in all these fields will eventually expand the use of PDT. Here we offer a brief review of our own contribution to the development of a photosensitizer for PDT - redaporfin - currently in Phase II clinical trials, and present data on its combination with two glycolysis inhibitors: 2-deoxyglucose and 3-bromopyruvate. We show that 3-bromopyruvate is more cytotoxic to a carcinoma cell line (CT26) than to a normal fibroblast (3T3) cell line, and that this selectivity is maintained in the in vitro combination with redaporfin-PDT. This combination was investigated in BALB/c mice with large subcutaneous CT26 tumors and it is shown that the cure rate in the combination is higher (33% cures) than in PDT (11% cures) or in 3-bromopyruvate (no cures) alone. The combination of redaporfin-PDT with 3-bromopyruvate illustrates the potential of combination therapies and how PDT benefits can be enhanced by systemic drugs with complementary targets.
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Affiliation(s)
| | - Luis G Arnaut
- CQC-IMS, Department of Chemistry, University of Coimbra, Coimbra, Portugal
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Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy. Pharmaceutics 2021; 13:pharmaceutics13091345. [PMID: 34575424 PMCID: PMC8470396 DOI: 10.3390/pharmaceutics13091345] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
Photodynamic therapy (PDT) is a promising non-invasive strategy in the fight against that which circumvents the systemic toxic effects of chemotherapeutics. It relies on photosensitizers (PSs), which are photoactivated by light irradiation and interaction with molecular oxygen. This generates highly reactive oxygen species (such as 1O2, H2O2, O2, ·OH), which kill cancer cells by necrosis or apoptosis. Despite the promising effects of PDT in cancer treatment, it still suffers from several shortcomings, such as poor biodistribution of hydrophobic PSs, low cellular uptake, and low efficacy in treating bulky or deep tumors. Hence, various nanoplatforms have been developed to increase PDT treatment effectiveness and minimize off-target adverse effects. Liposomes showed great potential in accommodating different PSs, chemotherapeutic drugs, and other therapeutically active molecules. Here, we review the state-of-the-art in encapsulating PSs alone or combined with other chemotherapeutic drugs into liposomes for effective tumor PDT.
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Gan J, Li S, Meng Y, Liao Y, Jiang M, Qi L, Li Y, Bai Y. The influence of photodynamic therapy on the Warburg effect in esophageal cancer cells. Lasers Med Sci 2020; 35:1741-1750. [PMID: 32034563 DOI: 10.1007/s10103-020-02966-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 01/13/2020] [Indexed: 12/16/2022]
Abstract
To investigate whether the Warburg effect is a key modulator on the resistance mechanism of photodynamic therapy (PDT). Glycolysis was examined by the test of lactate product and glucose uptake at different post-PDT time points. Cell viability was detected by the CCK-8 assay and cell proliferation was detected by colony formation assay. The expression of glycolysis and related proteins were examined by western blotting. Target gene was silenced by RNAi. In the present study, we assessed the effect of PDT on cancer cell glycolysis. Our team has demonstrated that pyruvate kinase M2 (PKM2), a key speed-limiting enzyme of glycolysis, was significantly overexpressed in patients with esophageal cancer. Our results in the present study showed that PKM2 was downregulated, and lactate product and glucose uptake were inhibited in cells exposed to 5-aminolevulinic acid (5-ALA)-mediated PDT at 4 h after treatment. However, at 24 h after PDT, we observed a substantial increase in PKM2 expression, lactate product, and glucose uptake. Moreover, silencing of PKM2 gene abrogated the upregulatory effect of PDT on glycolysis at late post-PDT period. 2-Deoxy-D-glucose (2-DG) is a recognized chemical inhibitor of glycolysis. The combined treatment of 2-DG and PDT significantly inhibited tumor growth in vitro at 24 h. These results demonstrate that PDT drives the Warburg effect in a time-dependent manner, and PKM2 plays an important role in this progress, which indicated that PKM2 may be a potential molecular target to increase the sensitivity of esophageal cancer cells to PDT.
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Affiliation(s)
- Junqing Gan
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China
| | - Shumin Li
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China
| | - Yu Meng
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China
| | - Yuanyu Liao
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China
| | - Mingxia Jiang
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China
| | - Ling Qi
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China
| | - Yanjing Li
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China.
| | - Yuxian Bai
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China.
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Deng Y, Song P, Chen X, Huang Y, Hong L, Jin Q, Ji J. 3-Bromopyruvate-Conjugated Nanoplatform-Induced Pro-Death Autophagy for Enhanced Photodynamic Therapy against Hypoxic Tumor. ACS NANO 2020; 14:9711-9727. [PMID: 32806075 DOI: 10.1021/acsnano.0c01350] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Autophagy triggered by reactive oxygen species (ROS) in photodynamic therapy (PDT) generally exhibits an anti-apoptotic effect to promote cell survival. Herein, an innovative supramolecular nanoplatform was fabricated for enhanced PDT by converting the role of autophagy from pro-survival to pro-death. The respiration inhibitor 3-bromopyruvate (3BP), which can act as an autophagy promoter and hypoxia ameliorator, was integrated into photosensitizer chlorin e6 (Ce6)-encapsulated nanoparticles to combat hypoxic tumor. 3BP could inhibit respiration by down-regulating HK-II and GAPDH expression to significantly reduce intracellular oxygen consumption rate, which could relieve tumor hypoxia for enhanced photodynamic cancer therapy. More importantly, the autophagy level was significantly elevated by the combination of 3BP and PDT determined by Western blot, immunofluorescent imaging, and transmission electron microscopy. It was very surprising that excessively activated autophagy promoted cell apoptosis, leading to the changeover of autophagy from pro-survival to pro-death. Therefore, PDT combined with 3BP could achieve efficient cell proliferation inhibition and tumor regression. Furthermore, hypoxia-inducible factor-1α (HIF-1α) could be down-regulated after tumor hypoxia was relieved by 3BP. Tumor metastasis could then be effectively inhibited by eliminating primary tumors and down-regulating HIF-1α expression. These results provide an inspiration for future innovative approaches of cancer therapy by triggering pro-death autophagy.
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Affiliation(s)
- Yongyan Deng
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
| | - Pengyu Song
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
| | - Xiaohui Chen
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
| | - Yue Huang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
| | - Liangjie Hong
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
| | - Qiao Jin
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China
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Feng X, Shi Y, Xie L, Zhang K, Wang X, Liu Q, Wang P. 2‐deoxy‐D‐glucose augments photodynamic therapy induced mitochondrial caspase‐independent apoptosis and energy‐mediated autophagy. Lasers Surg Med 2018; 51:352-362. [DOI: 10.1002/lsm.23020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Xiaolan Feng
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
| | - Yin Shi
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
| | - Lifen Xie
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
| | - Kun Zhang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
| | - Xiaobing Wang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
| | - Quanhong Liu
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
| | - Pan Wang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life SciencesShaanxi Normal UniversityXi'anShaanxiChina
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Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma. Oncotarget 2018; 7:65614-65626. [PMID: 27582536 PMCID: PMC5323179 DOI: 10.18632/oncotarget.11592] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 08/13/2016] [Indexed: 12/31/2022] Open
Abstract
In different fungal and algal species, the intracellular concentration of reduced glutathione (GSH) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3BP). Additionally, in the case of Cryptococcus neoformans cells 3BP exhibits a synergistic effect with buthionine sulfoximine (BSO), a known GSH depletion agent. This effect was observed when 3BP and BSO were used together at concentrations respectively of 4-5 and almost 8 times lower than their Minimal Inhibitory Concentration (MIC). Finally, at different concentrations of 3BP (equal to the half-MIC, MIC and double-MIC in a case of fungi, 1 mM and 2.5 mM for microalgae and 25, 50, 100 μM for human multiple myeloma (MM) cells), a significant decrease in GSH concentration is observed inside microorganisms as well as tumor cells. In contrast to the GSH concentration decrease, the presence of 3BP at concentrations corresponding to sub-MIC values or half maximal inhibitory concentration (IC50) clearly results in increasing the expression of genes encoding enzymes involved in the synthesis of GSH in Cryptococcus neoformans and MM cells. Moreover, as shown for the first time in the MM cell model, the drastic decrease in the ATP level and GSH concentration and the increase in the amount of ROS caused by 3BP ultimately results in cell death.
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Xie R, Xu T, Zhu J, Wei X, Zhu W, Li L, Wang Y, Han Y, Zhou J, Bai Y. The Combination of Glycolytic Inhibitor 2-Deoxyglucose and Microbubbles Increases the Effect of 5-Aminolevulinic Acid-Sonodynamic Therapy in Liver Cancer Cells. ULTRASOUND IN MEDICINE & BIOLOGY 2017; 43:2640-2650. [PMID: 28843620 DOI: 10.1016/j.ultrasmedbio.2017.06.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 06/16/2017] [Accepted: 06/29/2017] [Indexed: 06/07/2023]
Abstract
Sonodynamic therapy (SDT) overcomes the shortcoming of photodynamic therapy in the treatment of cancer. Previous studies indicated that the glycolysis inhibitor 2-deoxyglucose (2-DG) potentiated photodynamic therapy induced tumor cell death and microbubbles (MBs) improved the SDT performance. We hypothesized that the combination of 2-DG and MBs will increase the effect of 5-aminolevulinic acid (ALA)-SDT in HepG2 liver cancer cells. When cells were treated with 5-min ALA-SDT and 2-mmol/L 2-DG, the cell survival rate decreased to 73.0 ± 7.1% and 75.2 ± 7.9%, respectively. Furthermore, 2 mmol/L 2-DG increased 5-min ALA-SDT induced growth inhibition and augmented ALA-SDT induced cell apoptotic rate from 9.8 ± 0.7% to 17.4 ± 2.2%. In the combination group (2-DG and ALA-SDT group), HepG2 cells possessed typical apoptotic characters. 2-DG also increased ALA-SDT associated intracellular reactive oxygen species generation and loss of mitochondrial membrane potential. Moreover, SonoVue MBs had stimulatory function on cell viability inhibition, apoptosis, reactive oxygen species production and mitochondrial membrane potential loss for combination treatment. This study suggests a promising therapeutic strategy using a combination of 2-DG, MBs and ALA-SDT for treating liver cancer.
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Affiliation(s)
- Rui Xie
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tongying Xu
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jiuxin Zhu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China
| | - Xiaoli Wei
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wenting Zhu
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Longmin Li
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yufeng Wang
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Han
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jianhua Zhou
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuxian Bai
- Department of Digestive Internal Medicine & Photodynamic Therapy Center, Harbin Medical University Cancer Hospital, Harbin, China.
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11
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Deng X, Tang S, Wu Q, Tian J, Riley WW, Chen Z. Inactivation of Vibrio parahaemolyticus by antimicrobial photodynamic technology using methylene blue. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2016; 96:1601-1608. [PMID: 25989459 DOI: 10.1002/jsfa.7261] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 03/30/2015] [Accepted: 05/14/2015] [Indexed: 06/04/2023]
Abstract
BACKGROUND Vibrio parahaemolyticus is the leading causative pathogen of gastroenteritis often related to contaminated seafood. Photodynamic inactivation has been recently proposed as a strategy for killing cells and viruses. The objective of this study was to verify the bactericidal effects caused by photodynamic inactivation using methylene blue (MB) over V. parahaemolyticus via flow cytometry, agarose gel electrophoresis and sodium dodecyl sulfate polyacrylamide gel electrophoresis. Vibrio parahaemolyticus counts were determined using the most probable number method. A scanning electron microscope and a transmission electron microscope were employed to intuitively analyze internal and external cell structure. RESULTS Combination of MB and laser treatment significantly inhibited the growth of V. parahaemolyticus. The inactivation rate of V. parahaemolyticus was >99.99% and its counts were reduced by 5 log10 in the presence of 0.05 mg mL(-1) MB when illuminated with visible light (power density 200 mW cm(-2)) for 25 min. All inactivated cells showed morphological changes, leakage of cytoplasm and degradation of protein and DNA. CONCLUSION Results from this study indicated that photodynamic technology using MB produced significant inactivation of V. parahaemolyticus mainly brought about by the degradation of protein and DNA.
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Affiliation(s)
- Xi Deng
- Department of Food Science and Engineering, Jinan University, Guangzhou, 510632, China
| | - Shuze Tang
- Department of Food Science and Engineering, Jinan University, Guangzhou, 510632, China
| | - Qian Wu
- Department of Food Science and Engineering, Jinan University, Guangzhou, 510632, China
| | - Juan Tian
- Department of Food Science, South China Agricultural University, Guangzhou, 510642, China
| | - William W Riley
- Department of Food Science and Engineering, Jinan University, Guangzhou, 510632, China
| | - Zhenqiang Chen
- Department of Photoelectrical Engineering, Jinan University, Guangzhou, 510632, China
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Sinoporphyrin sodium mediated photodynamic therapy inhibits the migration associated with collapse of F-actin filaments cytoskeleton in MDA-MB-231 cells. Photodiagnosis Photodyn Ther 2015; 13:58-65. [PMID: 26742781 DOI: 10.1016/j.pdpdt.2015.12.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Revised: 11/25/2015] [Accepted: 12/22/2015] [Indexed: 01/10/2023]
Abstract
OBJECTIVE We previously demonstrated that the photosensitizer sinoporphyrin sodium (DVDMS) mediated photodynamic therapy (PDT) had potential advantages in inhibiting tumor growth and metastasis. However, details regarding the mechanism of cell migration inhibition remain unclear. Therefore, in this study, we aimed to investigate the effects of DVDMS-PDT on F-actin filaments, cell migration, apoptotic response and the possible interactions between them in human breast cancer MDA-MB-231 cells. MATERIALS AND METHODS The cell viability was evaluated by MTT and Guava ViaCount assays. The subcellular localization of DVDMS and reactive oxygen species (ROS) generation were analyzed by fluorescence microscope and flow cytometry. FITC-phalloidin was used to evaluate the changes of F-actin filaments. Cell migration was analyzed by scratch assay and Transwell assay. Cell apoptosis was determined by nuclear TUNEL staining and Annexin V-PE/7-AAD assay. Jasplakinolide, an F-actin stabilizer, was applied to dissect the influences of F-actin filaments disruption on cell migration and apoptosis. RESULTS DVDMS-PDT significantly suppressed cell proliferation, promoted early apoptotic response, triggered collapse of F-actin filaments and inhibited cell migration in MDA-MB-231 cells. Cell migration significantly increased when cells were pretreated with F-actin stabilizer jasplakinolide after PDT, while cell apoptosis was not obviously affected. Moreover, ROS was a key factor in causing collapse of F-actin filaments. CONCLUSION We demonstrated that DVDMS-PDT triggered cell apoptosis and collapse of F-actin filaments through the induction of ROS in MDA-MB-231 cells. F-actin filaments contributed to cell migration but produced no obvious effect on cell apoptosis.
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Kwiatkowska E, Wojtala M, Gajewska A, Soszyński M, Bartosz G, Sadowska-Bartosz I. Effect of 3-bromopyruvate acid on the redox equilibrium in non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cells. J Bioenerg Biomembr 2015; 48:23-32. [PMID: 26715289 DOI: 10.1007/s10863-015-9637-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 12/17/2015] [Indexed: 01/12/2023]
Abstract
Novel approaches to cancer chemotherapy employ metabolic differences between normal and tumor cells, including the high dependence of cancer cells on glycolysis ("Warburg effect"). 3-Bromopyruvate (3-BP), inhibitor of glycolysis, belongs to anticancer drugs basing on this principle. 3-BP was tested for its capacity to kill human non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cells. We found that 3-BP was more toxic for MDA-MB-231 cells than for MCF-7 cells. In both cell lines, a statistically significant decrease of ATP and glutathione was observed in a time- and 3-BP concentration-dependent manner. Transient increases in the level of reactive oxygen species and reactive oxygen species was observed, more pronounced in MCF-7 cells, followed by a decreasing tendency. Activities of glutathione peroxidase, glutathione reductase (GR) and glutathione S-transferase (GST) decreased in 3-BP treated MDA-MB-231 cells. For MCF-7 cells decreases of GR and GST activities were noted only at the highest concentration of 3-BP.These results point to induction of oxidative stress by 3-BP via depletion of antioxidants and inactivation of antioxidant enzymes, more pronounced in MDA-MB-231 cells, more sensitive to 3-BP.
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Affiliation(s)
- Ewa Kwiatkowska
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland
| | - Martyna Wojtala
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland
| | - Agnieszka Gajewska
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland
| | - Mirosław Soszyński
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland
| | - Grzegorz Bartosz
- Department of Biochemistry and Cell Biology, Faculty of Biology and Agriculture, University of Rzeszów, Zelwerowicza 4, 35-601, Rzeszów, Poland
| | - Izabela Sadowska-Bartosz
- Department of Biochemistry and Cell Biology, Faculty of Biology and Agriculture, University of Rzeszów, Zelwerowicza 4, 35-601, Rzeszów, Poland.
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Diedrich J, Gusky HC, Podgorski I. Adipose tissue dysfunction and its effects on tumor metabolism. Horm Mol Biol Clin Investig 2015; 21:17-41. [PMID: 25781550 DOI: 10.1515/hmbci-2014-0045] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/14/2015] [Indexed: 12/12/2022]
Abstract
Growing by an alarming rate in the Western world, obesity has become a condition associated with a multitude of diseases such as diabetes, metabolic syndrome and various cancers. Generally viewed as an abnormal accumulation of hypertrophied adipocytes, obesity is also a poor prognostic factor for recurrence and chemoresistance in cancer patients. With more than two-thirds of the adult population in the United States considered clinically overweight or obese, it is critical that the relationship between obesity and cancer is further emphasized and elucidated. Adipocytes are highly metabolically active cells, which, through release of adipokines and cytokines and activation of endocrine and paracrine pathways, affect processes in neighboring and distant cells, altering their normal homeostasis. This work will examine specifically how adipocyte-derived factors regulate the cellular metabolism of malignant cells within the tumor niche. Briefly, tumor cells undergo metabolic pressure towards a more glycolytic and hypoxic state through a variety of metabolic regulators and signaling pathways, i.e., phosphoinositol-3 kinase (PI3K), hypoxia-inducible factor-1 alpha (HIF-1α), and c-MYC signaling. Enhanced glycolysis and high lactate production are hallmarks of tumor progression largely because of a process known as the Warburg effect. Herein, we review the latest literature pertaining to the body of work on the interactions between adipose and tumor cells, and underlining the changes in cancer cell metabolism that have been targeted by the currently available treatments.
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Lee M, Yoon JH. Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 2015; 6:148-61. [PMID: 26322173 PMCID: PMC4549759 DOI: 10.4331/wjbc.v6.i3.148] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 05/26/2015] [Accepted: 07/21/2015] [Indexed: 02/05/2023] Open
Abstract
Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
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Glycolytic inhibitors 2-deoxyglucose and 3-bromopyruvate synergize with photodynamic therapy respectively to inhibit cell migration. J Bioenerg Biomembr 2015; 47:189-97. [PMID: 25631472 DOI: 10.1007/s10863-015-9604-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 01/19/2015] [Indexed: 01/06/2023]
Abstract
Most cancer cells have the specially increased glycolytic phenotype, which makes this pathway become an attractive therapeutic target. Although glycolytic inhibitor 2-deoxyglucose (2-DG) has been demonstrated to potentiate the cytotoxicity of photodynamic therapy (PDT), the impacts on cell migration after the combined treatment has never been reported yet. The present study aimed to analyze the influence of glycolytic inhibitors 2-DG and 3-bromopyruvate (3-BP) combined with Ce6-PDT on cell motility of Triple Negative Breast Cancer MDA-MB-231 cells. As determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium-bromide-Tetraz-olium (MTT) assay, more decreased cell viability was observed in 2-DG + PDT and 3-BP + PDT groups when compared with either monotherapy. Under optimal conditions, synergistic potentiation on cell membrane destruction and the decline of cell adhesion and cells migratory ability were observed in both 2-DG + PDT and 3-BP + PDT by electron microscope observation (SEM), wound healing and trans-well assays. Besides, serious microfilament network collapses as well as impairment of matrix metalloproteinases-9 (MMP-9) were notably improved after the combined treatments by immunofluorescent staining. These results suggest that 2-DG and 3-BP can both significantly potentiated Ce6-PDT efficacy of cell migration inhibition.
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