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1.
Mol Oncol ; 17(12): 2507-2525, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37704591

ABSTRACT

A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.


Subject(s)
Antineoplastic Agents , Multiple Myeloma , Humans , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Cell Line, Tumor , Plasma Cells , Multiple Myeloma/drug therapy , Apoptosis , Proto-Oncogene Proteins c-bcl-2/metabolism , bcl-X Protein/metabolism , Antineoplastic Agents/pharmacology
2.
Oncoimmunology ; 11(1): 2141973, 2022.
Article in English | MEDLINE | ID: mdl-36338146

ABSTRACT

Immunogenic cell death (ICD) has been proposed to be a crucial process for antitumor immunosurveillance. ICD is characterized by the exposure and emission of Damage Associated Molecular Patterns (DAMP), including calreticulin (CRT). A positive correlation between CRT exposure or total expression and improved anticancer immunosurveillance has been found in certain cancers, usually accompanied by favorable patient prognosis. In the present study, we sought to evaluate CRT levels in the plasma membrane of CD38+ bone marrow mononuclear cells (BMMCs) isolated from 71 patients with varying degrees of multiple myeloma (MM) disease and examine the possible relationship between basal CRT exposure and the bone marrow immune microenvironment, as well as its connection with different clinical markers. Data show that increased levels of cell surface-CRT were associated with more aggressive clinical features and with worse clinical prognosis in MM. High CRT expression in MM cells was associated with increased infiltration of NK cells, CD8+ T lymphocytes and dendritic cells (DC), indicative of an active anti-tumoral immune response, but also with a significantly higher presence of immunosuppressive Treg cells and increased expression of PD-L1 in myeloma cells.


Subject(s)
Calreticulin , Multiple Myeloma , Humans , Calreticulin/genetics , Calreticulin/metabolism , Prognosis , Immunity , Alarmins , Tumor Microenvironment
3.
Biochem Pharmacol ; 190: 114655, 2021 08.
Article in English | MEDLINE | ID: mdl-34129859

ABSTRACT

Dysregulation of cell cycle progression is a hallmark of cancer cells. In recent years, efforts have been devoted to the development of new therapies that target proteins involved in cell cycle regulation and mitosis. Novel targeted antimitotic drugs include inhibitors of aurora kinase family, polo-like kinase 1, Mps1, Eg5, CENP-5 and the APC/cyclosome complex. While certain new inhibitors reached the clinical trial stage, most were discontinued due to negative results. However, these therapies should not be readily dismissed. Based on recent advances concerning their mechanisms of action, new strategies could be devised to increase their efficacy and promote further clinical trials. Here we discuss three main lines of action to empower these therapeutic approaches: increasing cell death signals during mitotic arrest, targeting senescent cells and facilitating antitumor immune response through immunogenic cell death (ICD).


Subject(s)
Antineoplastic Agents/pharmacology , Mitosis/drug effects , Neoplasms/drug therapy , Animals , Drug Delivery Systems , Humans , Neoplasms/metabolism
4.
Trends Cancer ; 6(6): 518-532, 2020 06.
Article in English | MEDLINE | ID: mdl-32460005

ABSTRACT

In recent years immunotherapy has provided new hope for cancer patients. However, some patients eventually relapse. Immunological responses are thought to underlie the long-term effects of conventional or targeted therapies. Whether this influence emerges from direct effects on cancer cells through immunogenic cell death (ICD) or by modulating the immune environment requires further clarification. ICD-related molecular mechanisms are also shared by cell-intrinsic defense responses that combat foreign intrusions. Indeed, we could potentially mimic and harness these processes to improve cancer immunogenicity. In addition, the microbiome is materializing as a missing factor in the cancer-immune therapy axis. The emerging idea of manipulating the gut microbiota to improve responses to anticancer therapy is becoming increasingly popular, but further clinical authentication is needed.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dysbiosis/prevention & control , Gastrointestinal Microbiome/drug effects , Immunotherapy/methods , Neoplasms/therapy , Administration, Metronomic , Alarmins/immunology , Alarmins/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bacterial Translocation/drug effects , Bacterial Translocation/immunology , Disease Models, Animal , Dose-Response Relationship, Drug , Dose-Response Relationship, Immunologic , Dysbiosis/chemically induced , Dysbiosis/immunology , Dysbiosis/microbiology , Gastrointestinal Microbiome/immunology , Humans , Immunogenic Cell Death/drug effects , Immunogenic Cell Death/immunology , Immunotherapy/adverse effects , Immunotherapy/trends , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Depletion/methods , Maximum Tolerated Dose , Mice , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Neoplasms/immunology , Neoplasms/microbiology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology
6.
Front Cell Dev Biol ; 7: 50, 2019.
Article in English | MEDLINE | ID: mdl-31041312

ABSTRACT

Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of "immunogenic cell death" (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.

7.
J Med Chem ; 58(15): 5825-41, 2015 Aug 13.
Article in English | MEDLINE | ID: mdl-26147404

ABSTRACT

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl6(2-) or PF6(-) respectively, display almost identical IC50 values in the sub-micromolar range (25-335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration.


Subject(s)
Antineoplastic Agents/pharmacology , Gold/chemistry , Phosphoranes/chemistry , Platinum/chemistry , Animals , Antineoplastic Agents/chemistry , Cations , Cattle , Cell Line, Tumor , Crystallography, X-Ray , Cyclization , DNA/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Rats
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