|
1
|
Yin D, Wu X, Chen X, Chen JL, Xia X, Wang J, Chen X, Zhu XM. Enhanced anticancer effect of carfilzomib by codelivery of calcium peroxide nanoparticles targeting endoplasmic reticulum stress. Mater Today Bio 2025; 32:101649. [PMID: 40160245 PMCID: PMC11953955 DOI: 10.1016/j.mtbio.2025.101649] [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: 01/09/2025] [Revised: 02/15/2025] [Accepted: 03/08/2025] [Indexed: 04/02/2025] Open
Abstract
Encouraged by the clinical success of proteasome inhibitors treating hematological malignancy, continuous efforts are being made to improve their efficacy and expand their applications to solid tumor therapy. In this study, liposomes were used to encapsulate the proteasome inhibitor carfilzomib (CFZ) and calcium peroxide (CaO2) nanoparticles for effective combination therapy targeting the interplay between calcium overload and oxidative stress. Low-dose CaO2 synergistically enhances the anticancer effect of CFZ in the human glioblastoma U-87 MG cells. The reactive oxygen species (ROS) generation and glutathione depletion by low-dose CaO2 complement CFZ-induced ubiquitinated protein accumulation further triggering endoplasmic reticulum (ER) stress leading to calcium overload and mitochondrial dysfunction. The liposome-based codelivery system is capable of transporting CFZ and CaO2 simultaneously to the tumor, and results in a superior antitumor effect in U-87 MG tumor-bearing mice compared with monotherapy. Taken together, CaO2 holds great potential to sensitize proteasome inhibitors in the treatment of solid tumors, and this work also presents a new combination therapy strategy targeting the crosstalk between proteasome inhibitors and oxidative stress for future cancer therapy.
Collapse
Affiliation(s)
- Dan Yin
- State Key Laboratory of Quality Research in Chinese Medicines & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR, 999078, China
| | - Xuan Wu
- State Key Laboratory of Quality Research in Chinese Medicines & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR, 999078, China
| | - Xu Chen
- State Key Laboratory of Quality Research in Chinese Medicines & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR, 999078, China
| | - Jian-Li Chen
- State Key Laboratory of Quality Research in Chinese Medicines & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR, 999078, China
| | - Xinyue Xia
- Department of Physics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, 999077, China
| | - Jianfang Wang
- Department of Physics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, 999077, China
| | - Xiuping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, 999078, China
| | - Xiao-Ming Zhu
- State Key Laboratory of Quality Research in Chinese Medicines & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR, 999078, China
- Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Zhuhai, Guangdong, 519099, China
| |
Collapse
|
|
2
|
Sedlacek J. Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma. Clin Exp Med 2025; 25:176. [PMID: 40418254 DOI: 10.1007/s10238-025-01713-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Accepted: 05/01/2025] [Indexed: 05/27/2025]
Abstract
Genomic alterations and enormous monoclonal immunoglobulin production cause multiple myeloma to heavily depend on proteostasis mechanisms, including protein folding and degradation. These findings support the use of proteasome inhibitors for treating multiple myeloma and mantle cell lymphoma. Myeloma treatment has evolved, especially with the availability of new drugs, such as proteasome inhibitors, into therapeutic strategies for both frontline and relapsed/refractory disease settings. However, proteasome inhibitors are generally not effective enough to cure most patients. Natural resistance and eventual acquired resistance led to relapsed/refractory disease and poor prognosis. Advances in the understanding of cellular proteostasis and the development of innovative drugs that also target other proteostasis network components offer opportunities to exploit the intrinsic vulnerability of myeloma cells. This review outlines recent findings on the molecular mechanisms regulating cellular proteostasis pathways, as well as resistance, sensitivity, and escape strategies developed against proteasome inhibitors and provides a rationale and examples for novel combinations of proteasome inhibitors with FDA-approved drugs and investigational drugs targeting the NRF1 (NFE2L1)-mediated proteasome bounce-back response, redox homeostasis, heat shock response, unfolding protein response, autophagy, and VCP/p97 to increase proteotoxic stress, which can improve the efficacy of antimyeloma therapy based on proteasome inhibitors.
Collapse
Affiliation(s)
- Jindrich Sedlacek
- Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Průmyslová 595, 252 50, Vestec, Czech Republic.
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 16610, Prague, Czech Republic.
| |
Collapse
|
|
3
|
Kamal M, Shi Q, Shen SE, Cleeland C, Wang XS. Trajectory, interactions, and predictors of higher symptom burden during induction therapy for multiple myeloma. J Patient Rep Outcomes 2024; 8:141. [PMID: 39630196 PMCID: PMC11618278 DOI: 10.1186/s41687-024-00817-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 11/25/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Patients with multiple myeloma (MM) experience disabling symptoms that are difficult to manage and may persist after induction therapy. Monitoring disease-related and induction therapy-induced symptoms and identifying patients at greater risk for high symptom burden are unmet clinical needs. The objective of this study was to examine the trajectories of symptom severity over time and identify predictors of high symptom burden during MM induction therapy. METHODOLOGY Eligible patients with MM rated their symptoms by completing the MD Anderson Symptom Inventory MM module repeatedly during 16 weeks of induction therapy. Group-based trajectory modeling identified patient groups with persistently high-severity (versus low-severity) symptom trajectories over time. Quality of life (QOL) and affective and physical functioning status were assessed. Predictors of high symptom burden were examined by regression analysis. RESULTS Sixty-four MM patients participated. Most patients (89%) received bortezomib-based therapy. The five most-severe symptom trajectory groups were pain (59%), muscle weakness (46%), numbness (42%), disturbed sleep (41%), and fatigue (31%). Patients in the high-severity trajectory group for the five most-severe symptoms (31% of the sample) were more likely to have high-severity cognitive and affective symptoms. Patients in the high-severity trajectory groups for fatigue, muscle weakness, disturbed sleep, and bone aches were more likely to have high pain scores (all p < 0.05). Significant increases over time were observed in scores for pain (estimate: 0.026), numbness (0.051), muscle weakness (0.020), physical items (0.028), and affective items (0.014) (all p < 0.05). A higher baseline composite score of the five most-severe symptoms predicted worse QOL (- 6.24), and poor affective (0.80) and physical (1.10) statuses (all p < 0.01). Female sex predicted higher risk for being in the high-severity trajectory group for muscle weakness. CONCLUSION Almost one-third of MM patients suffer from up to 5 moderate to severe symptoms persistently, including pain, muscle weakness, numbness, disturbed sleep, and fatigue. Importantly, these results identify a group of symptoms that should be monitored and managed as part of routine patient care during MM induction therapy and suggest that pre-therapy pain management is necessary for better symptom control.
Collapse
Affiliation(s)
- Mona Kamal
- Department of Symptom Research, Unit 1450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Qiuling Shi
- Chongqing Medical University, Chongqing, China
| | - Shu-En Shen
- Department of Symptom Research, Unit 1450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Charles Cleeland
- Department of Symptom Research, Unit 1450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Xin Shelley Wang
- Department of Symptom Research, Unit 1450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
| |
Collapse
|
|
4
|
Jenke R, Oliinyk D, Zenz T, Körfer J, Schäker-Hübner L, Hansen FK, Lordick F, Meier-Rosar F, Aigner A, Büch T. HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer. Biochem Pharmacol 2024; 225:116257. [PMID: 38705532 DOI: 10.1016/j.bcp.2024.116257] [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: 01/18/2024] [Revised: 04/18/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Gastric cancer remains among the deadliest neoplasms worldwide, with limited therapeutic options. Since efficacies of targeted therapies are unsatisfactory, drugs with broader mechanisms of action rather than a single oncogene inhibition are needed. Preclinical studies have identified histone deacetylases (HDAC) as potential therapeutic targets in gastric cancer. However, the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. This is particularly true with regard to ferroptosis as an emerging concept of cell death. In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured and proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA and protein level. Upon HDACi treatment, lipid peroxidation was found increased in all cell lines. Class I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Results were also confirmed in primary human gastric cancer tissue cultures as a relevant ex vivo model. We identify the induction of ferroptosis as new mechanism of action of class I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle.
Collapse
Affiliation(s)
- Robert Jenke
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany
| | - Denys Oliinyk
- Jena University Hospital, Functional Proteomics, Research Center Lobeda, Jena, Germany
| | - Tamara Zenz
- Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany
| | - Justus Körfer
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; University Hospital Leipzig, Institute for Anatomy, Leipzig, Germany
| | - Linda Schäker-Hübner
- University of Bonn, Pharmaceutical Institute, Department of Pharmaceutical and Cell Biological Chemistry, Bonn, Germany
| | - Finn K Hansen
- University of Bonn, Pharmaceutical Institute, Department of Pharmaceutical and Cell Biological Chemistry, Bonn, Germany
| | - Florian Lordick
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany
| | - Florian Meier-Rosar
- Jena University Hospital, Functional Proteomics, Research Center Lobeda, Jena, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany
| | - Achim Aigner
- Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany.
| | - Thomas Büch
- Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany
| |
Collapse
|
|
5
|
Nakamura H, Arihara Y, Usami M, Takada K. ST2825, independent of MyD88, induces reactive oxygen species-dependent apoptosis in multiple myeloma cells. Biochem Biophys Rep 2024; 38:101681. [PMID: 38455592 PMCID: PMC10918488 DOI: 10.1016/j.bbrep.2024.101681] [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: 12/05/2023] [Revised: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 03/09/2024] Open
Abstract
Myeloid differentiation factor 88 (MyD88), which is a key regulator of nuclear factor kappa B (NF-κB), plays an important role in tumorigenesis in lymphoid malignancies such as Waldenstrom's macroglobulinemia (WM). However, its biological function in multiple myeloma (MM), which is a malignant plasma cell disorder like WM, remains unexplored. In this article, we first demonstrated that higher expression MyD88 was significantly correlated with poor survival in patients with MM using multiple publicly available datasets. Interestingly, bioinformatic analysis also revealed that MyD88 gene alteration, which is recognized in nearly 80% of patients with WM, was extremely rare in MM. In addition, ST2825 (a specific inhibitor of MyD88) suppressed cell growth followed by apoptosis. Furthermore, ST2825 induced intracellular reactive oxygen species (ROS) in MM cells, and N-acetyl-l-cysteine, which is known as a ROS scavenger, significantly decreased the number of apoptotic MM cells evoked by ST2825 treatment. Taken together, our results indicated that ST2825 leads to ROS-dependent apoptosis in MM cells and could be an attractive therapeutic candidate for patients with MM. By highlighting the pathological mechanism of MyD88 in MM, this study also provides novel treatment strategies to conquer MM.
Collapse
Affiliation(s)
- Hajime Nakamura
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Japan
| | - Yohei Arihara
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Japan
| | - Makoto Usami
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Japan
| |
Collapse
|
|
6
|
Ferro A, Pantazaka E, Athanassopoulos CM, Cuendet M. Histone deacetylase-based dual targeted inhibition in multiple myeloma. Med Res Rev 2023; 43:2177-2236. [PMID: 37191917 DOI: 10.1002/med.21972] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 04/08/2023] [Accepted: 04/30/2023] [Indexed: 05/17/2023]
Abstract
Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC-based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual-inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting-point for both reducing therapeutic doses and lowering the risk of developing drug resistance.
Collapse
Affiliation(s)
- Angelica Ferro
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
| | - Evangelia Pantazaka
- Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, Patras, Greece
- Laboratory of Biochemistry/Metastatic Signaling, Section of Genetics, Cell Biology, and Development, Department of Biology, University of Patras, Patras, Greece
| | | | - Muriel Cuendet
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
| |
Collapse
|
|
7
|
Holmberg LA, Maloney DG, Connelly-Smith L. Bortezomib and Vorinostat Therapy as Maintenance Therapy Post-Autologous Transplant for Non-Hodgkin's Lymphoma Using R-BEAM or BEAM Transplant Conditioning Regimen. Acta Haematol 2023; 147:300-309. [PMID: 37708877 DOI: 10.1159/000533944] [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: 01/06/2023] [Accepted: 08/29/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin's lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for multiple myeloma showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. METHODS NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan/carmustine, etoposide, cytarabine, melphalan. After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. RESULTS Nineteen patients received BV post-ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue, and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. CONCLUSIONS BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.
Collapse
Affiliation(s)
- Leona A Holmberg
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - David G Maloney
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Laura Connelly-Smith
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
8
|
Bu Z, Yang J, Zhang Y, Luo T, Fang C, Liang X, Peng Q, Wang D, Lin N, Zhang K, Tang W. Sequential Ubiquitination and Phosphorylation Epigenetics Reshaping by MG132-Loaded Fe-MOF Disarms Treatment Resistance to Repulse Metastatic Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301638. [PMID: 37303273 PMCID: PMC10427397 DOI: 10.1002/advs.202301638] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/07/2023] [Indexed: 06/13/2023]
Abstract
Abnormal epigenetic regulation is identified to correlate with cancer progression and renders tumor refractory and resistant to reactive oxygen species (ROS)-based anti-tumor actions. To address it, a sequential ubiquitination and phosphorylation epigenetics modulation strategy is developed and exemplified by the well-established Fe-metal-organic framework (Fe-MOF)-based chemodynamic therapy (CDT) nanoplatforms that load the 26S proteasome inhibitor (i.e., MG132). The encapsulated MG132 can blockade 26S proteasome, terminate ubiquitination, and further inhibit transcription factor phosphorylation (e.g., NF-κB p65), which can boost pro-apoptotic or misfolded protein accumulations, disrupt tumor homeostasis, and down-regulate driving genes expression of metastatic colorectal cancer (mCRC). Contributed by them, Fe-MOF-unlocked CDT is magnified to considerably elevate ROS content for repulsing mCRC, especially after combining with macrophage membrane coating-enabled tropism accumulation. Systematic experiments reveal the mechanism and signaling pathway of such a sequential ubiquitination and phosphorylation epigenetics modulation and explain how it could blockade ubiquitination and phosphorylation to liberate the therapy resistance to ROS and activate NF-κB-related acute immune responses. This unprecedented sequential epigenetics modulation lays a solid foundation to magnify oxidative stress and can serve as a general method to enhance other ROS-based anti-tumor methods.
Collapse
Affiliation(s)
- Zhaoting Bu
- Department of Gastrointestinal SurgeryGuangxi Medical University Cancer HospitalGuangxi Medical University.No. 71 Hedi RoadNanningGuangxi530021P. R. China
| | - Jianjun Yang
- Central Laboratory and Department of OrthopaedicsShanghai Tenth People's HospitalTongji University School of MedicineTongji University.No. 301 Yan‐chang‐zhong RoadShanghai200072P. R. China
| | - Yan Zhang
- Central Laboratory and Department of OrthopaedicsShanghai Tenth People's HospitalTongji University School of MedicineTongji University.No. 301 Yan‐chang‐zhong RoadShanghai200072P. R. China
| | - Tao Luo
- Department of Gastrointestinal SurgeryGuangxi Medical University Cancer HospitalGuangxi Medical University.No. 71 Hedi RoadNanningGuangxi530021P. R. China
| | - Chao Fang
- Central Laboratory and Department of OrthopaedicsShanghai Tenth People's HospitalTongji University School of MedicineTongji University.No. 301 Yan‐chang‐zhong RoadShanghai200072P. R. China
| | - Xiayi Liang
- Department of Gastrointestinal SurgeryGuangxi Medical University Cancer HospitalGuangxi Medical University.No. 71 Hedi RoadNanningGuangxi530021P. R. China
- Central Laboratory and Department of OrthopaedicsShanghai Tenth People's HospitalTongji University School of MedicineTongji University.No. 301 Yan‐chang‐zhong RoadShanghai200072P. R. China
| | - Qiuxia Peng
- Central Laboratory and Department of OrthopaedicsShanghai Tenth People's HospitalTongji University School of MedicineTongji University.No. 301 Yan‐chang‐zhong RoadShanghai200072P. R. China
| | - Duo Wang
- Department of Gastrointestinal SurgeryGuangxi Medical University Cancer HospitalGuangxi Medical University.No. 71 Hedi RoadNanningGuangxi530021P. R. China
| | - Ningjing Lin
- Department of Gastrointestinal SurgeryGuangxi Medical University Cancer HospitalGuangxi Medical University.No. 71 Hedi RoadNanningGuangxi530021P. R. China
| | - Kun Zhang
- Central Laboratory and Department of OrthopaedicsShanghai Tenth People's HospitalTongji University School of MedicineTongji University.No. 301 Yan‐chang‐zhong RoadShanghai200072P. R. China
- Central LaboratorySichuan Academy of Medical SciencesSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaNo. 32, West Second Section, First Ring RoadChengduSichuan610072P. R. China
| | - Weizhong Tang
- Department of Gastrointestinal SurgeryGuangxi Medical University Cancer HospitalGuangxi Medical University.No. 71 Hedi RoadNanningGuangxi530021P. R. China
| |
Collapse
|
|
9
|
Fonseca MDC, Marazzi-Diniz PHS, Leite MF, Ehrlich BE. Calcium signaling in chemotherapy-induced neuropathy. Cell Calcium 2023; 113:102762. [PMID: 37244172 DOI: 10.1016/j.ceca.2023.102762] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/18/2023] [Accepted: 05/19/2023] [Indexed: 05/29/2023]
Abstract
Alterations in calcium (Ca2+) signaling is a major mechanism in the development of chemotherapy-induced peripheral neuropathy (CIPN), a side effect caused by multiple chemotherapy regimens. CIPN is associated with numbness and incessant tingling in hands and feet which diminishes quality of life during treatment. In up to 50% of survivors, CIPN is essentially irreversible. There are no approved, disease-modifying treatments for CIPN. The only recourse for oncologists is to modify the chemotherapy dose, a situation that can compromise optimal chemotherapy and impact patient outcomes. Here we focus on taxanes and other chemotherapeutic agents that work by altering microtubule assemblies to kill cancer cells, but also have off-target toxicities. There have been many molecular mechanisms proposed to explain the effects of microtubule-disrupting drugs. In neurons, an initiating step in the off-target effects of treatment by taxane is binding to neuronal calcium sensor 1 (NCS1), a sensitive Ca2+ sensor protein that maintains the resting Ca2+ concentration and dynamically enhances responses to cellular stimuli. The taxane/NCS1 interaction causes a Ca2+ surge that starts a pathophysiological cascade of consequences. This same mechanism contributes to other conditions including chemotherapy-induced cognitive impairment. Strategies to prevent the Ca2+ surge are the foundation of current work.
Collapse
Affiliation(s)
- Matheus de Castro Fonseca
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States.
| | - Paulo H S Marazzi-Diniz
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - M Fatima Leite
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Barbara E Ehrlich
- Department of Pharmacology, School of Medicine, Yale University, New Haven, CT, United States.
| |
Collapse
|
|
10
|
Pal D, Raj K, Nandi SS, Sinha S, Mishra A, Mondal A, Lagoa R, Burcher JT, Bishayee A. Potential of Synthetic and Natural Compounds as Novel Histone Deacetylase Inhibitors for the Treatment of Hematological Malignancies. Cancers (Basel) 2023; 15:2808. [PMID: 37345145 PMCID: PMC10216849 DOI: 10.3390/cancers15102808] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 06/23/2023] Open
Abstract
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that remove or add acetyl groups to lysine residues of histones, respectively. Histone deacetylation causes DNA to more snugly encircle histones and decreases gene expression, whereas acetylation has the opposite effect. Through these small alterations in chemical structure, HATs and HDACs regulate DNA expression. Recent research indicates histone deacetylase inhibitors (HDACis) may be used to treat malignancies, including leukemia, B-cell lymphoma, virus-associated tumors, and multiple myeloma. These data suggest that HDACis may boost the production of immune-related molecules, resulting in the growth of CD8-positive T-cells and the recognition of nonreactive tumor cells by the immune system, thereby diminishing tumor immunity. The argument for employing epigenetic drugs in the treatment of acute myeloid leukemia (AML) patients is supported by evidence that both epigenetic changes and mutations in the epigenetic machinery contribute to AML etiology. Although hypomethylating drugs have been licensed for use in AML, additional epigenetic inhibitors, such as HDACis, are now being tested in humans. Preclinical studies evaluating the efficacy of HDACis against AML have shown the ability of specific agents, such as anobinostat, vorinostat, and tricostatin A, to induce growth arrest, apoptosis, autophagy and cell death. However, these inhibitors do not seem to be successful as monotherapies, but instead achieve results when used in conjunction with other medications. In this article, we discuss the mounting evidence that HDACis promote extensive histone acetylation, as well as substantial increases in reactive oxygen species and DNA damage in hematological malignant cells. We also evaluate the potential of various natural product-based HDACis as therapeutic agents to combat hematological malignancies.
Collapse
Affiliation(s)
- Dilipkumar Pal
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur 495 009, India
| | - Khushboo Raj
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur 495 009, India
| | - Shyam Sundar Nandi
- Department of Biotechnology, Indian Council for Medical Research-National Institute of Virology, Mumbai 400 012, India
| | - Surajit Sinha
- Department of Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | | | - Arijit Mondal
- Department of Pharmaceutical Chemistry, M.R. College of Pharmaceutical Sciences and Research, Balisha 743 234, India
| | - Ricardo Lagoa
- Associate Laboratory in Chemical Engineering, Polytechnic Institute of Leiria, Morro do Lena, Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Jack T. Burcher
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| |
Collapse
|
|
11
|
Song W, Chen Z, Shi C, Gao Y, Feng X, Li H, Li Z, Zhang M. Synergistic anticancer effect of a combination of chidamide and etoposide against NK/T cell lymphoma. Hematol Oncol 2023; 41:257-266. [PMID: 34854108 DOI: 10.1002/hon.2954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 11/23/2021] [Accepted: 11/26/2021] [Indexed: 12/12/2022]
Abstract
Natural killer/T cell lymphoma (NKTCL) is a highly aggressive hematological malignancy. However, there is currently no consensus on therapies for refractory/relapsed patients. In this study, we investigated the synergistic anticancer effect and potential mechanism of combining chidamide, a histone deacetylases (HDACs) inhibitor, and etoposide, a DNA-damaging agent, in NKTCL. We demonstrated that chidamide or etoposide alone dose- and time-dependently inhibited the cell viability of NKTCL cell lines, YT, NKYS and KHYG-1. Functional experiments suggested that combined chidamide and etoposide treatment exerted synergistic antiproliferation effect and enhanced cell apoptotic death in vitro and in vivo. Furthermore, the expression of DNA damage related proteins was detected and we also examined the alternations in histone acetylation, cell cycle progression, and mitochondrial membrane potential (MMP). The results suggested that increased histone acetylation, cell cycle arrest at the G2/M phase and loss of MMP, converging to greater DNA damage, might account for the synergism of the combination of chidamide and etoposide in NKTCL. Taken together, our study provides an evident for possible application on combining HDACs inhibitors and DNA-damaging agents for the treatment of NKTCL.
Collapse
Grants
- 182102310114 Department of Science & Technology of Henan province
- 81970184 National Natural Science Foundation of China
- 82070209 National Natural Science Foundation of China
- 82170183 National Natural Science Foundation of China
- U1904139 National Natural Science Foundation of China
- Oncology Department, State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, Translational Medical Center, Department of Nephrology of the First Affiliated Hospital of Zhengzhou University, and the Medical Sciences Academy and Research Institute of Nephrology of Zhengzhou University, and Core Unit of National Clinical Medical Research Center of Kidney Disease in Zhengzhou
- 182102310114 Department of Science & Technology of Henan province
- Oncology Department, State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, Translational Medical Center, Department of Nephrology of the First Affiliated Hospital of Zhengzhou University, and the Medical Sciences Academy and Research Institute of Nephrology of Zhengzhou University, and Core Unit of National Clinical Medical Research Center of Kidney Disease in Zhengzhou
Collapse
Affiliation(s)
- Wenting Song
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhan Chen
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, Henan, China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, Henan, China
| | - Cunzhen Shi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuyang Gao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoyan Feng
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongwen Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| |
Collapse
|
|
12
|
Coşkunpınar M, Erdoğdu B, Goker H. Asymptomatic unilateral phrenic nerve palsy after bortezomib treatment in a newly diagnosed multiple myeloma patient. J Oncol Pharm Pract 2023; 29:502-505. [PMID: 35786085 DOI: 10.1177/10781552221112151] [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: 02/04/2023]
Abstract
INTRODUCTION Bortezomib is the first chemotherapeutic agent of proteosome inhibitor class that can be used in newly diagnosed and relapsed/refractory multiple myeloma. It is well known that bortezomib has side effects such as peripheral sensory, motor, or autonomic neuropathy. In this paper, we will present our patient who developed unilateral phrenic nerve palsy as an autonomic neuropathy after six cycles of subcutaneous bortezomib treatment. This case differs from other cases in that our patient was asymptomatic. CASE REPORT A 57-year-old male patient was admitted with back pain and gait disturbances. In the thorax computed tomography, a soft tissue mass causing compression on the spinal canal was observed in the T12 vertebra. Bone biopsy pathology report resulted in diffuse plasma cell infiltration. The patient was diagnosed with stage ISS-3, IgG kappa type multiple myeloma. MANAGEMENT AND OUTCOME Subcutaneous bortezomib 1 × 2.2 mg (Days 1-4-8-11) + intravenous cyclophosphamide 1000 mg (Day 1) + intravenous dexamethasone 40 mg (Days 1-2-3-4) (VCD chemotherapy protocol) was started. Totally six cycles of VCD were administered. While the patient did not have any respiratory symptoms, an elevation consistent with phrenic nerve palsy was observed in the left hemidiaphragm in the thorax computed tomography that was taken during the preparation for autologous hematopoietic stem cell transplantation. DISCUSSION Bortezomib is a frequently used chemotherapeutic agent in patients with multiple myeloma and care should be taken in terms of the risk of developing phrenic nerve palsy in patients. There are cases of autonomic neuropathy developing after bortezomib treatment.
Collapse
Affiliation(s)
- Muharrem Coşkunpınar
- Department of Internal Medicine, 64005Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Batuhan Erdoğdu
- Department of Hematology, 64005Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Hakan Goker
- Department of Hematology, 64005Hacettepe University Faculty of Medicine, Ankara, Turkey
| |
Collapse
|
|
13
|
Abe K, Ikeda S, Nara M, Kitadate A, Tagawa H, Takahashi N. Hypoxia-induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase-1 in multiple myeloma. Cancer Med 2023; 12:9709-9722. [PMID: 36775962 PMCID: PMC10166934 DOI: 10.1002/cam4.5679] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/21/2022] [Accepted: 01/26/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. METHODS We performed cDNA microarray analysis for SP and non-SP obtained from RPMI-8226 and KMS-11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2 ). Genes specifically upregulated in hypoxic SP were examined. RESULTS Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein-coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase-1 (HMOX1/HO-1) is induced by hypoxia-inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia-induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. CONCLUSION These results suggest that the hypoxia-ROS-HMOX1 axis and hypoxia-induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments.
Collapse
Affiliation(s)
- Ko Abe
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Sho Ikeda
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Miho Nara
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Akihiro Kitadate
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Hiroyuki Tagawa
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Naoto Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| |
Collapse
|
|
14
|
Takeshita AA, Hammock BD, Wagner KM. Soluble epoxide hydrolase inhibition alleviates chemotherapy induced neuropathic pain. FRONTIERS IN PAIN RESEARCH (LAUSANNE, SWITZERLAND) 2023; 3:1100524. [PMID: 36700145 PMCID: PMC9868926 DOI: 10.3389/fpain.2022.1100524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 12/15/2022] [Indexed: 01/12/2023]
Abstract
Chemotherapy induced peripheral neuropathy (CIPN) is a particularly pernicious form of neuropathy and the associated pain is the primary dose-limiting factor of life-prolonging chemotherapy treatment. The prevalence of CIPN is high and can last long after treatment has been stopped. Currently, late in the COVID-19 pandemic, there are still increased psychological pressures on cancer patients as well as additional challenges in providing analgesia for them. These include the risks of nonsteroidal anti-inflammatory drug (NSAID) analgesics potentially masking early infection symptoms and the immunosuppression of steroidal and opiate based approaches. Even without these concerns, CIPN is often inadequately treated with few therapies that offer significant pain relief. The experiments we report use soluble epoxide hydrolase inhibitors (sEHI) which relieved this intractable pain in preclinical models. Doses of EC5026, an IND candidate intended to treat neuropathic pain, elicited dose dependent analgesic responses in multiple models including platinum-based, taxane, and vinca alkaloid-based CIPN pain in Sprague Dawley rats. At the same time as a class, the sEHI are known to result in fewer debilitating side effects of other analgesics, likely due to their novel mechanism of action. Overall, the observed dose-dependent analgesia in both male and female rats across multiple models of chemotherapy induced neuropathic pain holds promise as a useful tool when translated to the clinic.
Collapse
Affiliation(s)
| | - Bruce D. Hammock
- EicOsis LLC, Davis, CA, United States,Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, United States
| | - Karen M. Wagner
- EicOsis LLC, Davis, CA, United States,Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, United States,Correspondence: Karen M. Wagner ;
| |
Collapse
|
|
15
|
Wang W, Sun Y, Liu X, Kumar SK, Jin F, Dai Y. Dual-Targeted Therapy Circumvents Non-Genetic Drug Resistance to Targeted Therapy. Front Oncol 2022; 12:859455. [PMID: 35574302 PMCID: PMC9093074 DOI: 10.3389/fonc.2022.859455] [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: 01/21/2022] [Accepted: 03/14/2022] [Indexed: 02/05/2023] Open
Abstract
The introduction of various targeted agents into the armamentarium of cancer treatment has revolutionized the standard care of patients with cancer. However, like conventional chemotherapy, drug resistance, either preexisting (primary or intrinsic resistance) or developed following treatment (secondary or acquired resistance), remains the Achilles heel of all targeted agents with no exception, via either genetic or non-genetic mechanisms. In the latter, emerging evidence supports the notion that intracellular signaling pathways for tumor cell survival act as a mutually interdependent network via extensive cross-talks and feedback loops. Thus, dysregulations of multiple signaling pathways usually join forces to drive oncogenesis, tumor progression, invasion, metastasis, and drug resistance, thereby providing a basis for so-called "bypass" mechanisms underlying non-genetic resistance in response to targeted agents. In this context, simultaneous interruption of two or more related targets or pathways (an approach called dual-targeted therapy, DTT), via either linear or parallel inhibition, is required to deal with such a form of drug resistance to targeted agents that specifically inhibit a single oncoprotein or oncogenic pathway. Together, while most types of tumor cells are often addicted to two or more targets or pathways or can switch their dependency between them, DTT targeting either intrinsically activated or drug-induced compensatory targets/pathways would efficiently overcome drug resistance caused by non-genetic events, with a great opportunity that those resistant cells might be particularly more vulnerable. In this review article, we discuss, with our experience, diverse mechanisms for non-genetic resistance to targeted agents and the rationales to circumvent them in the treatment of cancer, emphasizing hematologic malignancies.
Collapse
Affiliation(s)
- Wei Wang
- Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yue Sun
- Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, China
| | - Xiaobo Liu
- Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, China
| | - Shaji K. Kumar
- Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, United States
| | - Fengyan Jin
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Yun Dai
- Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
16
|
Allegra A, Petrarca C, Di Gioacchino M, Casciaro M, Musolino C, Gangemi S. Modulation of Cellular Redox Parameters for Improving Therapeutic Responses in Multiple Myeloma. Antioxidants (Basel) 2022; 11:antiox11030455. [PMID: 35326105 PMCID: PMC8944660 DOI: 10.3390/antiox11030455] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 01/25/2023] Open
Abstract
Raised oxidative stress and abnormal redox status are typical features of multiple myeloma cells, and the identification of the intimate mechanisms that regulate the relationships between neoplastic cells and redox homeostasis may reveal possible new anti-myeloma therapeutic targets to increase the effectiveness of anti-myeloma drugs synergistically or to eradicate drug-resistant clones while reducing toxicity toward normal cells. An alteration of the oxidative state is not only responsible for the onset of multiple myeloma and its progression, but it also appears essential for the therapeutic response and for developing any chemoresistance. Our review aimed to evaluate the literature’s current data on the effects of oxidative stress on the response to drugs generally employed in the therapy of multiple myeloma, such as proteasome inhibitors, immunomodulators, and autologous transplantation. In the second part of the review, we analyzed the possibility of using other substances, often of natural origin, to modulate the oxidative stress to interfere with the progression of myelomatous disease.
Collapse
Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
- Correspondence: (A.A.); (M.D.G.)
| | - Claudia Petrarca
- Center for Advanced Studies and Technology, G. D’Annunzio University, 66100 Chieti, Italy;
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
| | - Mario Di Gioacchino
- Center for Advanced Studies and Technology, G. D’Annunzio University, 66100 Chieti, Italy;
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
- Correspondence: (A.A.); (M.D.G.)
| | - Marco Casciaro
- Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (M.C.); (S.G.)
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Sebastiano Gangemi
- Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (M.C.); (S.G.)
| |
Collapse
|
|
17
|
Multifunctional liposomal nanostructure-mediated siRNA/bortezomib co-delivery for SHARP1 knockdown in MLL-AF6 acute myeloid leukemia. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2022; 134:112663. [DOI: 10.1016/j.msec.2022.112663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 11/17/2022]
|
|
18
|
Aksenova AY, Zhuk AS, Lada AG, Zotova IV, Stepchenkova EI, Kostroma II, Gritsaev SV, Pavlov YI. Genome Instability in Multiple Myeloma: Facts and Factors. Cancers (Basel) 2021; 13:5949. [PMID: 34885058 PMCID: PMC8656811 DOI: 10.3390/cancers13235949] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/20/2021] [Accepted: 11/22/2021] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.
Collapse
Affiliation(s)
- Anna Y. Aksenova
- Laboratory of Amyloid Biology, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Anna S. Zhuk
- International Laboratory “Computer Technologies”, ITMO University, 197101 St. Petersburg, Russia;
| | - Artem G. Lada
- Department of Microbiology and Molecular Genetics, University of California, Davis, CA 95616, USA;
| | - Irina V. Zotova
- Department of Genetics and Biotechnology, St. Petersburg State University, 199034 St. Petersburg, Russia; (I.V.Z.); (E.I.S.)
- Vavilov Institute of General Genetics, St. Petersburg Branch, Russian Academy of Sciences, 199034 St. Petersburg, Russia
| | - Elena I. Stepchenkova
- Department of Genetics and Biotechnology, St. Petersburg State University, 199034 St. Petersburg, Russia; (I.V.Z.); (E.I.S.)
- Vavilov Institute of General Genetics, St. Petersburg Branch, Russian Academy of Sciences, 199034 St. Petersburg, Russia
| | - Ivan I. Kostroma
- Russian Research Institute of Hematology and Transfusiology, 191024 St. Petersburg, Russia; (I.I.K.); (S.V.G.)
| | - Sergey V. Gritsaev
- Russian Research Institute of Hematology and Transfusiology, 191024 St. Petersburg, Russia; (I.I.K.); (S.V.G.)
| | - Youri I. Pavlov
- Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Departments of Biochemistry and Molecular Biology, Microbiology and Pathology, Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| |
Collapse
|
|
19
|
He Y, Jiang D, Zhang K, Zhu Y, Zhang J, Wu X, Xia J, Zhu Y, Zou L, Hu J, Cui Y, Zhou W, Chen F. Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy. J Cancer 2021; 12:6198-6208. [PMID: 34539893 PMCID: PMC8425211 DOI: 10.7150/jca.61602] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/15/2021] [Indexed: 12/25/2022] Open
Abstract
Drug resistance is the major cause for disease relapse and patient death in multiple myeloma (MM). It is an urgent need to develop new therapies to overcome drug resistance in MM. Chidamide (CHI), a novel oral HDAC inhibitor targeting HDAC1, 2, 3 and 10, has shown potential therapeutic effect in MM. In this study, we determined that CHI exhibited significant anti-tumor effect on MM cells both in vitro and in vivo, which was positively correlated with the expression of HDAC1. Meanwhile, CHI enhanced Bortezomib (BTZ) effects synergistically in MM cells and a combination of CHI with BTZ induced myeloma cell apoptosis and G0/G1 arrest in vitro and in vivo. Mechanistically, the synergistic anti-tumor effect of CHI and BTZ was related with the increased production of reactive oxygen species (ROS) dependent DNA damage and the changes of cell apoptosis and cycle pathways. Our data indicate that CHI may be a suitable drug to sensitize BTZ in MM cells, which provides novel insight into the therapy for MM patients.
Collapse
Affiliation(s)
- Yanjuan He
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Duanfeng Jiang
- Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Kaixuan Zhang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yinghong Zhu
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jingyu Zhang
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xuan Wu
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jiliang Xia
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yan Zhu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lang Zou
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jian Hu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yajuan Cui
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wen Zhou
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Fangping Chen
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
20
|
Nanavati C, Mager DE. Network-Based Systems Analysis Explains Sequence-Dependent Synergism of Bortezomib and Vorinostat in Multiple Myeloma. AAPS JOURNAL 2021; 23:101. [PMID: 34403034 DOI: 10.1208/s12248-021-00622-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 07/05/2021] [Indexed: 12/22/2022]
Abstract
Bortezomib and vorinostat exhibit synergistic effects in multiple myeloma (MM) cells when given in sequence, and the purpose of this study was to evaluate the molecular determinants of the interaction using a systems pharmacology approach. A Boolean network model consisting of 79 proteins and 225 connections was developed using literature information characterizing mechanisms of drug action and intracellular signal transduction. Network visualization and structural analysis were conducted, and model simulations were compared with experimental data. Critical biomarkers, such as pNFκB, p53, cellular stress, and p21, were identified using measures of network centrality and model reduction. U266 cells were then exposed to bortezomib (3 nM) and vorinostat (2 μM) as single agents or in simultaneous and sequential (bortezomib for first 24 h, followed by addition of vorinostat for another 24 h) combinations. Temporal changes for nine of the critical proteins in the reduced Boolean model were measured over 48 h, and cellular proliferation was measured over 96 h. A mechanism-based systems model was developed that captured the biological basis of a bortezomib and vorinostat sequence-dependent pharmacodynamic interaction. The model was further extended in vivo by linking in vitro parameter values and dynamics of p21, caspase-3, and pAKT biomarkers to tumor growth in xenograft mice reported in the literature. Network-based methodologies and pharmacodynamic principles were integrated successfully to evaluate bortezomib and vorinostat interactions in a mechanistic and quantitative manner. The model can be potentially applied to evaluate their combination regimens and explore in vivo dosing regimens.
Collapse
Affiliation(s)
- Charvi Nanavati
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 431 Pharmacy Building Buffalo, New York, 14214, USA
| | - Donald E Mager
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 431 Pharmacy Building Buffalo, New York, 14214, USA.
| |
Collapse
|
|
21
|
Schütt J, Nägler T, Schenk T, Brioli A. Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications. Cancers (Basel) 2021; 13:cancers13164069. [PMID: 34439223 PMCID: PMC8392438 DOI: 10.3390/cancers13164069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/04/2021] [Accepted: 08/09/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Despite advances made in the last two decades, multiple myeloma (MM) is still an incurable disease. The genetic complexity of MM and the presence of intra-clonal heterogeneity are major contributors to disease relapse and the development of treatment resistance. Additionally, the bone marrow microenvironment is known to play a pivotal role in MM disease progression. Together with genetic modifications, epigenetic changes have been shown to influence MM development and progression. However, epigenetic treatments for MM are still lacking. This is mainly due to the high rate of adverse events of epigenetic drugs in clinical practice. In this review, we will focus on the role of epigenetic modifications in MM disease progression and the development of drug resistance, as well as their role in shaping the interplay between bone marrow stromal cells and MM cells. The current and future treatment strategies involving epigenetic drugs will also be addressed. Abstract Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.
Collapse
Affiliation(s)
- Jacqueline Schütt
- Clinic of Internal Medicine 2, Hematology and Oncology, Jena University Hospital, 07747 Jena, Germany
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, 07747 Jena, Germany
- Clinic of Internal Medicine C, Hematology and Oncology, Stem Cell Transplantation and Palliative Care, Greifswald University Medicine, 17475 Greifswald, Germany
| | - Theresa Nägler
- Clinic of Internal Medicine 2, Hematology and Oncology, Jena University Hospital, 07747 Jena, Germany
| | - Tino Schenk
- Clinic of Internal Medicine 2, Hematology and Oncology, Jena University Hospital, 07747 Jena, Germany
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, 07747 Jena, Germany
- Clinic of Internal Medicine C, Hematology and Oncology, Stem Cell Transplantation and Palliative Care, Greifswald University Medicine, 17475 Greifswald, Germany
| | - Annamaria Brioli
- Clinic of Internal Medicine 2, Hematology and Oncology, Jena University Hospital, 07747 Jena, Germany
- Clinic of Internal Medicine C, Hematology and Oncology, Stem Cell Transplantation and Palliative Care, Greifswald University Medicine, 17475 Greifswald, Germany
| |
Collapse
|
|
22
|
Ovejero-Sánchez M, González-Sarmiento R, Herrero AB. Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair. Neoplasia 2021; 23:515-528. [PMID: 33930758 PMCID: PMC8100353 DOI: 10.1016/j.neo.2021.04.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/08/2021] [Accepted: 04/10/2021] [Indexed: 12/24/2022]
Abstract
Ovarian cancer (OC) is the deadliest gynecologic malignancy, which is mainly due to late-stage diagnosis and chemotherapy resistance. Therefore, new and more effective treatments are urgently needed. The in vitro effects of Panobinostat (LBH), a histone deacetylase inhibitor that exerts pleiotropic antitumor effects but induces autophagy, in combination with Chloroquine (CQ), an autophagy inhibitor that avoid this cell survival mechanism, were evaluated in 4 OC cell lines. LBH and CQ inhibited ovarian cancer cell proliferation and induced apoptosis, and a strong synergistic effect was observed when combined. Deeping into their mechanisms of action we show that, in addition to autophagy modulation, treatment with CQ increased reactive oxygen species (ROS) causing DNA double strand breaks (DSBs), whereas LBH inhibited their repair by avoiding the correct recruitment of the recombinase Rad51 to DSBs. Interestingly, CQ-induced DSBs and cell death caused by CQ/LBH combination were largely abolished by the ROS scavenger N-Acetylcysteine, revealing the critical role of DSB generation in CQ/LBH-induced lethality. This role was also manifested by the synergy found when we combined CQ with Mirin, a well-known homologous recombination repair inhibitor. Altogether, our results provide a rationale for the clinical investigation of CQ/LBH combination in ovarian cancer.
Collapse
Affiliation(s)
- María Ovejero-Sánchez
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
| | - Ana Belén Herrero
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
| |
Collapse
|
|
23
|
Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma. Blood 2021; 137:49-60. [PMID: 32693406 DOI: 10.1182/blood.2020006731] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 06/30/2020] [Indexed: 01/14/2023] Open
Abstract
Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.
Collapse
|
|
24
|
Yussuf Khamis M, Wu HP, Ma Q, Li YH, Ma LY, Zhang XH, Liu HM. Overcome the tumor immunotherapy resistance by combination of the HDAC6 inhibitors with antitumor immunomodulatory agents. Bioorg Chem 2021; 109:104754. [PMID: 33677416 DOI: 10.1016/j.bioorg.2021.104754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/10/2021] [Accepted: 02/16/2021] [Indexed: 11/21/2022]
Abstract
Tumor immunotherapy is currently subject of intense scientific and clinical developments. In previous decade, therapists used natural immune system from the human body to treat several diseases. Although tumor immune disease is a big challenge, combinatorial therapeutic strategy has been succeeded to show the clinical significance. In this context, we discuss the HDAC6 and tumor immune diseases relationship. Also, we summarized the current state of knowledge that based on the combination treatments of the HDAC6 inhibitors (HDAC6is) with antitumor immunomodulatory agents. We observed that, the combination therapies slow down the tumor immune diseases by blocking the aggresome and proteasome pathway. The combination therapy was able to reduce M2 macrophage and increasing PD-L1 blockade sensitivity. Most importantly, multiple combinations of HDAC6is with other agents may consider as potential strategies to treat tumor immune diseases, by reducing the side effects and improve efficacy for the future clinical development.
Collapse
Affiliation(s)
- Mussa Yussuf Khamis
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Hui-Pan Wu
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Qin Ma
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Yi-Han Li
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Li-Ying Ma
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; China Meheco Topfond PharmaceuticalCo., Ltd., Zhumadian 463000, PR China
| | - Xin-Hui Zhang
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
| | - Hong-Min Liu
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
| |
Collapse
|
|
25
|
Fhu CW, Ali A. Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention. Cancers (Basel) 2021; 13:cancers13071513. [PMID: 33805973 PMCID: PMC8037609 DOI: 10.3390/cancers13071513] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. Dysregulation of the UPS results in loss of ability to maintain protein quality through proteolysis, and is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss the mechanisms linking dysregulated UPS to human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review. Abstract The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review.
Collapse
|
|
26
|
Paradzik T, Bandini C, Mereu E, Labrador M, Taiana E, Amodio N, Neri A, Piva R. The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma. Cancers (Basel) 2021; 13:1235. [PMID: 33799793 PMCID: PMC8000754 DOI: 10.3390/cancers13061235] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/04/2021] [Accepted: 03/06/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.
Collapse
Affiliation(s)
- Tina Paradzik
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy; (T.P.); (C.B.); (E.M.); (M.L.)
| | - Cecilia Bandini
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy; (T.P.); (C.B.); (E.M.); (M.L.)
| | - Elisabetta Mereu
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy; (T.P.); (C.B.); (E.M.); (M.L.)
| | - Maria Labrador
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy; (T.P.); (C.B.); (E.M.); (M.L.)
| | - Elisa Taiana
- Department of Oncology and Hemato-oncology, University of Milano, 20122 Milano, Italy; (E.T.); (A.N.)
- Hematology Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy;
| | - Antonino Neri
- Department of Oncology and Hemato-oncology, University of Milano, 20122 Milano, Italy; (E.T.); (A.N.)
- Hematology Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Roberto Piva
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy; (T.P.); (C.B.); (E.M.); (M.L.)
- Città Della Salute e della Scienza Hospital, 10126 Torino, Italy
| |
Collapse
|
|
27
|
Innao V, Rizzo V, Allegra AG, Musolino C, Allegra A. Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma. Cells 2021; 10:439. [PMID: 33669515 PMCID: PMC7922387 DOI: 10.3390/cells10020439] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/12/2021] [Accepted: 02/18/2021] [Indexed: 12/20/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.
Collapse
Affiliation(s)
- Vanessa Innao
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (V.I.); (A.G.A.); (C.M.)
| | - Vincenzo Rizzo
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Andrea Gaetano Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (V.I.); (A.G.A.); (C.M.)
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (V.I.); (A.G.A.); (C.M.)
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (V.I.); (A.G.A.); (C.M.)
| |
Collapse
|
|
28
|
Jenke R, Reßing N, Hansen FK, Aigner A, Büch T. Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives. Cancers (Basel) 2021; 13:634. [PMID: 33562653 PMCID: PMC7915831 DOI: 10.3390/cancers13040634] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/30/2021] [Accepted: 02/02/2021] [Indexed: 12/26/2022] Open
Abstract
The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond "classic" oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).
Collapse
Affiliation(s)
- Robert Jenke
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, D-04103 Leipzig, Germany
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| | - Nina Reßing
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, Rheinische Fried-rich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; (N.R.); (F.K.H.)
| | - Finn K. Hansen
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, Rheinische Fried-rich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; (N.R.); (F.K.H.)
| | - Achim Aigner
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| | - Thomas Büch
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| |
Collapse
|
|
29
|
de Nigris F, Ruosi C, Napoli C. Clinical efficiency of epigenetic drugs therapy in bone malignancies. Bone 2021; 143:115605. [PMID: 32829036 DOI: 10.1016/j.bone.2020.115605] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/07/2020] [Accepted: 08/15/2020] [Indexed: 12/17/2022]
Abstract
A great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the first line of therapies. Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways. Here, we offer an exhaustive review of such agents in these clinical settings. Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102 (Olutasidenib), inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (Tazemetostat) To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of Phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.
Collapse
Affiliation(s)
- Filomena de Nigris
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
| | - Carlo Ruosi
- Department of Public Health, Federico II University, 80132 Naples, Italy
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; IRCCS SDN, 80134 Naples, IT, Italy
| |
Collapse
|
|
30
|
Jeitany M, Prabhu A, Dakle P, Pathak E, Madan V, Kanojia D, Mukundan V, Jiang YY, Landesman Y, Tam WL, Kappei D, Koeffler HP. Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas. Cell Mol Life Sci 2021; 78:1837-1851. [PMID: 32851475 PMCID: PMC7904719 DOI: 10.1007/s00018-020-03620-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/19/2020] [Accepted: 08/07/2020] [Indexed: 01/09/2023]
Abstract
Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib's efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.
Collapse
Affiliation(s)
- Maya Jeitany
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
| | - Aishvaryaa Prabhu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Pushkar Dakle
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Elina Pathak
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Vikas Madan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Deepika Kanojia
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Vineeth Mukundan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Yan Yi Jiang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | | | - Wai Leong Tam
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - H Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore, Singapore
| |
Collapse
|
|
31
|
Holkova B, Shafer D, Yazbeck V, Dave S, Bose P, Tombes MB, Shrader E, Wan W, Bandyopadhyay D, Weir C, Collins EB, Garnett A, Kmieciak M, Roberts JD, Garcia-Manero G, Grant S. Phase 1 study of belinostat (PXD-101) and bortezomib (Velcade, PS-341) in patients with relapsed or refractory acute leukemia and myelodysplastic syndrome. Leuk Lymphoma 2020; 62:1187-1194. [PMID: 33356689 DOI: 10.1080/10428194.2020.1861270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.
Collapse
Affiliation(s)
- Beata Holkova
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Danielle Shafer
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Victor Yazbeck
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Sandeep Dave
- Department of Medicine, Duke University, Durham, NC, USA
| | - Prithviraj Bose
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mary Beth Tombes
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Ellen Shrader
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Wen Wan
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Statistics, Virginia Commonwealth University, Richmond, VA, USA
| | - Dipankar Bandyopadhyay
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Statistics, Virginia Commonwealth University, Richmond, VA, USA
| | - Caryn Weir
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Amanda Garnett
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Maciej Kmieciak
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - John D Roberts
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Steven Grant
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.,Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.,Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.,Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.,The Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA
| |
Collapse
|
|
32
|
Ge M, Qiao Z, Kong Y, Liang H, Sun Y, Lu H, Xu Z, Liu H. Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable resistance. Br J Cancer 2020; 124:770-776. [PMID: 33250513 PMCID: PMC7884794 DOI: 10.1038/s41416-020-01191-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 09/29/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Background Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. Methods MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Results Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. Conclusions We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.
Collapse
Affiliation(s)
- Maolin Ge
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Zhi Qiao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Yan Kong
- SJTU-Yale Joint Center of Biostatistics and Data Science, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Hongyu Liang
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China
| | - Yan Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Hui Lu
- SJTU-Yale Joint Center of Biostatistics and Data Science, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Zhenshu Xu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China.
| | - Han Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| |
Collapse
|
|
33
|
Martinovich GG, Martinovich IV, Vcherashniaya AV, Zenkov NK, Menshchikova EB, Cherenkevich SN. Chemosensitization of Tumor Cells by Phenolic Antioxidants: The Role of the Nrf2 Transcription Factor. Biophysics (Nagoya-shi) 2020. [DOI: 10.1134/s000635092006010x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
|
|
34
|
Recent advances in small molecular modulators targeting histone deacetylase 6. FUTURE DRUG DISCOVERY 2020. [DOI: 10.4155/fdd-2020-0023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Histone deacetylase 6 (HDAC6) is a unique isozyme in the HDAC family with various distinguished characters. HDAC6 is predominantly localized in the cytoplasm and has several specific nonhistone substrates, such as α-tubulin, cortactin, Hsp90, tau and peroxiredoxins. Accumulating evidence reveals that targeting HDAC6 may serve as a promising therapeutic strategy for the treatment of cancers, neurological disorders and immune diseases, making the development of HDAC6 inhibitors particularly attractive. Recently, multitarget drug design and proteolysis targeting chimera technology have also been applied in the discovery of novel small molecular modulators targeting HDAC6. In this review, we briefly describe the structural features and biological functions of HDAC6 and discuss the recent advances in HDAC6 modulators, including selective inhibitors, chimeric inhibitors and proteolysis targeting chimeras for multiple therapeutic purposes.
Collapse
|
|
35
|
Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, Milardi D, Lacal PM, Marini S, Purrello R, Graziani G, Coletta M. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges. Pharmacol Ther 2020; 213:107579. [PMID: 32442437 PMCID: PMC7236745 DOI: 10.1016/j.pharmthera.2020.107579] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 01/10/2023]
Abstract
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
Collapse
Affiliation(s)
- G R Tundo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| | | | - A M Santoro
- CNR, Institute of Crystallography, Catania, Italy
| | - A Coletta
- Department of Chemistry, University of Aarhus, Aarhus, Denmark
| | - F Oddone
- IRCCS-Fondazione Bietti, Rome, Italy
| | - G Grasso
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - D Milardi
- CNR, Institute of Crystallography, Catania, Italy
| | - P M Lacal
- Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy
| | - S Marini
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - R Purrello
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - G Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - M Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| |
Collapse
|
|
36
|
Proteotoxic Stress and Cell Death in Cancer Cells. Cancers (Basel) 2020; 12:cancers12092385. [PMID: 32842524 PMCID: PMC7563887 DOI: 10.3390/cancers12092385] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.
Collapse
|
|
37
|
Ge M, Li D, Qiao Z, Sun Y, Kang T, Zhu S, Wang S, Xiao H, Zhao C, Shen S, Xu Z, Liu H. Restoring MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors. Oncogene 2020; 39:5888-5901. [PMID: 32733069 PMCID: PMC7471105 DOI: 10.1038/s41388-020-01408-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/16/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022]
Abstract
MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.
Collapse
Affiliation(s)
- Maolin Ge
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Dan Li
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Zhi Qiao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Yan Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 200092, Shanghai, China
| | - Shouhai Zhu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Shifen Wang
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China
| | - Hua Xiao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Chunjun Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Shuhong Shen
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Zhenshu Xu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China.
| | - Han Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| |
Collapse
|
|
38
|
Kulka LAM, Fangmann PV, Panfilova D, Olzscha H. Impact of HDAC Inhibitors on Protein Quality Control Systems: Consequences for Precision Medicine in Malignant Disease. Front Cell Dev Biol 2020; 8:425. [PMID: 32582706 PMCID: PMC7291789 DOI: 10.3389/fcell.2020.00425] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 05/07/2020] [Indexed: 12/21/2022] Open
Abstract
Lysine acetylation is one of the major posttranslational modifications (PTM) in human cells and thus needs to be tightly regulated by the writers of this process, the histone acetyl transferases (HAT), and the erasers, the histone deacetylases (HDAC). Acetylation plays a crucial role in cell signaling, cell cycle control and in epigenetic regulation of gene expression. Bromodomain (BRD)-containing proteins are readers of the acetylation mark, enabling them to transduce the modification signal. HDAC inhibitors (HDACi) have been proven to be efficient in hematologic malignancies with four of them being approved by the FDA. However, the mechanisms by which HDACi exert their cytotoxicity are only partly resolved. It is likely that HDACi alter the acetylation pattern of cytoplasmic proteins, contributing to their anti-cancer potential. Recently, it has been demonstrated that various protein quality control (PQC) systems are involved in recognizing the altered acetylation pattern upon HDACi treatment. In particular, molecular chaperones, the ubiquitin proteasome system (UPS) and autophagy are able to sense the structurally changed proteins, providing additional targets. Recent clinical studies of novel HDACi have proven that proteins of the UPS may serve as biomarkers for stratifying patient groups under HDACi regimes. In addition, members of the PQC systems have been shown to modify the epigenetic readout of HDACi treated cells and alter proteostasis in the nucleus, thus contributing to changing gene expression profiles. Bromodomain (BRD)-containing proteins seem to play a potent role in transducing the signaling process initiating apoptosis, and many clinical trials are under way to test BRD inhibitors. Finally, it has been demonstrated that HDACi treatment leads to protein misfolding and aggregation, which may explain the effect of panobinostat, the latest FDA approved HDACi, in combination with the proteasome inhibitor bortezomib in multiple myeloma. Therefore, proteins of these PQC systems provide valuable targets for precision medicine in cancer. In this review, we give an overview of the impact of HDACi treatment on PQC systems and their implications for malignant disease. We exemplify the development of novel HDACi and how affected proteins belonging to PQC can be used to determine molecular signatures and utilized in precision medicine.
Collapse
Affiliation(s)
- Linda Anna Michelle Kulka
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Pia-Victoria Fangmann
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Diana Panfilova
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Heidi Olzscha
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| |
Collapse
|
|
39
|
Proteomic analysis identifies mechanism(s) of overcoming bortezomib resistance via targeting ubiquitin receptor Rpn13. Leukemia 2020; 35:550-561. [PMID: 32424294 DOI: 10.1038/s41375-020-0865-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/29/2020] [Accepted: 05/05/2020] [Indexed: 12/15/2022]
Abstract
Our prior study showed that inhibition of 19S proteasome-associated ubiquitin receptor Rpn13 can overcome bortezomib resistance in MM cells. Here, we performed proteomic analysis of Rpn13 inhibitor (RA190)-treated MM cells and identified an antioxidant enzyme superoxide dismutase (SOD1) as a mediator of Rpn13 signaling. SOD1 levels are higher in MM patient cells versus normal PBMCs; and importantly, SOD1 expression correlates with the progression of disease and shorter survival. Functional validation studies show that RA190-induced cytotoxicity in bortezomib-sensitive and -resistant MM cells is associated with decrease in SOD1 levels; conversely, forced expression of SOD1 inhibits RA190-induced cell death. Genetic knockdown and biochemical blockade of SOD1 with LCS-1 sensitizes bortezomib-resistant MM cells to bortezomib. SOD1 inhibitor LCS-1 decreases viability in MM cell lines and patient cells. LCS-1-induced cell death is associated with: (1) increase in superoxide and ROS levels; (2) activation of caspases, and p53/p21 signaling; (3) decrease in MCL-1, BCLxL, CDC2, cyclin-B1, and c-Myc; (4) ER stress response; and (5) inhibition of proteasome function. In animal model studies, LCS-1 inhibits xenografted bortezomib-resistant human MM cell growth and prolongs host survival. Our studies therefore show that targeting Rpn13 overcomes bortezomib resistance by decreasing cellular SOD1 levels, and provide the rationale for novel therapeutics targeting SOD1 to improve patient outcome in MM.
Collapse
|
|
40
|
Manni S, Fregnani A, Barilà G, Zambello R, Semenzato G, Piazza F. Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From "Omics" Research. Front Oncol 2020; 10:802. [PMID: 32500036 PMCID: PMC7243738 DOI: 10.3389/fonc.2020.00802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/23/2020] [Indexed: 12/20/2022] Open
Abstract
While the modern therapeutic armamentarium to treat multiple myeloma (MM) patients allows a longer control of the disease, this second-most-frequent hematologic cancer is still uncurable in the vast majority of cases. Since MM plasma cells are subjected to various types of chronic cellular stress and the integrity of specific stress-coping pathways is essential to ensure MM cell survival, not surprisingly the most efficacious anti-MM therapy are those that make use of proteasome inhibitors and/or immunomodulatory drugs, which target the biochemical mechanisms of stress management. Based on this notion, the recently realized discoveries on MM pathobiology through high-throughput techniques (genomic, transcriptomic, and other "omics"), in order for them to be clinically useful, should be elaborated to identify novel vulnerabilities in this disease. This groundwork of information will likely allow the design of novel therapies against targetable molecules/pathways, in an unprecedented opportunity to change the management of MM according to the principle of "precision medicine." In this review, we will discuss some examples of therapeutically actionable molecules and pathways related to the regulation of cellular fitness and stress resistance in MM.
Collapse
Affiliation(s)
- Sabrina Manni
- Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy
- Foundation for Advanced Biomedical Research – Veneto Institute of Molecular Medicine (FABR-VIMM), Padova, Italy
| | - Anna Fregnani
- Foundation for Advanced Biomedical Research – Veneto Institute of Molecular Medicine (FABR-VIMM), Padova, Italy
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, Padova, Italy
| | - Gregorio Barilà
- Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy
- Foundation for Advanced Biomedical Research – Veneto Institute of Molecular Medicine (FABR-VIMM), Padova, Italy
| | - Renato Zambello
- Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy
- Foundation for Advanced Biomedical Research – Veneto Institute of Molecular Medicine (FABR-VIMM), Padova, Italy
| | - Gianpietro Semenzato
- Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy
- Foundation for Advanced Biomedical Research – Veneto Institute of Molecular Medicine (FABR-VIMM), Padova, Italy
| | - Francesco Piazza
- Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy
- Foundation for Advanced Biomedical Research – Veneto Institute of Molecular Medicine (FABR-VIMM), Padova, Italy
| |
Collapse
|
|
41
|
Kamal M, Wang XS, Shi Q, Zyczynski TM, Davis C, Williams LA, Lin HK, Garcia-Gonzalez A, Cleeland CS, Orlowski R. Symptom burden and its functional impact in patients with "symptomatic" relapsed or refractory multiple myeloma. Support Care Cancer 2020; 29:467-475. [PMID: 32390093 DOI: 10.1007/s00520-020-05493-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/20/2020] [Indexed: 11/28/2022]
Abstract
PURPOSE Relapsed or refractory multiple myeloma (RRMM) is labeled "symptomatic" based on laboratory values, but not relevant to quantitative measure of patient's perspectives. This study aimed to describe symptom burden, health status, and quality of life in RRMM patients. METHODS The cross-sectional study included 184 MM patients (141 RRMM cases and 43 MM patients on follow-up without diagnosis/treatment of RRMM disease as controls), while 64 RRMM patients also provided longitudinal patient-reported outcomes (PROs) data. Symptomatic status was based on clinical measures of disease activity. PROs included the MD Anderson Symptom Inventory multiple myeloma module (MDASI-MM), single-item quality of life (SIQOL), and EuroQol-5D (EQ-5D). Wilcoxon rank test and effect size were used for comparisons. Regression models were used to describe symptom trajectory and to identify predictors of high symptom burden during 3 months of RRMM therapy. RESULTS Most patients were clinically identified as symptomatic (93%). RRMM patients tended to report more severe symptoms, with significantly lower QOL scores and more severe fatigue, poor appetite, and lower enjoyment of life compared with controls (all p < 0.05). In RRMM patients, lower hemoglobin and higher B-2 microglobulin levels significantly correlated with higher burdens of fatigue, pain, and muscle weakness and also with lower QOL and EQ-5D scores (all p < 0.05). During RRMM therapy, being female, with any comorbidity, ≥ 65 years old, and ≥ 5 years MM history, contributed to high symptoms burden and poor QOL status (each p < 0.05). CONCLUSIONS MDASI-MM modules were sensitive to detect the RRMM-related symptoms burden, which correlated with objective clinical measures. RRMM patients reported a more compromised QOL.
Collapse
Affiliation(s)
- Mona Kamal
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,Department of Clincal Oncology, Ain Shams University, Cairo, Egypt
| | - Xin Shelley Wang
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Qiuling Shi
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | | | | | - Loretta A Williams
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hui-Kai Lin
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Araceli Garcia-Gonzalez
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Charles S Cleeland
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Robert Orlowski
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| |
Collapse
|
|
42
|
Miles MA, Harris MA, Hawkins CJ. Proteasome inhibitors trigger mutations via activation of caspases and CAD, but mutagenesis provoked by the HDAC inhibitors vorinostat and romidepsin is caspase/CAD-independent. Apoptosis 2020; 24:404-413. [PMID: 30997620 DOI: 10.1007/s10495-019-01543-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Genotoxic anti-cancer therapies such as chemotherapy and radiotherapy can contribute to an increase in second malignancies in cancer survivors due to their oncogenic effects on non-cancerous cells. Inhibition of histone deacetylase (HDAC) proteins or the proteasome differ from chemotherapy in that they eliminate cancer cells by regulating gene expression or cellular protein equilibrium, respectively. As members of these drug classes have been approved for clinical use in recent times, we investigated whether these two drug classes exhibit similar mutagenic capabilities as chemotherapy. The HDAC inhibitors vorinostat/SAHA and romidepsin/FK288 were found to induce DNA damage, and mis-repair of this damage manifested into mutations in clonogenically viable surviving cells. DNA damage and mutations were also detected in cells treated with the proteasome inhibitor bortezomib. Exposure to both drug classes stimulated caspase activation consistent with apoptotic cell death. Inhibition of caspases protected cells from bortezomib-induced acute (but not clonogenic) death and mutagenesis, implying caspases were required for the mutagenic action of bortezomib. This was also observed for second generation proteasome inhibitors. Cells deficient in caspase-activated DNase (CAD) also failed to acquire DNA damage or mutations following treatment with bortezomib. Surprisingly, vorinostat and romidepsin maintained an equivalent level of killing and mutagenic ability regardless of caspase or CAD activity. Our findings indicate that both drug classes harbour mutagenic potential in vitro. If recapitulated in vivo, the mutagenicity of these agents may influence the treatment of cancer patients who are more susceptible to oncogenic mutations due to dysfunctional DNA repair pathways.
Collapse
Affiliation(s)
- Mark A Miles
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia.
| | - Michael A Harris
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia
| | - Christine J Hawkins
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia
| |
Collapse
|
|
43
|
Nadeem O, Anderson KC. The safety of current and emerging therapies for multiple myeloma. Expert Opin Drug Saf 2020; 19:269-279. [DOI: 10.1080/14740338.2020.1733968] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Omar Nadeem
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Kenneth C. Anderson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
44
|
Moore DC, Ringley JT, Nix D, Muslimani A. Impact of Body Mass Index on the Incidence of Bortezomib-induced Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:168-173. [DOI: 10.1016/j.clml.2019.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 07/08/2019] [Accepted: 08/22/2019] [Indexed: 11/30/2022]
|
|
45
|
Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies. Sci Rep 2020; 10:3080. [PMID: 32080210 PMCID: PMC7033174 DOI: 10.1038/s41598-020-58366-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022] Open
Abstract
We performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1–2.3] vs. 3.5 months [95% CI, 1.7–5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8–9.8] vs. 12.7 months [95% CI, 7.1–18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.
Collapse
|
|
46
|
Wu X, Xia J, Zhang J, Zhu Y, Wu Y, Guo J, Chen S, Lei Q, Meng B, Kuang C, Feng X, He Y, Shen Y, Li X, Qiu L, Li G, Zhou W. Phosphoglycerate dehydrogenase promotes proliferation and bortezomib resistance through increasing reduced glutathione synthesis in multiple myeloma. Br J Haematol 2020; 190:52-66. [PMID: 32037523 DOI: 10.1111/bjh.16503] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/28/2019] [Indexed: 12/27/2022]
Abstract
The serine synthesis pathway (SSP) is active in multiple cancers. Previous study has shown that bortezomib (BTZ) resistance is associated with an increase in the SSP in multiple myeloma (MM) cells; however, the underlying mechanisms of SSP-induced BTZ resistance remain unclear. In this study, we found that phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in the SSP, was significantly elevated in CD138+ cells derived from patients with relapsed MM. Moreover, high PHGDH conferred inferior survival in MM. We also found that overexpression of PHDGH in MM cells led to increased cell growth, tumour formation, and resistance to BTZ in vitro and in vivo, while inhibition of PHGDH by short hairpin RNA or NCT-503, a specific inhibitor of PHGDH, inhibited cell growth and BTZ resistance in MM cells. Subsequent mechanistic studies demonstrated PHGDH decreased reactive oxygen species (ROS) through increasing reduced glutathione (GSH) synthesis, thereby promoting cell growth and BTZ resistance in MM cells. Furthermore, adding GSH to PHGDH silenced MM cells reversed S phase arrest and BTZ-induced cell death. These findings support a mechanism in which PHGDH promotes proliferation and BTZ resistance through increasing GSH synthesis in MM cells. Therefore, targeting PHGDH is a promising strategy for MM therapy.
Collapse
Affiliation(s)
- Xuan Wu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Jiliang Xia
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Jingyu Zhang
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Yinghong Zhu
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Yangbowen Wu
- Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jiaojiao Guo
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Shilian Chen
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Qian Lei
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Bin Meng
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Chunmei Kuang
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Xiangling Feng
- Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Yanjuan He
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi Shen
- Department of Orthopaedic Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xin Li
- Department of Hematology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lugui Qiu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China
| | - Guancheng Li
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Wen Zhou
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
47
|
Ibrahim EY, Ehrlich BE. Prevention of chemotherapy-induced peripheral neuropathy: A review of recent findings. Crit Rev Oncol Hematol 2020; 145:102831. [PMID: 31783290 PMCID: PMC6982645 DOI: 10.1016/j.critrevonc.2019.102831] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 01/12/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of chemotherapy that is frequently experienced by patients receiving treatment for cancer. CIPN is caused by many of the most commonly used chemotherapeutic agents, including taxanes, vinca alkaloids, and bortezomib. Pain and sensory abnormalities may persist for months, or even years after the cessation of chemotherapy. The management of CIPN is a significant challenge, as it is not possible to predict which patients will develop symptoms, the timing for the appearance of symptoms can develop anytime during the chemotherapy course, there are no early indications that warrant a reduction in the dosage to halt CIPN progression, and there are no drugs approved to prevent or alleviate CIPN. This review focuses on the etiology of CIPN and will highlight the various approaches developed for prevention and treatment. The goal is to guide studies to identify, test, and standardize approaches for managing CIPN.
Collapse
Affiliation(s)
- Eiman Y Ibrahim
- Departments of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, CT, 06510, USA.
| | - Barbara E Ehrlich
- Departments of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, CT, 06510, USA.
| |
Collapse
|
|
48
|
From tea to treatment; epigallocatechin gallate and its potential involvement in minimizing the metabolic changes in cancer. Nutr Res 2019; 74:23-36. [PMID: 31918176 DOI: 10.1016/j.nutres.2019.12.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 01/09/2023]
Abstract
As the most abundant bioactive polyphenol in green tea, epigallocatechin gallate (EGCG) is a promising natural product that should be used in the discovery and development of potential drug leads. Due to its association with chemoprevention, EGCG may find a role in the development of therapeutics for prostate cancer. Natural products have long been used as a scaffold for drug design, as their already noted bioactivity can help accelerate the development of novel treatments. Green tea and the EGCG contained within have become associated with chemoprevention, and both in vitro and in vivo studies have correlated EGCG to inhibiting cell growth and increasing the metabolic stress of cancer cells, possibly giving merit to its long utilized therapeutic use in traditional therapies. There is accumulating evidence to suggest EGCG's role as an inhibitor of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling cascade, acting upon major axis points within cancer survival pathways. The purpose of this review is to examine the research conducted on tea along with EGCG in the areas of the treatment of and/or prevention of cancer. This review discusses Camellia sinensis as well as the bioactive phytochemical compounds contained within. Clinical uses of tea are explored, and possible pathways for activity are discussed before examining the evidence for EGCG's potential for acting on these processes. EGCG is identified as being a possible lead phytochemical for future drug design investigations.
Collapse
|
|
49
|
Holmberg LA, Green D, Libby E, Becker PS. Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma. Acta Haematol 2019; 143:146-154. [PMID: 31434076 DOI: 10.1159/000501298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 06/01/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. PATIENTS AND METHODS We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. RESULTS The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. CONCLUSIONS BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.
Collapse
Affiliation(s)
- Leona A Holmberg
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,
- Department of Medicine, University of Washington, Seattle, Washington, USA,
| | - Damian Green
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Edward Libby
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - P S Becker
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
50
|
Hu H, Petrosyan A, Osna NA, Liu T, Olou AA, Alakhova DY, Singh PK, Kabanov AV, Faber EA, Bronich TK. Pluronic block copolymers enhance the anti-myeloma activity of proteasome inhibitors. J Control Release 2019; 306:149-164. [PMID: 31121280 PMCID: PMC6822276 DOI: 10.1016/j.jconrel.2019.05.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/30/2019] [Accepted: 05/15/2019] [Indexed: 02/08/2023]
Abstract
Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.
Collapse
Affiliation(s)
- Hangting Hu
- Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, United States of America
| | - Armen Petrosyan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States of America
| | - Natalia A Osna
- Liver Study Unit, VA Medical Center, Research Service (151), 4101 Woolworth Avenue, Omaha, NE 68105, United States of America
| | - Tong Liu
- Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, United States of America
| | - Appolinaire A Olou
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, United States of America
| | - Daria Y Alakhova
- Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599, United States of America
| | - Pankaj K Singh
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, United States of America
| | - Alexander V Kabanov
- Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599, United States of America; Carolina Institute for Nanomedicine, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, United States of America
| | - Edward A Faber
- Department of Internal Medicine, Division of Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE 68198, United States of America
| | - Tatiana K Bronich
- Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, United States of America.
| |
Collapse
|